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K+ Channels: Function‐Structural Overview

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Abstract

Potassium channels are particularly important in determining the shape and duration of the action potential, controlling the membrane potential, modulating hormone secretion, epithelial function and, in the case of those K+ channels activated by Ca2+, damping excitatory signals. The multiplicity of roles played by K+ channels is only possible to their mammoth diversity that includes at present 70 K+ channels encoding genes in mammals. Today, thanks to the use of cloning, mutagenesis, and the more recent structural studies using x‐ray crystallography, we are in a unique position to understand the origins of the enormous diversity of this superfamily of ion channels, the roles they play in different cell types, and the relations that exist between structure and function. With the exception of two‐pore K+ channels that are dimers, voltage‐dependent K+ channels are tetrameric assemblies and share an extremely well conserved pore region, in which the ion‐selectivity filter resides. In the present overview, we discuss in the function, localization, and the relations between function and structure of the five different subfamilies of K+ channels: (a) inward rectifiers, Kir; (b) four transmembrane segments‐2 pores, K2P; (c) voltage‐gated, Kv; (d) the Slo family; and (e) Ca2+‐activated SK family, SKCa. © 2012 American Physiological Society. Compr Physiol 2:2087‐2149, 2012.

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Figure 1. Figure 1.

Potassium channel families arranged according to their subunit structure. Potassium channel families can be grouped in those having two transmembrane segments (2TM; Kir), 4TM (2‐pore domain), 6TM (voltage gated and SK), and 7TM (Slo). Note that for the sake of simplicity the large‐conductance Slo channel family includes the Slo2.x channels, which have only six transmembrane domains. The 6TM domain class can be divided into four families: Voltage‐gated Kv, voltage‐gated KCNQ‐type (KCNQ); ether‐a‐go‐go (Eag), and Ca2+‐activated channels (SK). Subdivisions of the voltage‐gated Kv channels into four subfamilies and Eag into three subfamilies are also named according to the Drosophila melanogaster genes. In the SK family IKCa1 stands for intermediate conductance Ca2+‐activated K+ channel.

Figure 2. Figure 2.

Phylogenetic tree of Kir channels and their current‐voltage curves. (A) Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human Kir family. International Union of Pharmacology and Hugo Gene Nomenclature Committee names of the genes are shown. The subunits were classified into four functional groups following Hibino et al. (). (B) Inward rectification and conductance are strongly external K+ concentration‐dependent. I‐V relationships are of the starfish egg cell membrane at four different Kext concentrations in Na+‐free media. Continuous and broken line indicates instantaneous and steady‐state current, respectively (adapted. with permission, from reference ). Notice that K+ conductance develops at voltages negative to the equilibrium potential for K+ (EK). (C) I‐V relationship characteristic of a “weak” inward rectifier. (D) In “strong” inward rectifiers K+ conductance tends to zero as the membrane potential is depolarized and contrary to expectations the crossover phenomena produces an increase in K+ conductance at voltages larger than the crossover voltage despite the decrease in the K+ driving force.

Figure 3. Figure 3.

Kir2.1 induces a smooth muscle cell hyperpolarization when Kext increases. (A) The average current densities at three different [Kext] were obtained in response to a voltage ramp from −130 to 0 mV lasting for 140 ms. (B) Ba2+‐sensitive currents densities recorded in the same condition as in A. (C) Elevation of Kext from 3 mmol/L to 15 mmol/L caused a membrane potential hyperpolarization of smooth muscle cells [adapted, with permission, from Filosa et al. ()]. (D) Chord conductance‐voltage curve at the same experimental conditions as in B. Notice that there is an appreciable increase in smooth muscle cells Kir conductance as the [Kext] is raised at physiological membrane potentials (−50 to −40 mV).

Figure 4. Figure 4.

Dual modulation of KG channels by G protein‐coupled receptor (GPCR) and the topology and structure of Kir6.x. (A) Agonist activation of GPCR coupled to pertussis (PTX)‐sensitive αi/o‐type of G protein promotes activation of KG channels. Activation of KG channels is induced by binding to the channel‐forming protein of the βγ complex of the G protein. Agonist binding to αq‐type of G protein results in channel inhibition that is a consequence of the activation of phospholipase C (PLC), which in turn hydrolyses phosphatidyl‐inositol‐4,5‐bisphosphate (PIP2). Other modulators include tyrosine kinase (TK), Ca2+‐calmodulin‐dependent kinase 2 (CAMK2), and protein phosphatase (PP1). Modified, with permission, from reference . For more details, see text. (B) SUR subunits contain 17 transmembrane segments assembled in three domains, TMD0‐2, and containing two nucleotide‐binding domains (NBD) contained between TMD1 and TMD2 (NBD1) and in the C‐terminus (NBD2). The structures show top and side views of the entire KATP channel complex analyzed at 18 Å resolution. Blue represents Kir6.x. Red represents the rest of SUR and yellow represents TMD0 of SUR [adapted, with permission, from Mikhailov et al. ()].

Figure 5. Figure 5.

Kir channel crystal structure and cation‐binding sites. (A) Voltage dependence in Kir channels arises as a consequence of the movement of K+ ions contained in the cytoplasmic pore. (B) Crystal structure of a Kir3.1‐prokaryotic Kir channel chimera determined at 2.2 Å. Seven Rb+ ions were located in the conduction pore. Two constriction sites, F181 side chain and residues 302‐309 Cα atoms in the G‐loop are colored in blue. For the sake of clarity only two subunits are shown [adapted, with permission, from Nishida et al. ()]. (C) Crystal structure of the cytoplasmic pore of S225E mutant of Kir3.1 (yellow) and the Kir chimera () (cyan). Na+ ions are represented by orange spheres and Rb+ ions by pink spheres. (D) Crystal structure model of the cytoplasmic pore of S225E mutant Kir3.1 corresponding to the boxed region in A. The residues, Q225, G227, G261, D260, F255, and S256, interact directly or through water molecules with the Na+ ions located at S8‐S11. The positions of the phenylalanines coordinating the Na+ through π‐cation interactions at site S10 are shown [adapted, with permission, from Xu et al. ()].

Figure 6. Figure 6.

Molecular determinants of inward rectification and location of modulators binding sites in the cytoplasmic domain of KG channels. (A, B) Amino acid residues in the cytoplasmic pore determining inward rectification in Kir2.1 channels. (C) Current‐voltage relationships for different Kir2.1 point mutants [adapted, with permission, from Pegan et al. ()]. (D) The structure shown contains the cytoplasmic domains of Kir3.1 a G protein‐gated channel and the transmembrane domains and pore region of the chimeric Kir channel. The regions implicated in Na+, PIP2, G protein, and alcohol binding are shown [adapted, with permission from Luscher and Slensinger ()].

Figure 7. Figure 7.

Diversity of 2‐pore (2P)‐domain K+ channel (K2P) subunits and membrane topology. (A) The alignment was made using the web tool: Phylogeny.fr (), with different sequences of human two pore K+ channels obtained from gene bank accession numbers from KCNK1 to KCNK18: NP_002236, NP_055032, NP_002237.1, NP_201567.1, NP_003731.1., NP_004814.1., NP_005705.1., NP_057685.1., NP_066984.1., NP_071338.1., NP_071337.2., NP_071753.1., NP_115491.1., NP_113648.2., and NP_862823.1. (B) Putative membrane topology of the two‐pore domain K+ channels. Green spheres indicate pH sensing residues and their predicted location in the first turret loop and M4 transmembrane domain. (C) Multiple sequence alignment of the outer and inner helix region of KcsA, hERG, and several K2P K+ channels. Amino acid residues colored in red show the K+ channel signature sequence, corresponding to the selectivity filter.

Figure 8. Figure 8.

Polymodal nature of K2P channels receptors. (A) TREK‐1 channels are modulated by stretch, heat, intracellular acidosis, depolarization, lipids, general anaesthetics, and tonically inhibited by the actin cytoskeleton [adapted, with permission, from Patel and Honoré ()]. (B) Polymodal regulation of TREK‐1 and TREK‐2. Activation of the Gs/cAMP/protein kinase A (PKA) and the Gq/phospholipase C (PLC)/Diacyl Glycerol (DAG)/protein kinase C (PKC) signaling pathway inhibit TREK channels by phosphorylating serine residues present on the C‐terminal. TREK‐1 is activated via the NO/cGMP/Protei kinase G (PKG) pathway, but the PKG phosphorylation consensus site is missing in TREK‐2. (Arrows indicate stimulation; lines with T ending represent inhibition.) [Modified, with permission, from Enyedi and Czirják ().] (C) Regulation of TASK‐1 and TASK‐3. The channels are inhibited by extracellular acidification (EC) acidification as a result of protonation of histidine98 in the second extracellular loop. Anandamide inhibits both TASK‐1 and TASK‐3. Hypoxia inhibits TASK current indirectly. TASK channels are activated by halothane and isoflurane but they are not influenced by chloroform or ether. The polycation ruthenium red and Zn2+ allow pharmacological distinction between the two closely related channel subunits. Dashed lines represent effects on targets; arrows indicate stimulation; lines with T ending represent inhibition. [Modified, with permission, from Enyedi and Czirják ().]

Figure 9. Figure 9.

K2P channel activation by different stimuli. (A) Top: TREK‐1 activation was graded with membrane stretch in a cell‐attached patch from oocytes expressing TREK‐1. The inset shows channel openings with an enlarged time scale. In this patch, a small conductance endogenous channel was also present. Bottom‐graded reversible negative pressure activation of hTRAAK in physiological K+ conditions. The patch was held at 0 mV and the zero current is indicated by a dashed line [from Patél et. al () and Lesage and Lazdunski ()]. (B) TREK‐1 channels show outward rectification. Single‐channel currents recorded in absence of Mg2+ at −100 mV (left trace), 0 mV (middle trace), and 100 mV (right trace) at atmospheric pressure (top traces) and at a steady pressure of −30 mm Hg (bottom traces). Po denotes open probability [adapted, with permission, from Maingret et al. ()]. (C) Thermosensitivity. Cell‐attached patches from COS‐7 cells incubated at different bath temperatures are shown for TREK‐1 and TRAAK [adapted, with permission, from Kang et al. ()]. (D) The C‐terminus of TREK‐2 is required for sensitivity to fatty acids and pH. (Top) Wild‐type TREK‐2 expressed in COS‐7 cells is robustly activated by a decrease in intracellular pH. Middle. The pH sensitivity is abolished in a chimeric mutant that consists of the core transmembrane segments of TREK‐2 and the C‐terminus of TASK‐3 (red) (chimera TREK‐2–TASK‐3C) indicating that C‐terminus of TREK‐2 is require to pH sensitivity. (Bottom) The sensitivity of a TRAAK–TASK‐3C chimera to pH is similar to wild‐type TRAAK, which indicates that the C‐terminus of TRAAK is unlikely to mediate activation by pH [adapted, with permission, from Kim ()]. (E) Left. TREK‐1 is reversibly opened by chloroform (0.8 mmol/L). Voltage was linearly depolarized with a voltage ramp from −120 to 100 mV. Current becomes zero at a membrane potential equal to the equilibrium potential for K+ (−80 mV). Inset: stimulation of the K+ current by chloroform (CHCl3) is concentration dependent and observed at pharmacologically relevant concentrations. Right top. Chloroform (0.8 mmol/L) induces reproducible membrane hyperpolarizations. Right bottom. Halothane (1 mmol/L; 0 mV) induces TREK‐1 single‐channel activity characterized by rapid flickering between closed and open states [modified, with permission, from Franks and Honore ()]. (F) Fatty acid activation of TRAAK and TREK in COS cells. (Left side) Current‐voltage relationships obtained in an inside‐out patch with voltage ramps ranging from –150 to +50 mV, 500 ms in duration, before (control), after 3 min perfusion with 10 μmol/L AA and after the wash. Inset: effects of 10 μmol/L AA on TRAAK currents recorded in an inside‐out patch clamped at +20 mV. The zero current level is indicated by an arrow. (Right side) Inside out patch currents were recorded at 0mV from transfected COS cells. The zero current levels are indicated by a dotted line. The histograms represent the ratio of the mean currents recorded before (Icontrol) or after 10 μmol/L of AA application (I), gray and black color denotes absence or coexpression of A‐kinase anchoring protein (AKAP150), respectively [adapted, with permission, from Sandoz et al. () and Fink et al. ()].

Figure 10. Figure 10.

K2P channel structure. (A) Homology model for ΔK2PØ (K2PØ channel variant lacking AA from 299 to 1000) channel shows bilateral symmetry with a 4‐fold symmetric selectivity filter. Color red indicates monomer A (from residue 1 to 152) and color blue monomer B (from residue 174 to 276). (B) Extracellular (top) and cytoplasmic (bottom) sides reveals overall symmetry like a parallelogram. The model includes residues 1 to 276 without the TM1‐P1 loop (residues 30‐91), TM2‐TM3 linker (residues 153‐173), and TM2‐P2 loop (residues 225‐238). (Bottom) Side view of domain I of both subunits. The glutaminase interacting protein (GIP) motif (G129‐I130‐P131) in TM2 is indicated. Side view of domain II of both subunits. Proline residue 183 and 192 in TM3 are indicated. (C) Structure of a mutant TASK‐3 channel modeled in an open state, using the structure of KvAP [adapted, with permission, from Jiang et al. ()] as template. It is hypothesized that channels open through flexion of M2 and M4 around hinge glycines G117 and G231. The positions of these hinge glycines are indicated as spheres in the helices M2 and M4. Gain of function mutants stabilizes the open state through altered side chain‐side chain interactions between residues. A possible H‐bond between Thr in position 237 of M4 (in mutant A237T) and N133, which may contribute to stabilizing the open state, is indicated. The model gives a bond length of 3.2 Å. (D) K2P3.1 model, illustrating the interactions of a water molecule with the backbone of Tyr‐96 and Gly‐97 and the side chains of Thr‐89 and His‐98 in the unprotonated form of His‐98, according to molecular dynamic simulations, based on Yuill et al. (). (E) pH‐sensing mechanism of human K2P2.1. Ribbon representation of one subunit of the bacterial KcsA potassium channel, based on the published structure [Doyle et al. ()]. Predicted hydrogen bonds between KcsA residues are presented as orange lines. The side chain of Glu‐51 is predicted to form hydrogen bonds with the backbone amide groups of Val‐84 and Thr‐85 and the side chain hydroxyl group of Thr‐85. The homologous K2P2.1 residues are Glu‐84 (red), Arg‐166, and Thr‐167 (blue), respectively. KcsA Ala‐54 and Leu‐59 were replaced in this presentation by histidines, as present at the homologous positions in K2P2.1 [i.e., His‐87 and His‐141 (green), respectively] based on Cohen et al. (). (F) Homology model of the TASK‐3 K2P channel. Illustrating the proximity of the two E30 (yellow) and two T103 (blue) residues (view looking from the top down). The model was created using Modeller 9v7 () based on the KcsA structure as template [originally solved by Doyle et al. ()].

Figure 11. Figure 11.

Organization of the voltage‐dependent K+ channel superfamily. Phylogenetic tree for the Kv1‐12 families. Amino acid sequence alignments of the human channel Kv proteins were created using CLUSTALW. Only the hydrophobic cores (S1‐S6) were used for analysis. The IUPHAR and HGNC names are shown together with the genes’ chromosomal localization and other commonly used name. The alignment was made using the web tool: Phylogeny.fr (), with different sequences of human two pore K+ channels obtained from gene bank accession numbers: KCNH1: NM_002238.3, KCNH2: NP_000229.1., KCNH3:NP_036416.1., KCNH5: NP_647479.2., KCNH6: NP_110406.1., KCNH7: NP_150375.2., KCNH8: NP_653234.2., KCNQ1: NP_000209.2., KCNQ2: NP_004509.2., KCNQ3: NP_004510.1., KCNQ4: NP_004691.2., KCNQ5: NP_062816.2., KCNS1: NP_002242.2., KCNS2: NP_065748.1., KCNS3: NP_002243.3., KCNV1: NP_055194.1., KNCG1: NP_002228.2., KCNG4: NP_758857.1., KCNF1: NP_002227.2., KCNV2: NP_598004.1., KCNG3: NP_579875.1., KCND1: NP_004970.3., KCND2: NP_036413.1., KCND3: NP_004971.2., KCNB1: NP_004966.1., KCNB2: NP_004761.2., KCNC1: NP_004967.1., KCNC2: NP_631874.1., KCNC3: NP_004968.2., KCNC4: NP_004969.2., KCNA1: NP_000208.2., KCNA2: NP_004965.1., KCNA3: NP_002223.3., KCNA4: NP_002224.1., KCNA5: NP_002225.2., KCNA6: NP_002226.1., KCNA7: NP_114092.2., KCNA10: NP_005540.1.

Figure 12. Figure 12.

Organization and structure of the Kv1.2/Kv2.1 chimeric channel (PDB_ID: 2RAR). Lateral (left) and top (right) views of the protein embedded in the membrane. Arginine residues important for voltage dependence are shown in sticks. For clarity, two monomers are shown in light gray. The secondary structure of the amino acid sequence (below) is color coded to match the respective transmembrane and functional segments of the protein. Potassium ions are represented in green and the oxygen of water molecules in red. The cytosolic structure hanging from the main protein body is the tratramerization domain, T.

Figure 13. Figure 13.

Kvβ1 inactivate currents of a Kv1 channel. (A) Delayed rectifier currents elicited by voltage steps in the absence of Kvβ‐subunit. (B) Coexpression with Kvβ (α+β). (C) A single‐voltage pulse shown in a large time scale. More details in reference .

Figure 14. Figure 14.

K+ currents diversity in Kv channels family. The indicated rat Kv channels were transiently expressed in HEK 293 cells. For each channel, whole‐cell K+ currents at +40 mV were measured in similar physiological conditions. Modified, with permission, from reference .

Figure 15. Figure 15.

K currents from Kv7 and EAG families. Modulation of heteromeric KCNQ2/3 current by extracellular H+ ions. (A) Whole‐cell KCNQ2/3 currents from a HEK‐293 cell in bathing solutions of differing pH were elicited by depolarizing voltage steps (1.5 s duration) from a holding potential of −70 mV. (B) Whole‐cell KCNQ2/3 current activation curves in bathing solutions of different pHs (). (C) Isochronal activation of human ether‐a‐go‐go‐related gene (HERG) channels. Membrane potential was stepped from −80 mV to a test potential between −70 and 100 mV, in intervals of 10 mV, for 2 s, followed by step to −50 mV. The HERG characteristic rapid rise in the tails of current account for a very fast recovery from inactivation and a slower inactivation ().

Figure 16. Figure 16.

Gating currents elicited by the squid potassium channels. (A) Superimposed 10 ms traces of gating and ionic currents recorded at three different voltages taken a 20°C degrees. Na+‐gating currents are missed because at this temperature they are too fast for the recording system (modified, with permission, from reference ). (B) Voltage dependency of the gating charge (open symbols) and the ionic conductance (filled symbols). (C) Kinetics of the gating and ionic currents (B and C modified, with permission, from reference ).

Figure 17. Figure 17.

Structural determinants for the voltage sensitivity in voltage‐gated K+ channels. (A) Structure of a single monomer depicting the voltage‐sensor domain (VSD) and the pore domain. Arginines R1, R2, R3, and R4 (corresponding to Shaker R362, R365, R368, and R371) are represented in stick form. (B) Possible trajectories for the gating charges (for more details see text).

Figure 18. Figure 18.

Structural design of the K+ conduction system. (A) Ions in the pore of the KcsA bacterial channel (PDB_ID: 1K4C). All possible K+‐binding sites are shown. Hydration water molecules are shown in red with a Van der Waal radius of 0.5 Å. (B) Ion conduction is due to two alternating and energetically equivalent configurations in ion occupancy (for more details see text).

Figure 19. Figure 19.

Mechanical movements of the voltage‐sensitive pore opening. (A) Side and enlarged bottom views of the residues that change in accessibility during the opening of the Shaker activation gate (residues 470‐474; in blue), that do no change in accessibility during gating (residues 481‐486, in red), and residues that may form the gate (residues 475‐479; in green). After reference . (B) Allosteric surface proposed for the interaction between the S4 and S5 linker (in blue and gray) with the S6 C‐terminal half of two adjacent subunits (in yellow and orange).

Figure 20. Figure 20.

Phylogenetic tree of Slo channels family in mammals and membrane topology of the α‐ and β‐subunits of Slo1 channels. (A) The four genes present in Slo channels families: Slo, Slo2.1, Slo 2.2, and Slo3. (B) The α‐subunit of Slo1 contains seven transmembrane segments divided in two domains [voltage‐sensor domain, (VSD) and pore region] that is normally associated to β‐subunits consisting of two transmembrane segments. β2 and β3 have an inactivating particle on their N‐terminus able to interact with the channel internal vestibule and block the passage of K+ through the channel. The α‐subunit contains a long C‐terminus domain in which two regulators of K+ conductance domains (RCK1 and RCK2) are present. Spread throughout in the BK C‐terminus are located the binding sites for Ca2+ and Mg2+ (for more details on the divalent cation‐binding sites see Section “Carboxy terminus”). (C) (Top) The α‐subunit has a voltage‐sensing domain formed by the S0 to S4 segments. Four charged residues contribute to the channel voltage membrane sensitivity, D153, R167 in S2, D186 in S3, and R213 in S4. (Bottom) The pore region formed by S5, the pore helix, the pore loop, and the S6 transmembrane. Three amino acid residues have been identified in the BK pore as partially responsible for the channel high conductance, D292, E321, and E324.

Figure 21. Figure 21.

Polymodal activation of Slo channels. (A) Slo1 channel single‐channel activity increases its open probability in response to an increase in the membrane voltage. Upper trace was taken at −60 mV. Openings are downward deflections in the current. Lower trace was taken at 80 mV. Upward deflections are opening events. The opening of two independent channels can be appreciated in this current record. Open probability also increases with increasing intracellular calcium (1, 10, and 100 μmol/L) at a fixed voltage (+60 mV). (B) Slo2.2 channels single‐channel activity increases with high intracellular sodium. Perfusion using 80 mmol/L intracellular sodium elicited four conductance levels, which are reduced to just one with nominal 0 sodium concentration (top). (Bottom) The same type of experiment performed at a compressed time scale. (C) Single‐channel activity of cloned Slo3 increases with the alkalinization and depolarizing voltages. Upper, single‐channel activity increases at positive potentials. Bottom, single‐channel recordings at +80 mV at several intracellular pHs.

Figure 22. Figure 22.

Functional differences between β‐subunits. (A) Macroscopic currents were elicited by voltage pulses between −200 and +200 mV at 5 nmol/L (left) and 2.8 μmol/L (right) intracellular calcium. All currents were recorded in the inside‐out configuration. Notice the change in the activation and the deactivation kinetics when β1 and β2IR (β2 inactivation removed) are coexpressed with the α‐subunit. Current records in the third line were obtained by coexpressing the α with the β2‐subunit. Notice that currents inactivate. (B) Voltage activation curves obtained from tail currents (the currents measured at the beginning of the repolarizing pulse; −60 mV) of recordings showed in A at 5 nmol/L (open symbols) and 2.8 μmol/L intracellular calcium (filled symbols) (modified, with permission, from reference ). (C) Macroscopic currents of α + β4 channels (upper), and the activation curves at different calcium concentrations (lower). Notice the slower activation and deactivation kinetic produced by the β4‐subunit. (D) Comparison of the voltage activation curves at different Ca2+ concentrations between channels formed by expressing the α‐subunit alone (left) or by expressing α + β4 (adapted, with permission, from reference ).

Figure 23. Figure 23.

Physiological roles of Slo1 channels. (A) Proposed physiological roles of Slo1 channels. α‐ and β1‐subunits are shown as cartoons. (Adapted, with permission, from reference .) (B) Thanks to the close proximity of Slo1 (BKCa) and voltage‐dependent Ca2+ channels (VDCC), the increase of Ca2+ concentration induced by the opening of VDCC (up to 10 μmol/L in the neighborhood of Slo1 channels) promotes the opening of Slo1 channels (top). (Bottom) Current‐voltage relationship obtained in an oocyte expressing only Slo1 (open circles) and coexpressing Slo1 and VDCC. The colocalization of these two channels allows an increase in the K+ current that decreases when the potential approaches the reversal potential for Ca2+ indicating that K+ currents were elicited by the increase in internal Ca2+ concentration induced by the VDCC opening. (Adapted, with permission, from reference .) (C) In vascular smooth muscle cells, β1‐subunits confer the required Ca2+ sensitivity for effective coupling between Ca2+ sparks and spontaneous outward currents. [Adapted, with permission, from reference .] (D) In chromaffin cells, slowed Slo1 deactivation kinetics allows β2‐subunit‐expressing cells to fire a train of action potentials. (Adapted, with permission, from reference .)

Figure 24. Figure 24.

Allosteric models for Slo1 activation by voltage and Ca2+. (A) Allosteric scheme for channel activation by voltage. J is the equilibrium constant governing the equilibrium between resting and active configuration of the voltages sensor. D is the allosteric factor and L is the intrinsic equilibrium for channel opening. Notice that the channel can open when all voltage sensors are in their resting configuration. (Adapted, with permission, from reference .) (B) Allosteric kinetic scheme for activation by Ca2+. K is the equilibrium constant for calcium sensor activation and C is an allosteric factor. (C) The combination of A and B produces a two‐tiered 50‐state kinetic model. [Adapted, with permission, from reference .) (D) The complete allosteric model taking into account that Slo1 channels are tetramers and including some interaction between the voltage sensor and Ca2+ binding (allosteric factor E). In this type of mechanism neither voltage, nor Ca2+ binding is strictly coupled to channel opening, these three processes are independent equilibria that interact allosterically with each other. (Adapted, with permission, from reference .)

Figure 25. Figure 25.

Structural organization of the Slo 1 channel and the crystal structure of the gating ring. (A) Transmembrane segments location using the cysteine cross‐linking technique. Kv1.2/Kv2.1 chimera S1 to S6 with superimposed, labeled circles, uniquely colored for each subunit. White numbered circles correspond to TM1 and TM2 of the β1‐subunit. (Adapted, with permission, from reference .) (B) Slo1 20 Å structure resolved with electron cryomicroscopy. The large protrusion at the periphery of the voltage sensor has been suggested to correspond to S0 and the external N‐terminus. (C) Superimposed to the Slo1 structure shown in C is the structure of the transmembrane (TM) domains of Kv1.2 and the gating ring of the MthK channel (adapted, with permission, from reference ). (D) Slo1 channel RCK1 and RCK2 domains of one subunit showing the position of the Ca2+‐binding site (calcium bowl) in the RCK2 domain. Calcium (yellow ball) is coordinated by D892/D895/D897/Q889 (modified, with permission, from reference ). (E) Slo1 gating ring at 6 Å resolution. The ring is viewed down the 4‐fold symmetry axis with RCK1 in blue and RCK2 in red. Calcium ions are shown as yellow spheres. (F) The open gating ring structure from the MthK channel viewed down the 4‐fold axis of symmetry. Notice that a Ca2+ binds to the assembly interface in the Slo1 gating ring whereas two Ca2+ ions bind to the flexible interface in the MthK gating ring. (Modified, with permission, from reference .)

Figure 26. Figure 26.

KCa2 channels activation: single‐channel currents. Single‐channel current from arterial chemoreceptor cells. The inside‐out patch containing one observable open channel during 200‐ms depolarizations from −80 mV to the indicated membrane potentials. Solutions: 130 mmol/L K, 0.01 mmol/L Ca2+//130 mmol/L K, 10 mmol/L EGTA. (Adapted, with permission, from reference .)

Figure 27. Figure 27.

Topology of KCa2 channels and family dendogram. (A) Dendogram of the human SK channels genes constructed using t coffee and ClustalW. Genebank accession numbers: NC_000019 (KCNN1), NC_000005 (KCNN2), NC_000001 (KCNN3), and NC_000019 (KCNN4). (B) Proposed topology for KCa2 channels, showing a canonical six‐transmembrane segments organization (S1‐S6) whence S5 and S6 form the ion‐conduction pathway (shown in cyan) and the S4 segment. The intracellular Ca2+ regulation is given by the calmodulin‐binding domain (CaMBD) located in the C‐terminus (black segment). (C) Sequence alignment of the human SK channels (hSK1, hSK2, and hSK3). The transmembrane segments, S1 to S6, are boxed in gray. The pore region (P‐Region) is boxed in cyan. The CaMBD is indicated by black bars. Orange boxed amino acids and red residues show different phosphorylations sites conserved along the family. (Adapted, with permission, from reference .)

Figure 28. Figure 28.

KCa2 channel C‐terminal calmodulin‐binding domain. Calmodulin protein and KCa2 C‐terminal calmodulin‐binding domain complex was crystallized at a 1.6 Å resolution (PDB: 1G4Y). Calmodulin protein is shown in cyan with two of the four calcium bowls occupied by Ca2+ (yellow balls). The center of the calmodulin molecule is in contact with the KCa2 C‐terminal domain (pale brown) ().

Figure 29. Figure 29.

Physiological functions of KCa2 channels. Schematic representation of SK channel function in central nervous system (A) afterhyperpolarization (AHP): CA1 pyramidal neuron whole cell current clamp recording. Twenty action potentials were elicited at 50 Hz in control (black) or apamin (red, 100 nmol/L) bath solutions. The control trace shows the development of an interspike AHP and a posttetanus AHP that is blocked by apamin. Plateau potentials: apamin prolonged the duration of the plateau potential but did not affect the amplitude. (B) Substantia nigra. Pacemaker: perforated‐patch current‐clamp recording of a dopamine neuron in control or apamin (300 nmol/L) bath solutions. On the left is a 4 s trace representative of a 5‐min recording. On the right, the interspike interval (ISI) frequency distribution is plotted for each recording. Apamin significantly decreased the pacemaker precision as shown by the increase in the coefficient of variation (CV). (C) Cerebellum. Trimodal firing: extracellular field recordings of individual cerebellar Purkinje neurons the tonic activity of the cells changed to random bursting when 100 nmol/L apamin was bath applied. (D) Auditory hair cells. Continuous firing: whole cell patch current‐clamp recording from inner ear hair cells in the acutely dissected organ of Corti of a P5 rat. Voltage responses induced by a continuous 30 pA depolarizing current from the resting potential of –59 mV are shown. Bath application of 300 nmol/L apamin gradually abolished the evoked action potentials, indicating that KCa2 channel activity is necessary for continued firing. (Modified, with permission, from reference .)



Figure 1.

Potassium channel families arranged according to their subunit structure. Potassium channel families can be grouped in those having two transmembrane segments (2TM; Kir), 4TM (2‐pore domain), 6TM (voltage gated and SK), and 7TM (Slo). Note that for the sake of simplicity the large‐conductance Slo channel family includes the Slo2.x channels, which have only six transmembrane domains. The 6TM domain class can be divided into four families: Voltage‐gated Kv, voltage‐gated KCNQ‐type (KCNQ); ether‐a‐go‐go (Eag), and Ca2+‐activated channels (SK). Subdivisions of the voltage‐gated Kv channels into four subfamilies and Eag into three subfamilies are also named according to the Drosophila melanogaster genes. In the SK family IKCa1 stands for intermediate conductance Ca2+‐activated K+ channel.



Figure 2.

Phylogenetic tree of Kir channels and their current‐voltage curves. (A) Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human Kir family. International Union of Pharmacology and Hugo Gene Nomenclature Committee names of the genes are shown. The subunits were classified into four functional groups following Hibino et al. (). (B) Inward rectification and conductance are strongly external K+ concentration‐dependent. I‐V relationships are of the starfish egg cell membrane at four different Kext concentrations in Na+‐free media. Continuous and broken line indicates instantaneous and steady‐state current, respectively (adapted. with permission, from reference ). Notice that K+ conductance develops at voltages negative to the equilibrium potential for K+ (EK). (C) I‐V relationship characteristic of a “weak” inward rectifier. (D) In “strong” inward rectifiers K+ conductance tends to zero as the membrane potential is depolarized and contrary to expectations the crossover phenomena produces an increase in K+ conductance at voltages larger than the crossover voltage despite the decrease in the K+ driving force.



Figure 3.

Kir2.1 induces a smooth muscle cell hyperpolarization when Kext increases. (A) The average current densities at three different [Kext] were obtained in response to a voltage ramp from −130 to 0 mV lasting for 140 ms. (B) Ba2+‐sensitive currents densities recorded in the same condition as in A. (C) Elevation of Kext from 3 mmol/L to 15 mmol/L caused a membrane potential hyperpolarization of smooth muscle cells [adapted, with permission, from Filosa et al. ()]. (D) Chord conductance‐voltage curve at the same experimental conditions as in B. Notice that there is an appreciable increase in smooth muscle cells Kir conductance as the [Kext] is raised at physiological membrane potentials (−50 to −40 mV).



Figure 4.

Dual modulation of KG channels by G protein‐coupled receptor (GPCR) and the topology and structure of Kir6.x. (A) Agonist activation of GPCR coupled to pertussis (PTX)‐sensitive αi/o‐type of G protein promotes activation of KG channels. Activation of KG channels is induced by binding to the channel‐forming protein of the βγ complex of the G protein. Agonist binding to αq‐type of G protein results in channel inhibition that is a consequence of the activation of phospholipase C (PLC), which in turn hydrolyses phosphatidyl‐inositol‐4,5‐bisphosphate (PIP2). Other modulators include tyrosine kinase (TK), Ca2+‐calmodulin‐dependent kinase 2 (CAMK2), and protein phosphatase (PP1). Modified, with permission, from reference . For more details, see text. (B) SUR subunits contain 17 transmembrane segments assembled in three domains, TMD0‐2, and containing two nucleotide‐binding domains (NBD) contained between TMD1 and TMD2 (NBD1) and in the C‐terminus (NBD2). The structures show top and side views of the entire KATP channel complex analyzed at 18 Å resolution. Blue represents Kir6.x. Red represents the rest of SUR and yellow represents TMD0 of SUR [adapted, with permission, from Mikhailov et al. ()].



Figure 5.

Kir channel crystal structure and cation‐binding sites. (A) Voltage dependence in Kir channels arises as a consequence of the movement of K+ ions contained in the cytoplasmic pore. (B) Crystal structure of a Kir3.1‐prokaryotic Kir channel chimera determined at 2.2 Å. Seven Rb+ ions were located in the conduction pore. Two constriction sites, F181 side chain and residues 302‐309 Cα atoms in the G‐loop are colored in blue. For the sake of clarity only two subunits are shown [adapted, with permission, from Nishida et al. ()]. (C) Crystal structure of the cytoplasmic pore of S225E mutant of Kir3.1 (yellow) and the Kir chimera () (cyan). Na+ ions are represented by orange spheres and Rb+ ions by pink spheres. (D) Crystal structure model of the cytoplasmic pore of S225E mutant Kir3.1 corresponding to the boxed region in A. The residues, Q225, G227, G261, D260, F255, and S256, interact directly or through water molecules with the Na+ ions located at S8‐S11. The positions of the phenylalanines coordinating the Na+ through π‐cation interactions at site S10 are shown [adapted, with permission, from Xu et al. ()].



Figure 6.

Molecular determinants of inward rectification and location of modulators binding sites in the cytoplasmic domain of KG channels. (A, B) Amino acid residues in the cytoplasmic pore determining inward rectification in Kir2.1 channels. (C) Current‐voltage relationships for different Kir2.1 point mutants [adapted, with permission, from Pegan et al. ()]. (D) The structure shown contains the cytoplasmic domains of Kir3.1 a G protein‐gated channel and the transmembrane domains and pore region of the chimeric Kir channel. The regions implicated in Na+, PIP2, G protein, and alcohol binding are shown [adapted, with permission from Luscher and Slensinger ()].



Figure 7.

Diversity of 2‐pore (2P)‐domain K+ channel (K2P) subunits and membrane topology. (A) The alignment was made using the web tool: Phylogeny.fr (), with different sequences of human two pore K+ channels obtained from gene bank accession numbers from KCNK1 to KCNK18: NP_002236, NP_055032, NP_002237.1, NP_201567.1, NP_003731.1., NP_004814.1., NP_005705.1., NP_057685.1., NP_066984.1., NP_071338.1., NP_071337.2., NP_071753.1., NP_115491.1., NP_113648.2., and NP_862823.1. (B) Putative membrane topology of the two‐pore domain K+ channels. Green spheres indicate pH sensing residues and their predicted location in the first turret loop and M4 transmembrane domain. (C) Multiple sequence alignment of the outer and inner helix region of KcsA, hERG, and several K2P K+ channels. Amino acid residues colored in red show the K+ channel signature sequence, corresponding to the selectivity filter.



Figure 8.

Polymodal nature of K2P channels receptors. (A) TREK‐1 channels are modulated by stretch, heat, intracellular acidosis, depolarization, lipids, general anaesthetics, and tonically inhibited by the actin cytoskeleton [adapted, with permission, from Patel and Honoré ()]. (B) Polymodal regulation of TREK‐1 and TREK‐2. Activation of the Gs/cAMP/protein kinase A (PKA) and the Gq/phospholipase C (PLC)/Diacyl Glycerol (DAG)/protein kinase C (PKC) signaling pathway inhibit TREK channels by phosphorylating serine residues present on the C‐terminal. TREK‐1 is activated via the NO/cGMP/Protei kinase G (PKG) pathway, but the PKG phosphorylation consensus site is missing in TREK‐2. (Arrows indicate stimulation; lines with T ending represent inhibition.) [Modified, with permission, from Enyedi and Czirják ().] (C) Regulation of TASK‐1 and TASK‐3. The channels are inhibited by extracellular acidification (EC) acidification as a result of protonation of histidine98 in the second extracellular loop. Anandamide inhibits both TASK‐1 and TASK‐3. Hypoxia inhibits TASK current indirectly. TASK channels are activated by halothane and isoflurane but they are not influenced by chloroform or ether. The polycation ruthenium red and Zn2+ allow pharmacological distinction between the two closely related channel subunits. Dashed lines represent effects on targets; arrows indicate stimulation; lines with T ending represent inhibition. [Modified, with permission, from Enyedi and Czirják ().]



Figure 9.

K2P channel activation by different stimuli. (A) Top: TREK‐1 activation was graded with membrane stretch in a cell‐attached patch from oocytes expressing TREK‐1. The inset shows channel openings with an enlarged time scale. In this patch, a small conductance endogenous channel was also present. Bottom‐graded reversible negative pressure activation of hTRAAK in physiological K+ conditions. The patch was held at 0 mV and the zero current is indicated by a dashed line [from Patél et. al () and Lesage and Lazdunski ()]. (B) TREK‐1 channels show outward rectification. Single‐channel currents recorded in absence of Mg2+ at −100 mV (left trace), 0 mV (middle trace), and 100 mV (right trace) at atmospheric pressure (top traces) and at a steady pressure of −30 mm Hg (bottom traces). Po denotes open probability [adapted, with permission, from Maingret et al. ()]. (C) Thermosensitivity. Cell‐attached patches from COS‐7 cells incubated at different bath temperatures are shown for TREK‐1 and TRAAK [adapted, with permission, from Kang et al. ()]. (D) The C‐terminus of TREK‐2 is required for sensitivity to fatty acids and pH. (Top) Wild‐type TREK‐2 expressed in COS‐7 cells is robustly activated by a decrease in intracellular pH. Middle. The pH sensitivity is abolished in a chimeric mutant that consists of the core transmembrane segments of TREK‐2 and the C‐terminus of TASK‐3 (red) (chimera TREK‐2–TASK‐3C) indicating that C‐terminus of TREK‐2 is require to pH sensitivity. (Bottom) The sensitivity of a TRAAK–TASK‐3C chimera to pH is similar to wild‐type TRAAK, which indicates that the C‐terminus of TRAAK is unlikely to mediate activation by pH [adapted, with permission, from Kim ()]. (E) Left. TREK‐1 is reversibly opened by chloroform (0.8 mmol/L). Voltage was linearly depolarized with a voltage ramp from −120 to 100 mV. Current becomes zero at a membrane potential equal to the equilibrium potential for K+ (−80 mV). Inset: stimulation of the K+ current by chloroform (CHCl3) is concentration dependent and observed at pharmacologically relevant concentrations. Right top. Chloroform (0.8 mmol/L) induces reproducible membrane hyperpolarizations. Right bottom. Halothane (1 mmol/L; 0 mV) induces TREK‐1 single‐channel activity characterized by rapid flickering between closed and open states [modified, with permission, from Franks and Honore ()]. (F) Fatty acid activation of TRAAK and TREK in COS cells. (Left side) Current‐voltage relationships obtained in an inside‐out patch with voltage ramps ranging from –150 to +50 mV, 500 ms in duration, before (control), after 3 min perfusion with 10 μmol/L AA and after the wash. Inset: effects of 10 μmol/L AA on TRAAK currents recorded in an inside‐out patch clamped at +20 mV. The zero current level is indicated by an arrow. (Right side) Inside out patch currents were recorded at 0mV from transfected COS cells. The zero current levels are indicated by a dotted line. The histograms represent the ratio of the mean currents recorded before (Icontrol) or after 10 μmol/L of AA application (I), gray and black color denotes absence or coexpression of A‐kinase anchoring protein (AKAP150), respectively [adapted, with permission, from Sandoz et al. () and Fink et al. ()].



Figure 10.

K2P channel structure. (A) Homology model for ΔK2PØ (K2PØ channel variant lacking AA from 299 to 1000) channel shows bilateral symmetry with a 4‐fold symmetric selectivity filter. Color red indicates monomer A (from residue 1 to 152) and color blue monomer B (from residue 174 to 276). (B) Extracellular (top) and cytoplasmic (bottom) sides reveals overall symmetry like a parallelogram. The model includes residues 1 to 276 without the TM1‐P1 loop (residues 30‐91), TM2‐TM3 linker (residues 153‐173), and TM2‐P2 loop (residues 225‐238). (Bottom) Side view of domain I of both subunits. The glutaminase interacting protein (GIP) motif (G129‐I130‐P131) in TM2 is indicated. Side view of domain II of both subunits. Proline residue 183 and 192 in TM3 are indicated. (C) Structure of a mutant TASK‐3 channel modeled in an open state, using the structure of KvAP [adapted, with permission, from Jiang et al. ()] as template. It is hypothesized that channels open through flexion of M2 and M4 around hinge glycines G117 and G231. The positions of these hinge glycines are indicated as spheres in the helices M2 and M4. Gain of function mutants stabilizes the open state through altered side chain‐side chain interactions between residues. A possible H‐bond between Thr in position 237 of M4 (in mutant A237T) and N133, which may contribute to stabilizing the open state, is indicated. The model gives a bond length of 3.2 Å. (D) K2P3.1 model, illustrating the interactions of a water molecule with the backbone of Tyr‐96 and Gly‐97 and the side chains of Thr‐89 and His‐98 in the unprotonated form of His‐98, according to molecular dynamic simulations, based on Yuill et al. (). (E) pH‐sensing mechanism of human K2P2.1. Ribbon representation of one subunit of the bacterial KcsA potassium channel, based on the published structure [Doyle et al. ()]. Predicted hydrogen bonds between KcsA residues are presented as orange lines. The side chain of Glu‐51 is predicted to form hydrogen bonds with the backbone amide groups of Val‐84 and Thr‐85 and the side chain hydroxyl group of Thr‐85. The homologous K2P2.1 residues are Glu‐84 (red), Arg‐166, and Thr‐167 (blue), respectively. KcsA Ala‐54 and Leu‐59 were replaced in this presentation by histidines, as present at the homologous positions in K2P2.1 [i.e., His‐87 and His‐141 (green), respectively] based on Cohen et al. (). (F) Homology model of the TASK‐3 K2P channel. Illustrating the proximity of the two E30 (yellow) and two T103 (blue) residues (view looking from the top down). The model was created using Modeller 9v7 () based on the KcsA structure as template [originally solved by Doyle et al. ()].



Figure 11.

Organization of the voltage‐dependent K+ channel superfamily. Phylogenetic tree for the Kv1‐12 families. Amino acid sequence alignments of the human channel Kv proteins were created using CLUSTALW. Only the hydrophobic cores (S1‐S6) were used for analysis. The IUPHAR and HGNC names are shown together with the genes’ chromosomal localization and other commonly used name. The alignment was made using the web tool: Phylogeny.fr (), with different sequences of human two pore K+ channels obtained from gene bank accession numbers: KCNH1: NM_002238.3, KCNH2: NP_000229.1., KCNH3:NP_036416.1., KCNH5: NP_647479.2., KCNH6: NP_110406.1., KCNH7: NP_150375.2., KCNH8: NP_653234.2., KCNQ1: NP_000209.2., KCNQ2: NP_004509.2., KCNQ3: NP_004510.1., KCNQ4: NP_004691.2., KCNQ5: NP_062816.2., KCNS1: NP_002242.2., KCNS2: NP_065748.1., KCNS3: NP_002243.3., KCNV1: NP_055194.1., KNCG1: NP_002228.2., KCNG4: NP_758857.1., KCNF1: NP_002227.2., KCNV2: NP_598004.1., KCNG3: NP_579875.1., KCND1: NP_004970.3., KCND2: NP_036413.1., KCND3: NP_004971.2., KCNB1: NP_004966.1., KCNB2: NP_004761.2., KCNC1: NP_004967.1., KCNC2: NP_631874.1., KCNC3: NP_004968.2., KCNC4: NP_004969.2., KCNA1: NP_000208.2., KCNA2: NP_004965.1., KCNA3: NP_002223.3., KCNA4: NP_002224.1., KCNA5: NP_002225.2., KCNA6: NP_002226.1., KCNA7: NP_114092.2., KCNA10: NP_005540.1.



Figure 12.

Organization and structure of the Kv1.2/Kv2.1 chimeric channel (PDB_ID: 2RAR). Lateral (left) and top (right) views of the protein embedded in the membrane. Arginine residues important for voltage dependence are shown in sticks. For clarity, two monomers are shown in light gray. The secondary structure of the amino acid sequence (below) is color coded to match the respective transmembrane and functional segments of the protein. Potassium ions are represented in green and the oxygen of water molecules in red. The cytosolic structure hanging from the main protein body is the tratramerization domain, T.



Figure 13.

Kvβ1 inactivate currents of a Kv1 channel. (A) Delayed rectifier currents elicited by voltage steps in the absence of Kvβ‐subunit. (B) Coexpression with Kvβ (α+β). (C) A single‐voltage pulse shown in a large time scale. More details in reference .



Figure 14.

K+ currents diversity in Kv channels family. The indicated rat Kv channels were transiently expressed in HEK 293 cells. For each channel, whole‐cell K+ currents at +40 mV were measured in similar physiological conditions. Modified, with permission, from reference .



Figure 15.

K currents from Kv7 and EAG families. Modulation of heteromeric KCNQ2/3 current by extracellular H+ ions. (A) Whole‐cell KCNQ2/3 currents from a HEK‐293 cell in bathing solutions of differing pH were elicited by depolarizing voltage steps (1.5 s duration) from a holding potential of −70 mV. (B) Whole‐cell KCNQ2/3 current activation curves in bathing solutions of different pHs (). (C) Isochronal activation of human ether‐a‐go‐go‐related gene (HERG) channels. Membrane potential was stepped from −80 mV to a test potential between −70 and 100 mV, in intervals of 10 mV, for 2 s, followed by step to −50 mV. The HERG characteristic rapid rise in the tails of current account for a very fast recovery from inactivation and a slower inactivation ().



Figure 16.

Gating currents elicited by the squid potassium channels. (A) Superimposed 10 ms traces of gating and ionic currents recorded at three different voltages taken a 20°C degrees. Na+‐gating currents are missed because at this temperature they are too fast for the recording system (modified, with permission, from reference ). (B) Voltage dependency of the gating charge (open symbols) and the ionic conductance (filled symbols). (C) Kinetics of the gating and ionic currents (B and C modified, with permission, from reference ).



Figure 17.

Structural determinants for the voltage sensitivity in voltage‐gated K+ channels. (A) Structure of a single monomer depicting the voltage‐sensor domain (VSD) and the pore domain. Arginines R1, R2, R3, and R4 (corresponding to Shaker R362, R365, R368, and R371) are represented in stick form. (B) Possible trajectories for the gating charges (for more details see text).



Figure 18.

Structural design of the K+ conduction system. (A) Ions in the pore of the KcsA bacterial channel (PDB_ID: 1K4C). All possible K+‐binding sites are shown. Hydration water molecules are shown in red with a Van der Waal radius of 0.5 Å. (B) Ion conduction is due to two alternating and energetically equivalent configurations in ion occupancy (for more details see text).



Figure 19.

Mechanical movements of the voltage‐sensitive pore opening. (A) Side and enlarged bottom views of the residues that change in accessibility during the opening of the Shaker activation gate (residues 470‐474; in blue), that do no change in accessibility during gating (residues 481‐486, in red), and residues that may form the gate (residues 475‐479; in green). After reference . (B) Allosteric surface proposed for the interaction between the S4 and S5 linker (in blue and gray) with the S6 C‐terminal half of two adjacent subunits (in yellow and orange).



Figure 20.

Phylogenetic tree of Slo channels family in mammals and membrane topology of the α‐ and β‐subunits of Slo1 channels. (A) The four genes present in Slo channels families: Slo, Slo2.1, Slo 2.2, and Slo3. (B) The α‐subunit of Slo1 contains seven transmembrane segments divided in two domains [voltage‐sensor domain, (VSD) and pore region] that is normally associated to β‐subunits consisting of two transmembrane segments. β2 and β3 have an inactivating particle on their N‐terminus able to interact with the channel internal vestibule and block the passage of K+ through the channel. The α‐subunit contains a long C‐terminus domain in which two regulators of K+ conductance domains (RCK1 and RCK2) are present. Spread throughout in the BK C‐terminus are located the binding sites for Ca2+ and Mg2+ (for more details on the divalent cation‐binding sites see Section “Carboxy terminus”). (C) (Top) The α‐subunit has a voltage‐sensing domain formed by the S0 to S4 segments. Four charged residues contribute to the channel voltage membrane sensitivity, D153, R167 in S2, D186 in S3, and R213 in S4. (Bottom) The pore region formed by S5, the pore helix, the pore loop, and the S6 transmembrane. Three amino acid residues have been identified in the BK pore as partially responsible for the channel high conductance, D292, E321, and E324.



Figure 21.

Polymodal activation of Slo channels. (A) Slo1 channel single‐channel activity increases its open probability in response to an increase in the membrane voltage. Upper trace was taken at −60 mV. Openings are downward deflections in the current. Lower trace was taken at 80 mV. Upward deflections are opening events. The opening of two independent channels can be appreciated in this current record. Open probability also increases with increasing intracellular calcium (1, 10, and 100 μmol/L) at a fixed voltage (+60 mV). (B) Slo2.2 channels single‐channel activity increases with high intracellular sodium. Perfusion using 80 mmol/L intracellular sodium elicited four conductance levels, which are reduced to just one with nominal 0 sodium concentration (top). (Bottom) The same type of experiment performed at a compressed time scale. (C) Single‐channel activity of cloned Slo3 increases with the alkalinization and depolarizing voltages. Upper, single‐channel activity increases at positive potentials. Bottom, single‐channel recordings at +80 mV at several intracellular pHs.



Figure 22.

Functional differences between β‐subunits. (A) Macroscopic currents were elicited by voltage pulses between −200 and +200 mV at 5 nmol/L (left) and 2.8 μmol/L (right) intracellular calcium. All currents were recorded in the inside‐out configuration. Notice the change in the activation and the deactivation kinetics when β1 and β2IR (β2 inactivation removed) are coexpressed with the α‐subunit. Current records in the third line were obtained by coexpressing the α with the β2‐subunit. Notice that currents inactivate. (B) Voltage activation curves obtained from tail currents (the currents measured at the beginning of the repolarizing pulse; −60 mV) of recordings showed in A at 5 nmol/L (open symbols) and 2.8 μmol/L intracellular calcium (filled symbols) (modified, with permission, from reference ). (C) Macroscopic currents of α + β4 channels (upper), and the activation curves at different calcium concentrations (lower). Notice the slower activation and deactivation kinetic produced by the β4‐subunit. (D) Comparison of the voltage activation curves at different Ca2+ concentrations between channels formed by expressing the α‐subunit alone (left) or by expressing α + β4 (adapted, with permission, from reference ).



Figure 23.

Physiological roles of Slo1 channels. (A) Proposed physiological roles of Slo1 channels. α‐ and β1‐subunits are shown as cartoons. (Adapted, with permission, from reference .) (B) Thanks to the close proximity of Slo1 (BKCa) and voltage‐dependent Ca2+ channels (VDCC), the increase of Ca2+ concentration induced by the opening of VDCC (up to 10 μmol/L in the neighborhood of Slo1 channels) promotes the opening of Slo1 channels (top). (Bottom) Current‐voltage relationship obtained in an oocyte expressing only Slo1 (open circles) and coexpressing Slo1 and VDCC. The colocalization of these two channels allows an increase in the K+ current that decreases when the potential approaches the reversal potential for Ca2+ indicating that K+ currents were elicited by the increase in internal Ca2+ concentration induced by the VDCC opening. (Adapted, with permission, from reference .) (C) In vascular smooth muscle cells, β1‐subunits confer the required Ca2+ sensitivity for effective coupling between Ca2+ sparks and spontaneous outward currents. [Adapted, with permission, from reference .] (D) In chromaffin cells, slowed Slo1 deactivation kinetics allows β2‐subunit‐expressing cells to fire a train of action potentials. (Adapted, with permission, from reference .)



Figure 24.

Allosteric models for Slo1 activation by voltage and Ca2+. (A) Allosteric scheme for channel activation by voltage. J is the equilibrium constant governing the equilibrium between resting and active configuration of the voltages sensor. D is the allosteric factor and L is the intrinsic equilibrium for channel opening. Notice that the channel can open when all voltage sensors are in their resting configuration. (Adapted, with permission, from reference .) (B) Allosteric kinetic scheme for activation by Ca2+. K is the equilibrium constant for calcium sensor activation and C is an allosteric factor. (C) The combination of A and B produces a two‐tiered 50‐state kinetic model. [Adapted, with permission, from reference .) (D) The complete allosteric model taking into account that Slo1 channels are tetramers and including some interaction between the voltage sensor and Ca2+ binding (allosteric factor E). In this type of mechanism neither voltage, nor Ca2+ binding is strictly coupled to channel opening, these three processes are independent equilibria that interact allosterically with each other. (Adapted, with permission, from reference .)



Figure 25.

Structural organization of the Slo 1 channel and the crystal structure of the gating ring. (A) Transmembrane segments location using the cysteine cross‐linking technique. Kv1.2/Kv2.1 chimera S1 to S6 with superimposed, labeled circles, uniquely colored for each subunit. White numbered circles correspond to TM1 and TM2 of the β1‐subunit. (Adapted, with permission, from reference .) (B) Slo1 20 Å structure resolved with electron cryomicroscopy. The large protrusion at the periphery of the voltage sensor has been suggested to correspond to S0 and the external N‐terminus. (C) Superimposed to the Slo1 structure shown in C is the structure of the transmembrane (TM) domains of Kv1.2 and the gating ring of the MthK channel (adapted, with permission, from reference ). (D) Slo1 channel RCK1 and RCK2 domains of one subunit showing the position of the Ca2+‐binding site (calcium bowl) in the RCK2 domain. Calcium (yellow ball) is coordinated by D892/D895/D897/Q889 (modified, with permission, from reference ). (E) Slo1 gating ring at 6 Å resolution. The ring is viewed down the 4‐fold symmetry axis with RCK1 in blue and RCK2 in red. Calcium ions are shown as yellow spheres. (F) The open gating ring structure from the MthK channel viewed down the 4‐fold axis of symmetry. Notice that a Ca2+ binds to the assembly interface in the Slo1 gating ring whereas two Ca2+ ions bind to the flexible interface in the MthK gating ring. (Modified, with permission, from reference .)



Figure 26.

KCa2 channels activation: single‐channel currents. Single‐channel current from arterial chemoreceptor cells. The inside‐out patch containing one observable open channel during 200‐ms depolarizations from −80 mV to the indicated membrane potentials. Solutions: 130 mmol/L K, 0.01 mmol/L Ca2+//130 mmol/L K, 10 mmol/L EGTA. (Adapted, with permission, from reference .)



Figure 27.

Topology of KCa2 channels and family dendogram. (A) Dendogram of the human SK channels genes constructed using t coffee and ClustalW. Genebank accession numbers: NC_000019 (KCNN1), NC_000005 (KCNN2), NC_000001 (KCNN3), and NC_000019 (KCNN4). (B) Proposed topology for KCa2 channels, showing a canonical six‐transmembrane segments organization (S1‐S6) whence S5 and S6 form the ion‐conduction pathway (shown in cyan) and the S4 segment. The intracellular Ca2+ regulation is given by the calmodulin‐binding domain (CaMBD) located in the C‐terminus (black segment). (C) Sequence alignment of the human SK channels (hSK1, hSK2, and hSK3). The transmembrane segments, S1 to S6, are boxed in gray. The pore region (P‐Region) is boxed in cyan. The CaMBD is indicated by black bars. Orange boxed amino acids and red residues show different phosphorylations sites conserved along the family. (Adapted, with permission, from reference .)



Figure 28.

KCa2 channel C‐terminal calmodulin‐binding domain. Calmodulin protein and KCa2 C‐terminal calmodulin‐binding domain complex was crystallized at a 1.6 Å resolution (PDB: 1G4Y). Calmodulin protein is shown in cyan with two of the four calcium bowls occupied by Ca2+ (yellow balls). The center of the calmodulin molecule is in contact with the KCa2 C‐terminal domain (pale brown) ().



Figure 29.

Physiological functions of KCa2 channels. Schematic representation of SK channel function in central nervous system (A) afterhyperpolarization (AHP): CA1 pyramidal neuron whole cell current clamp recording. Twenty action potentials were elicited at 50 Hz in control (black) or apamin (red, 100 nmol/L) bath solutions. The control trace shows the development of an interspike AHP and a posttetanus AHP that is blocked by apamin. Plateau potentials: apamin prolonged the duration of the plateau potential but did not affect the amplitude. (B) Substantia nigra. Pacemaker: perforated‐patch current‐clamp recording of a dopamine neuron in control or apamin (300 nmol/L) bath solutions. On the left is a 4 s trace representative of a 5‐min recording. On the right, the interspike interval (ISI) frequency distribution is plotted for each recording. Apamin significantly decreased the pacemaker precision as shown by the increase in the coefficient of variation (CV). (C) Cerebellum. Trimodal firing: extracellular field recordings of individual cerebellar Purkinje neurons the tonic activity of the cells changed to random bursting when 100 nmol/L apamin was bath applied. (D) Auditory hair cells. Continuous firing: whole cell patch current‐clamp recording from inner ear hair cells in the acutely dissected organ of Corti of a P5 rat. Voltage responses induced by a continuous 30 pA depolarizing current from the resting potential of –59 mV are shown. Bath application of 300 nmol/L apamin gradually abolished the evoked action potentials, indicating that KCa2 channel activity is necessary for continued firing. (Modified, with permission, from reference .)

References
 1. Adams PR, Constanti A, Brown DA, Clark RB. Intracellular Ca2+ activates a fast voltage‐sensitive K+ current in vertebrate sympathetic neurones. Nature 296: 746‐749, 1982.
 2. Adelman JP, Shen KZ, Kavanaugh MP, Warren RA, Wu YN, Lagrutta A, Bond CT, North RA. Calcium‐activated potassium channels expressed from cloned complementary DNAs. Neuron 9: 209‐216, 1992.
 3. Aggarwal SK, MacKinnon R. Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron 16: 1169‐1177, 1996.
 4. Ahern CA, Horn R. Specificity of charge‐carrying residues in the voltage sensor of potassium channels. J Gen Physiol 123: 205‐216, 2004.
 5. Ahern CA, Horn R. Focused electric field across the voltage sensor of potassium channels. Neuron 48: 25‐29, 2005.
 6. Aldrich RW Jr., Getting PA, Thompson SH. Mechanism of frequency‐dependent broadening of molluscan neurone soma spikes. J Physiol 291: 531‐544, 1979.
 7. Ando M, Takeuchi S. Immunological identification of an inward rectifier K+ channel (Kir4.1) in the intermediate cell (melanocyte) of the cochlear stria vascularis of gerbils and rats. Cell Tissue Res 298: 179‐183, 1999.
 8. Anumonwo JM, Lopatin AN. Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol 48: 45‐54, 2010.
 9. Armstrong CM. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J Gen Physiol 54: 553‐575, 1969.
 10. Armstrong CM. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58: 413‐437, 1971.
 11. Armstrong CM. Potassium pores of nerve and muscle membranes. Membranes 3: 325‐358, 1975.
 12. Armstrong CM, Bezanilla F. Currents related to movement of the gating particles of the sodium channels. Nature 242: 459‐461, 1973.
 13. Armstrong CM, Bezanilla F. Charge movement associated with the opening and closing of the activation gates of the Na channels. J Gen Physiol 63: 533‐552, 1974.
 14. Armstrong CM, Bezanilla F. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol 70: 567‐590, 1977.
 15. Armstrong CM, Loboda A. A model for 4‐aminopyridine action on K channels: Similarities to tetraethylammonium ion action. Biophys J 81: 895‐904, 2001.
 16. Art JJ, Fettiplace R. Variation of membrane properties in hair cells isolated from the turtle cochlea. J Physiol 385: 207‐242, 1987.
 17. Art JJ, Wu YC, Fettiplace R. The calcium‐activated potassium channels of turtle hair cells. J Gen Physiol 105: 49‐72, 1995.
 18. Ashcroft FM, Gribble FM. New windows on the mechanism of action of K(ATP) channel openers. Trends Pharmacol Sci 21: 439‐445, 2000.
 19. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta‐cell. Prog Biophys Mol Biol 54: 87‐143, 1989.
 20. Ashmole I, Vavoulis DV, Stansfeld PJ, Mehta PR, Feng JF, Sutcliffe MJ, Stanfield PR. The response of the tandem pore potassium channel TASK‐3 (K(2P)9.1) to voltage: Gating at the cytoplasmic mouth. J Physiol 587: 4769‐4783, 2009.
 21. Atkinson NS, Robertson GA, Ganetzky B. A component of calcium‐activated potassium channels encoded by the Drosophila slo locus. Science 253: 551‐555, 1991.
 22. Bacci A, Huguenard JR, Prince DA. Long‐lasting self‐inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431: 312‐316, 2004.
 23. Bao L, Rapin AM, Holmstrand EC, Cox DH. Elimination of the BK(Ca) channel's high‐affinity Ca(2+) sensitivity. J Gen Physiol 120: 173‐189, 2002.
 24. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 384: 78‐80, 1996.
 25. Barmeyer C, Rahner C, Yang Y, Sigworth FJ, Binder HJ, Rajendran VM. Cloning and identification of tissue‐specific expression of KCNN4 splice variants in rat colon. Am J Physiol Cell Physiol 299: C251‐C263, 2010.
 26. Baukrowitz T, Yellen G. Use‐dependent blockers and exit rate of the last ion from the multi‐ion pore of a K+ channel. Science 271: 653‐656, 1996.
 27. Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two‐pore potassium channels. Nat Neurosci 11: 772‐779, 2008.
 28. Bautista L, Castro MJ, Lopez‐Barneo J, Castellano A. Hypoxia inducible factor‐2alpha stabilization and maxi‐K+ channel beta1‐subunit gene repression by hypoxia in cardiac myocytes: Role in preconditioning. Circ Res 104: 1364‐1372, 2009.
 29. Bayliss DA, Barrett PQ. Emerging roles for two‐pore‐domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci 29: 566‐575, 2008.
 30. Bean BP. Neurophysiology: Stressful pacemaking. Nature 447: 1059‐1060, 2007.
 31. Beckh S, Pongs O. Members of the RCK potassium channel family are differentially expressed in the rat nervous system. EMBO J 9: 777‐782, 1990.
 32. Behrens R, Nolting A, Reimann F, Schwarz M, Waldschutz R, Pongs O. hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large‐conductance calcium‐activated potassium channel beta subunit family. FEBS Lett 474: 99‐106, 2000.
 33. Ben‐Abu Y, Zhou Y, Zilberberg N, Yifrach O. Inverse coupling in leak and voltage‐activated K +channel gates underlies distinct roles in electrical signaling. Nat Struc Mol Biol 16: 71‐79, 2009.
 34. Bender K, Wellner‐Kienitz MC, Inanobe A, Meyer T, Kurachi Y, Pott L. Overexpression of monomeric and multimeric GIRK4 subunits in rat atrial myocytes removes fast desensitization and reduces inward rectification of muscarinic K(+) current (I(K(ACh))). Evidence for functional homomeric GIRK4 channels. J Biol Chem 276: 28873‐28880, 2001.
 35. Benton DC, Monaghan AS, Hosseini R, Bahia PK, Haylett DG, Moss GW. Small conductance Ca2+‐activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells. J Physiol 553: 13‐19, 2003.
 36. Bentzen BH, Nardi A, Calloe K, Madsen LS, Olesen SP, Grunnet M. The small molecule NS11021 is a potent and specific activator of Ca2+‐activated big‐conductance K+ channels. Mol Pharmacol 72: 1033‐1044, 2007.
 37. Berkefeld H, Fakler B. Repolarizing responses of BKCa‐Cav complexes are distinctly shaped by their Cav subunits. J Neurosci 28: 8238‐8245, 2008.
 38. Berkefeld H, Sailer CA, Bildl W, Rohde V, Thumfart JO, Eble S, Klugbauer N, Reisinger E, Bischofberger J, Oliver D, Knaus HG, Schulte U, Fakler B. BKCa‐Cav channel complexes mediate rapid and localized Ca2+‐activated K+ signaling. Science 314: 615‐620, 2006.
 39. Bezanilla F. How membrane proteins sense voltage. Nat Rev 9: 323‐332, 2008.
 40. Bezanilla F, Armstrong CM. Negative conductance caused by entry of sodium and cesium ions into the potassium channels of squid axons. J Gen Physiol 60: 588‐608, 1972.
 41. Bezanilla F, Armstrong CM. Gating currents of the sodium channels: Three ways to block them. Science 183: 753‐754, 1974.
 42. Bezanilla F, Armstrong CM. Properties of the sodium channel gating current. Cold Spring Harb Symp Quant Biol 40: 297‐304, 1976.
 43. Bezanilla F, Taylor RE, Fernandez JM. Distribution and kinetics of membrane dielectric polarization. 1. Long‐term inactivation of gating currents. J Gen Physiol 79: 21‐40, 1982.
 44. Bezanilla F, White MM, Taylor RE. Gating currents associated with potassium channel activation. Nature 296: 657‐659, 1982.
 45. Bhalla T, Rosenthal JJ, Holmgren M, Reenan R. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol 11: 950‐956, 2004.
 46. Bhattacharjee A, Gan L, Kaczmarek LK. Localization of the Slack potassium channel in the rat central nervous system. J Comp Neurol 454: 241‐254, 2002.
 47. Bhattacharjee A, Joiner WJ, Wu M, Yang Y, Sigworth FJ, Kaczmarek LK. Slick (Slo2.1), a rapidly‐gating sodium‐activated potassium channel inhibited by ATP. J Neurosci 23: 11681‐11691, 2003.
 48. Bhattacharjee A, Kaczmarek LK. For K+ channels, Na+ is the new Ca2+. Trends Neurosci 28: 422‐428, 2005.
 49. Bhattacharjee A, von Hehn CA, Mei X, Kaczmarek LK. Localization of the Na+‐activated K+ channel Slick in the rat central nervous system. J Comp Neurol 484: 80‐92, 2005.
 50. Blatz AL, Magleby KL. Single apamin‐blocked Ca‐activated K+ channels of small conductance in cultured rat skeletal muscle. Nature 323: 718‐720, 1986.
 51. Bleich M, Schlatter E, Greger R. The luminal K+ channel of the thick ascending limb of Henle's loop. Pflugers Arch 415: 449‐460, 1990.
 52. Bockenhauer D, Zilberberg N, Goldstein SA. KCNK2: Reversible conversion of a hippocampal potassium leak into a voltage‐dependent channel. Nat Neurosci 4: 486‐491, 2001.
 53. Bond CT, Ammala C, Ashfield R, Blair TA, Gribble F, Khan RN, Lee K, Proks P, Rowe IC, Sakura H, et al. Cloning and functional expression of the cDNA encoding an inwardly‐rectifying potassium channel expressed in pancreatic beta‐cells and in the brain. FEBS Lett 367: 61‐66, 1995.
 54. Bond CT, Maylie J, Adelman JP. SK channels in excitability, pacemaking and synaptic integration. Curr Opin Neurobiol 15: 305‐311, 2005.
 55. Bond CT, Pessia M, Xia XM, Lagrutta A, Kavanaugh MP, Adelman JP. Cloning and expression of a family of inward rectifier potassium channels. Receptors Channels 2: 183‐191, 1994.
 56. Borchert GH, Yang C, Kolar F. Mitochondrial BKCa channels contribute to protection of cardiomyocytes isolated from chronically hypoxic rats. Am J Physiol Heart Circ Physiol 300: H507‐H513, 2011.
 57. Braun M, Ramracheya R, Bengtsson M, Zhang Q, Karanauskaite J, Partridge C, Johnson PR, Rorsman P. Voltage‐gated ion channels in human pancreatic beta‐cells: Electrophysiological characterization and role in insulin secretion. Diabetes 57: 1618‐1628, 2008.
 58. Brelidze TI, Niu X, Magleby KL. A ring of eight conserved negatively charged amino acids doubles the conductance of BK channels and prevents inward rectification. Proc Natl Acad Sci U S A 100: 9017‐9022, 2003.
 59. Brenner R, Chen QH, Vilaythong A, Toney GM, Noebels JL, Aldrich RW. BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat Neurosci 8: 1752‐1759, 2005.
 60. Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW. Cloning and functional characterization of novel large conductance calcium‐activated potassium channel beta subunits, hKCNMB3 and hKCNMB4. J Biol Chem 275: 6453‐6461, 2000.
 61. Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, Patterson AJ, Nelson MT, Aldrich RW. Vasoregulation by the beta1 subunit of the calcium‐activated potassium channel. Nature 407: 870‐876, 2000.
 62. Brock MW, Mathes C, Gilly WF. Selective open‐channel block of Shaker (Kv1) potassium channels by s‐nitrosodithiothreitol (SNDTT). J Gen Physiol 118: 113‐134, 2001.
 63. Broomand A, Elinder F. Large‐scale movement within the voltage‐sensor paddle of a potassium channel‐support for a helical‐screw motion. Neuron 59: 770‐777, 2008.
 64. Brown MR, Kronengold J, Gazula VR, Spilianakis CG, Flavell RA, von Hehn CA, Bhattacharjee A, Kaczmarek LK. Amino‐termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. J Physiol 586: 5161‐5179, 2008.
 65. Bruening‐Wright A, Schumacher MA, Adelman JP, Maylie J. Localization of the activation gate for small conductance Ca2+‐activated K+ channels. J Neurosci 22: 6499‐6506, 2002.
 66. Brüning E, Blumfeldr‐Albertus H. Jasmina und die Lotosblume. Berlin: Der Kinderbuchverlag, 1986, p. 77.
 67. Budelli G, Hage TA, Wei A, Rojas P, Jong YJ, O'Malley K, Salkoff L. Na+‐activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci 12: 745‐750, 2009.
 68. Burgess GM, Claret M, Jenkinson DH. Effects of quinine and apamin on the calcium‐dependent potassium permeability of mammalian hepatocytes and red cells. J Physiol 317: 67‐90, 1981.
 69. Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L. mSlo, a complex mouse gene encoding “maxi” calcium‐activated potassium channels. Science 261: 221‐224, 1993.
 70. Cai X, Liang CW, Muralidharan S, Kao JP, Tang CM, Thompson SM. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44: 351‐364, 2004.
 71. Campbell DS, Holt CE. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32: 1013‐1026, 2001.
 72. Campos FV, Chanda B, Roux B, Bezanilla F. Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of Shaker K channel. Proc Natl Acad Sci U S A 104: 7904‐7909, 2007.
 73. Campos Rosa J, Galanakis D, Piergentili A, Bhandari K, Ganellin CR, Dunn PM, Jenkinson DH. Synthesis, molecular modeling, and pharmacological testing of bis‐quinolinium cyclophanes: Potent, non‐peptidic blockers of the apamin‐sensitive Ca(2+)‐activated K(+) channel. J Med Chem 43: 420‐431, 2000.
 74. Candia S, Garcia ML, Latorre R. Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)‐activated K+ channel. Biophys J 63: 583‐590, 1992.
 75. Carvacho I, Gonzalez W, Torres YP, Brauchi S, Alvarez O, Gonzalez‐Nilo FD, Latorre R. Intrinsic electrostatic potential in the BK channel pore: Role in determining single channel conductance and block. J Gen Physiol 131: 147‐161, 2008.
 76. Casis O, Olesen SP, Sanguinetti MC. Mechanism of action of a novel human ether‐a‐go‐go‐related gene channel activator. Mol Pharmacol 69: 658‐665, 2006.
 77. Castle NA, Strong PN. Identification of two toxins from scorpion (Leiurus quinquestriatus) venom which block distinct classes of calcium‐activated potassium channel. FEBS Lett 209: 117‐121, 1986.
 78. Catterall WA. Structure and function of voltage‐sensitive ion channels. Science 242: 50‐61, 1988.
 79. Cingolani LA, Gymnopoulos M, Boccaccio A, Stocker M, Pedarzani P. Developmental regulation of small‐conductance Ca2+‐activated K+ channel expression and function in rat Purkinje neurons. J Neurosci 22: 4456‐4467, 2002.
 80. Claydon TW, Makary SY, Dibb KM, Boyett MR. The selectivity filter may act as the agonist‐activated gate in the G protein‐activated Kir3.1/Kir3.4 K+ channel. J Biol Chem 278: 50654‐50663, 2003.
 81. Clement JPt, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar‐Bryan L, Bryan J. Association and stoichiometry of K(ATP) channel subunits. Neuron 18: 827‐838, 1997.
 82. Cohen A, Ben‐Abu Y, Hen S, Zilberberg N. A novel mechanism for human K2P2.1 channel gating. Facilitation of C‐type gating by protonation of extracellular histidine residues. J Biol Chem 283: 19448‐19455, 2008.
 83. Cohen A, Ben‐Abu Y, Zilberberg N. Gating the pore of potassium leak channels. Eur Biophys J 39: 61‐73, 2009.
 84. Cordero‐Morales JF, Cuello LG, Zhao Y, Jogini V, Cortes DM, Roux B, Perozo E. Molecular determinants of gating at the potassium‐channel selectivity filter. Nat Struct Mol Biol 13: 311‐318, 2006.
 85. Cordero‐Morales JF, Jogini V, Lewis A, Vasquez V, Cortes DM, Roux B, Perozo E. Molecular driving forces determining potassium channel slow inactivation. Nat Struct Mol Biol 14: 1062‐1069, 2007.
 86. Covarrubias M, Bhattacharji A, De Santiago‐Castillo JA, Dougherty K, Kaulin YA, Na‐Phuket TR, Wang G. The neuronal Kv4 channel complex. Neurochem Res 33: 1558‐1567, 2008.
 87. Cuello LG, Jogini V, Cortes DM, Perozo E. Structural mechanism of C‐type inactivation in K(+) channels. Nature 466: 203‐208.
 88. Cui G, Okamoto T, Morikawa H. Spontaneous opening of T‐type Ca2+ channels contributes to the irregular firing of dopamine neurons in neonatal rats. J Neurosci 24: 11079‐11087, 2004.
 89. Cui J, Aldrich RW. Allosteric linkage between voltage and Ca(2+)‐dependent activation of BK‐type mslo1 K(+) channels. Biochemistry 39: 15612‐15619, 2000.
 90. Cui J, Yang H, Lee US. Molecular mechanisms of BK channel activation. Cell Mol Life Sci 66: 852‐875, 2009.
 91. Cha A, Snyder GE, Selvin PR, Bezanilla F. Atomic scale movement of the voltage‐sensing region in a potassium channel measured via spectroscopy. Nature 402: 809‐813, 1999.
 92. Chakrapani S, Cordero‐Morales JF, Jogini V, Pan AC, Cortes DM, Roux B, Perozo E. On the structural basis of modal gating behavior in K(+) channels. Nat Struct Mol Biol 18: 67‐74, 2011.
 93. Chandy KG, Cahalan M, Pennington M, Norton RS, Wulff H, Gutman GA. Potassium channels in T lymphocytes: Toxins to therapeutic immunosuppressants. Toxicon 39: 1269‐1276, 2001.
 94. Chemin J, Patel A, Duprat F, Zanzouri M, Lazdunski M, Honore E. Lysophosphatidic acid‐operated K+ channels. J Biol Chem 280: 4415‐4421, 2005.
 95. Chemin J, Patel AJ, Duprat F, Lauritzen I, Lazdunski M, Honore E. A phospholipid sensor controls mechanogating of the K+ channel TREK‐1. EMBO J 24: 44‐53, 2005.
 96. Chen H, Kronengold J, Yan Y, Gazula VR, Brown MR, Ma L, Ferreira G, Yang Y, Bhattacharjee A, Sigworth FJ, Salkoff L, Kaczmarek LK. The N‐terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium‐activated potassium channels. J Neurosci 29: 5654‐5665, 2009.
 97. Chen JQ, Galanakis D, Ganellin CR, Dunn PM, Jenkinson DH. bis‐Quinolinium cyclophanes: 8,14‐diaza‐1,7(1, 4)‐diquinolinacyclotetradecaphane (UCL 1848), a highly potent and selective, nonpeptidic blocker of the apamin‐sensitive Ca(2+)‐activated K(+) channel. J Med Chem 43: 3478‐3481, 2000.
 98. Chen L, Tian L, MacDonald SH, McClafferty H, Hammond MS, Huibant JM, Ruth P, Knaus HG, Shipston MJ. Functionally diverse complement of large conductance calcium‐ and voltage‐activated potassium channel (BK) alpha‐subunits generated from a single site of splicing. J Biol Chem 280: 33599‐33609, 2005.
 99. Chen M, Gan G, Wu Y, Wang L, Ding J. Lysine‐rich extracellular rings formed by hbeta2 subunits confer the outward rectification of BK channels. PLoS One 3: e2114, 2008.
 100. Chen X, Yuan LL, Zhao C, Birnbaum SG, Frick A, Jung WE, Schwarz TL, Sweatt JD, Johnston D. Deletion of Kv4.2 gene eliminates dendritic A‐type K+ current and enhances induction of long‐term potentiation in hippocampal CA1 pyramidal neurons. J Neurosci 26: 12143‐12151, 2006.
 101. Chicchi GG, Gimenez‐Gallego G, Ber E, Garcia ML, Winquist R, Cascieri MA. Purification and characterization of a unique, potent inhibitor of apamin binding from Leiurus quinquestriatus hebraeus venom. J Biol Chem 263: 10192‐10197, 1988.
 102. Cho H, Nam GB, Lee SH, Earm YE, Ho WK. Phosphatidylinositol 4,5‐bisphosphate is acting as a signal molecule in alpha(1)‐adrenergic pathway via the modulation of acetylcholine‐activated K(+) channels in mouse atrial myocytes. J Biol Chem 276: 159‐164, 2001.
 103. Choi KL, Aldrich RW, Yellen G. Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage‐activated K+ channels. Proc Natl Acad Sci U S A 88: 5092‐5095, 1991.
 104. D'Adamo MC, Liu Z, Adelman JP, Maylie J, Pessia M. Episodic ataxia type‐1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel. EMBO J 17: 1200‐1207, 1998.
 105. D'Hoedt D, Hirzel K, Pedarzani P, Stocker M. Domain analysis of the calcium‐activated potassium channel SK1 from rat brain. Functional expression and toxin sensitivity. J Biol Chem 279: 12088‐12092, 2004.
 106. Day M, Carr DB, Ulrich S, Ilijic E, Tkatch T, Surmeier DJ. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci 25: 8776‐8787, 2005.
 107. del Camino D, Holmgren M, Liu Y, Yellen G. Blocker protection in the pore of a voltage‐gated K+ channel and its structural implications. Nature 403: 321‐325, 2000.
 108. Demo SD, Yellen G. The inactivation gate of the Shaker K+ channel behaves like an open‐channel blocker. Neuron 7: 743‐753, 1991.
 109. Dereeper A, Guignon V, Blanc G, Audic S, Buffet S, Chevenet F, Dufayard JF, Guindon S, Lefort V, Lescot M, Claverie JM, Gascuel O. Phylogeny.fr: Robust phylogenetic analysis for the non‐specialist. Nucleic Acids Res 36: W465‐W469, 2008.
 110. Diaz L, Meera P, Amigo J, Stefani E, Alvarez O, Toro L, Latorre R. Role of the S4 segment in a voltage‐dependent calcium‐sensitive potassium (hSlo) channel. J Biol Chem 273: 32430‐32436, 1998.
 111. Diness TG, Yeh YH, Qi XY, Chartier D, Tsuji Y, Hansen RS, Olesen SP, Grunnet M, Nattel S. Antiarrhythmic properties of a rapid delayed‐rectifier current activator in rabbit models of acquired long QT syndrome. Cardiovasc Res 79: 61‐69, 2008.
 112. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U. The G protein‐gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation 112: 3697‐3706, 2005.
 113. Dougherty K, De Santiago‐Castillo JA, Covarrubias M. Gating charge immobilization in Kv4.2 channels: The basis of closed‐state inactivation. J Gen Physiol 131: 257‐273, 2008.
 114. Douglas RM, Lai JC, Bian S, Cummins L, Moczydlowski E, Haddad GG. The calcium‐sensitive large‐conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain. Neuroscience 139: 1249‐1261, 2006.
 115. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R. The structure of the potassium channel: Molecular basis of K+ conduction and selectivity. Science 280: 69‐77, 1998.
 116. Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion. Pharmacol Rev 55: 105‐131, 2003.
 117. Dryer SE. Na(+)‐activated K+ channels: A new family of large‐conductance ion channels. Trends Neurosci 17: 155‐160, 1994.
 118. Dryer SE, Fujii JT, Martin AR. A Na+‐activated K+ current in cultured brain stem neurones from chicks. J Physiol 410: 283‐296, 1989.
 119. Du W, Bautista JF, Yang H, Diez‐Sampedro A, You SA, Wang L, Kotagal P, Luders HO, Shi J, Cui J, Richerson GB, Wang QK. Calcium‐sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37: 733‐738, 2005.
 120. Dufer M, Neye Y, Horth K, Krippeit‐Drews P, Hennige A, Widmer H, McClafferty H, Shipston MJ, Haring HU, Ruth P, Drews G. BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells. Diabetologia 54: 423‐432, 2011.
 121. Dunn PM. Dequalinium, a selective blocker of the slow afterhyperpolarization in rat sympathetic neurones in culture. Eur J Pharmacol 252: 189‐194, 1994.
 122. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16: 5464‐5471, 1997.
 123. Edgerton JR, Reinhart PH. Distinct contributions of small and large conductance Ca2+‐activated K+ channels to rat Purkinje neuron function. J Physiol 548: 53‐69, 2003.
 124. Egan TM, Dagan D, Kupper J, Levitan IB. Properties and rundown of sodium‐activated potassium channels in rat olfactory bulb neurons. J Neurosci 12: 1964‐1976, 1992.
 125. Eisenman G, Latorre R, Miller C. Multi‐ion conduction and selectivity in the high‐conductance Ca++‐activated K+ channel from skeletal muscle. Biophys J 50: 1025‐1034, 1986.
 126. Elgoyhen AB, Johnson DS, Boulter J, Vetter DE, Heinemann S. Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79: 705‐715, 1994.
 127. Elkins T, Ganetzky B, Wu CF. A Drosophila mutation that eliminates a calcium‐dependent potassium current. Proc Natl Acad Sci U S A 83: 8415‐8419, 1986.
 128. Enyedi P, Czirjak G. Molecular background of leak K+ currents: Two‐pore domain potassium channels. Physiol Rev 90: 559‐605, 2010.
 129. Faber ES. Functions and modulation of neuronal SK channels. Cell Biochem Biophys 55: 127‐139, 2009.
 130. Faber ES, Sah P. Physiological role of calcium‐activated potassium currents in the rat lateral amygdala. J Neurosci 22: 1618‐1628, 2002.
 131. Fakler B, Adelman JP. Control of K(Ca) channels by calcium nano/microdomains. Neuron 59: 873‐881, 2008.
 132. Fakler B, Schultz JH, Yang J, Schulte U, Brandle U, Zenner HP, Jan LY, Ruppersberg JP. Identification of a titratable lysine residue that determines sensitivity of kidney potassium channels (ROMK) to intracellular pH. EMBO J 15: 4093‐4099, 1996.
 133. Fang Y, Schram G, Romanenko VG, Shi C, Conti L, Vandenberg CA, Davies PF, Nattel S, Levitan I. Functional expression of Kir2.x in human aortic endothelial cells: The dominant role of Kir2.2. Am J Physiol Cell Physiol 289: C1134‐C1144, 2005.
 134. Fernandez‐Alacid L, Aguado C, Ciruela F, Martin R, Colon J, Cabanero MJ, Gassmann M, Watanabe M, Shigemoto R, Wickman K, Bettler B, Sanchez‐Prieto J, Lujan R. Subcellular compartment‐specific molecular diversity of pre‐ and post‐synaptic GABA‐activated GIRK channels in Purkinje cells. J Neurochem 110: 1363‐1376, 2009.
 135. Fernandez‐Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, Marrugat J, Valverde MA. Gain‐of‐function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 113: 1032‐1039, 2004.
 136. Ferrer J, Nichols CG, Makhina EN, Salkoff L, Bernstein J, Gerhard D, Wasson J, Ramanadham S, Permutt A. Pancreatic islet cells express a family of inwardly rectifying K+ channel subunits which interact to form G‐protein‐activated channels. J Biol Chem 270: 26086‐26091, 1995.
 137. Fettiplace R, Fuchs PA. Mechanisms of hair cell tuning. Annu Rev Physiol 61: 809‐834, 1999.
 138. Figueroa KP, Minassian NA, Stevanin G, Waters M, Garibyan V, Forlani S, Strzelczyk A, Burk K, Brice A, Durr A, Papazian DM, Pulst SM. KCNC3: phenotype, mutations, channel biophysics‐a study of 260 familial ataxia patients. Hum Mutat 31: 191‐196.
 139. Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, Nelson MT. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9: 1397‐1403, 2006.
 140. Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, Lazdunski M. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K +channel. EMBO J 15: 6854‐6862, 1996.
 141. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M. A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J 17: 3297‐3308, 1998.
 142. FitzHugh R. An electronic model of the nerve membrane for demonstration purposes. J Appl Physiol 21: 305‐308, 1966a.
 143. Fitzhugh R. Theoretical effect of temperature on threshold in the Hodgkin‐Huxley nerve model. J Gen Physiol 49: 989‐1005, 1966b.
 144. Fleidervish IA, Lasser‐Ross N, Gutnick MJ, Ross WN. Na+ imaging reveals little difference in action potential‐evoked Na+ influx between axon and soma. Nat Neurosci 13: 852‐860, 2010.
 145. Fowler CE, Aryal P, Suen KF, Slesinger PA. Evidence for association of GABA(B) receptors with Kir3 channels and regulators of G protein signalling (RGS4) proteins. J Physiol 580: 51‐65, 2007.
 146. Franceschetti S, Lavazza T, Curia G, Aracri P, Panzica F, Sancini G, Avanzini G, Magistretti J. Na+‐activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons. J Neurophysiol 89: 2101‐2111, 2003.
 147. Franks NP, Honore E. The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci 25: 601‐608, 2004.
 148. Fukushima N. LPA in neural cell development. J Cell Biochem 92: 993‐1003, 2004.
 149. Ganfornina MD, Lopez‐Barneo J. Potassium channel types in arterial chemoreceptor cells and their selective modulation by oxygen. J Gen Physiol 100: 401‐426, 1992.
 150. Geiger JR, Jonas P. Dynamic control of presynaptic Ca(2+) inflow by fast‐inactivating K(+) channels in hippocampal mossy fiber boutons. Neuron 28: 927‐939, 2000.
 151. Ghatta S, Nimmagadda D, Xu X, O'Rourke ST. Large‐conductance, calcium‐activated potassium channels: Structural and functional implications. Pharmacol Ther 110: 103‐116, 2006.
 152. Giangiacomo KM, Becker J, Garsky C, Schmalhofer W, Garcia ML, Mullmann TJ. Novel alpha‐KTx sites in the BK channel and comparative sequence analysis reveal distinguishing features of the BK and KV channel outer pore. Cell Biochem Biophys 52: 47‐58, 2008.
 153. Giangiacomo KM, Garcia ML, McManus OB. Mechanism of iberiotoxin block of the large‐conductance calcium‐activated potassium channel from bovine aortic smooth muscle. Biochemistry 31: 6719‐6727, 1992.
 154. Gil Z, Magleby KL, Silberberg SD. Membrane‐pipette interactions underlie delayed voltage activation of mechanosensitive channels in Xenopus oocytes. Biophys J 76: 3118‐3127, 1999.
 155. Glauner KS, Mannuzzu LM, Gandhi CS, Isacoff EY. Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel. Nature 402: 813‐817, 1999.
 156. Gola M, Crest M. Colocalization of active KCa channels and Ca2+ channels within Ca2+ domains in helix neurons. Neuron 10: 689‐699, 1993.
 157. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S. International Union of Pharmacology. LV. Nomenclature and molecular relationships of two‐P potassium channels. Pharmacol Rev 57: 527‐540, 2005.
 158. Goldstein SA, Price LA, Rosenthal DN, Pausch MH. ORK1, a potassium‐selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 93: 13256‐13261, 1996.
 159. Gonzalez‐Perez V, Neely A, Tapia C, Gonzalez‐Gutierrez G, Contreras G, Orio P, Lagos V, Rojas G, Estevez T, Stack K, Naranjo D. Slow inactivation in Shaker K channels is delayed by intracellular tetraethylammonium. J Gen Physiol 132: 633‐650, 2008.
 160. Gonzalez‐Perez V, Stack K, Boric K, Naranjo D. Reduced voltage sensitivity in a K+‐channel voltage sensor by electric field remodeling. Proc Natl Acad Sci U S A 107: 5178‐5183.
 161. Gonzalez C, Koch HP, Drum BM, Larsson HP. Strong cooperativity between subunits in voltage‐gated proton channels. Nature structural & molecular biology 17: 51‐56, 2010.
 162. Gonzalez C, Morera FJ, Rosenmann E, Alvarez O, Latorre R. S3b amino acid residues do not shuttle across the bilayer in voltage‐dependent Shaker K+ channels. Proc Natl Acad Sci U S A 102: 5020‐5025, 2005.
 163. Gonzalez C, Rosenman E, Bezanilla F, Alvarez O, Latorre R. Modulation of the Shaker K(+) channel gating kinetics by the S3‐S4 linker. J Gen Physiol 115: 193‐208, 2000.
 164. Gonzalez C, Rosenman E, Bezanilla F, Alvarez O, Latorre R. Periodic perturbations in Shaker K+channel gating kinetics by deletions in the S3‐S4 linker. Proc Natl Acad Sci U S A 98: 9617‐9623, 2001.
 165. Graulich A, Dilly S, Farce A, Scuvee‐Moreau J, Waroux O, Lamy C, Chavatte P, Seutin V, Liegeois JF. Synthesis and radioligand binding studies of bis‐isoquinolinium derivatives as small conductance Ca(2+)‐activated K(+) channel blockers. J Med Chem 50: 5070‐5075, 2007.
 166. Graulich A, Lamy C, Alleva L, Dilly S, Chavatte P, Wouters J, Seutin V, Liegeois JF. Bis‐tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non‐quaternary non‐peptidic small conductance Ca(2+)‐activated K(+) channel blockers. Bioorg Med Chem Lett 18: 3440‐3445, 2008.
 167. Graulich A, Mercier F, Scuvee‐Moreau J, Seutin V, Liegeois JF. Synthesis and biological evaluation of N‐methyl‐laudanosine iodide analogues as potential SK channel blockers. Bioorg Med Chem 13: 1201‐1209, 2005.
 168. Gribkoff VK, Lum‐Ragan JT, Boissard CG, Post‐Munson DJ, Meanwell NA, Starrett JE Jr., Kozlowski ES, Romine JL, Trojnacki JT, McKay MC, Zhong J, Dworetzky SI. Effects of channel modulators on cloned large‐conductance calcium‐activated potassium channels. Mol Pharmacol 50: 206‐217, 1996.
 169. Grimm PR, Foutz RM, Brenner R, Sansom SC. Identification and localization of BK‐beta subunits in the distal nephron of the mouse kidney. Am J Physiol Renal Physiol 293: F350‐F359, 2007.
 170. Grimm PR, Sansom SC. BK channels and a new form of hypertension. Kidney Int 78: 956‐962, 2010.
 171. Grissmer S, Nguyen AN, Aiyar J, Hanson DC, Mather RJ, Gutman GA, Karmilowicz MJ, Auperin DD, Chandy KG. Pharmacological characterization of five cloned voltage‐gated K +channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol 45: 1227‐1234, 1994.
 172. Gross GJ, Auchampach JA. Blockade of ATP‐sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 70: 223‐233, 1992.
 173. Grunnet M, Jespersen T, Angelo K, Frokjaer‐Jensen C, Klaerke DA, Olesen SP, Jensen BS. Pharmacological modulation of SK3 channels. Neuropharmacology 40: 879‐887, 2001.
 174. Grunnet M, Kaufmann WA. Coassembly of big conductance Ca2+‐activated K+ channels and L‐type voltage‐gated Ca2+ channels in rat brain. J Biol Chem 279: 36445‐36453, 2004.
 175. Gu N, Hu H, Vervaeke K, Storm JF. SK (KCa2) channels do not control somatic excitability in CA1 pyramidal neurons but can be activated by dendritic excitatory synapses and regulate their impact. J Neurophysiol 100: 2589‐2604, 2008.
 176. Gu N, Vervaeke K, Hu H, Storm JF. Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after‐hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J Physiol 566: 689‐715, 2005.
 177. Gu N, Vervaeke K, Storm JF. BK potassium channels facilitate high‐frequency firing and cause early spike frequency adaptation in rat CA1 hippocampal pyramidal cells. J Physiol 580: 859‐882, 2007.
 178. Gumina RJ, Pucar D, Bast P, Hodgson DM, Kurtz CE, Dzeja PP, Miki T, Seino S, Terzic A. Knockout of Kir6.2 negates ischemic preconditioning‐induced protection of myocardial energetics. Am J Physiol Heart Circ Physiol 284: H2106‐H2113, 2003.
 179. Guo D, Ramu Y, Klem AM, Lu Z. Mechanism of rectification in inward‐rectifier K+ channels. J Gen Physiol 121: 261‐275, 2003.
 180. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, Nerbonne JM. Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ Res 90: 586‐593, 2002.
 181. Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stuhmer W, Wang X. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage‐gated potassium channels. Pharmacol Rev 57: 473‐508, 2005.
 182. Guy HR, Seetharamulu P. Molecular model of the action potential sodium channel. Proc Natl Acad Sci U S A 83: 508‐512, 1986.
 183. Ha TS, Heo MS, Park CS. Functional effects of auxiliary beta4‐subunit on rat large‐conductance Ca(2+)‐activated K(+) channel. Biophys J 86: 2871‐2882, 2004.
 184. Hackos DH, Chang TH, Swartz KJ. Scanning the intracellular S6 activation gate in the shaker K +channel. J Gen Physiol 119: 521‐532, 2002.
 185. Hagiwara S, Miyazaki S, Rosenthal NP. Potassium current and the effect of cesium on this current during anomalous rectification of the egg cell membrane of a starfish. J Gen Physiol 67: 621‐638, 1976.
 186. Hallworth NE, Wilson CJ, Bevan MD. Apamin‐sensitive small conductance calcium‐activated potassium channels, through their selective coupling to voltage‐gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. J Neurosci 23: 7525‐7542, 2003.
 187. Han J, Kang D, Kim D. Functional properties of four splice variants of a human pancreatic tandem‐pore K+ channel, TALK‐1. Am J Physiol Cell Physiol 285: C529‐C538, 2003.
 188. Han X, Light PE, Giles WR, French RJ. Identification and properties of an ATP‐sensitive K+ current in rabbit sino‐atrial node pacemaker cells. J Physiol 490(Pt 2): 337‐350, 1996.
 189. Hansen RS, Diness TG, Christ T, Demnitz J, Ravens U, Olesen SP, Grunnet M. Activation of human ether‐a‐go‐go‐related gene potassium channels by the diphenylurea 1,3‐bis‐(2‐hydroxy‐5‐trifluoromethyl‐phenyl)‐urea (NS1643). Mol Pharmacol 69: 266‐277, 2006.
 190. Haug T, Sigg D, Ciani S, Toro L, Stefani E, Olcese R. Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part I: Aspartate 292 modulates K+ conduction by external surface charge effect. J Gen Physiol 124: 173‐184, 2004.
 191. He C, Zhang H, Mirshahi T, Logothetis DE. Identification of a potassium channel site that interacts with G protein betagamma subunits to mediate agonist‐induced signaling. J Biol Chem 274: 12517‐12524, 1999.
 192. Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity and regulation of renal potassium channels. Physiol Rev 85: 319‐371, 2005.
 193. Heginbotham L, Lu Z, Abramson T, MacKinnon R. Mutations in the K+ channel signature sequence. Biophys J 66: 1061‐1067, 1994.
 194. Heginbotham L, MacKinnon R. The aromatic binding site for tetraethylammonium ion on potassium channels. Neuron 8: 483‐491, 1992.
 195. Heinemann SH, Rettig J, Graack HR, Pongs O. Functional characterization of Kv channel beta‐subunits from rat brain. J Physiol 493(Pt 3): 625‐633, 1996.
 196. Hermanstyne TO, Kihira Y, Misono K, Deitchler A, Yanagawa Y, Misonou H. Immunolocalization of the voltage‐gated potassium channel Kv2.2 in GABAergic neurons in the basal forebrain of rats and mice. J Comp Neurol 518: 4298‐4310.
 197. Hervieu GJ, Cluderay JE, Gray CW, Green PJ, Ranson JL, Randall AD, Meadows HJ. Distribution and expression of TREK‐1, a two‐pore‐domain potassium channel, in the adult rat CNS. Neuroscience 103: 899‐919, 2001.
 198. Hess D, Nanou E, El Manira A. Characterization of Na+‐activated K+ currents in larval lamprey spinal cord neurons. J Neurophysiol 97: 3484‐3493, 2007.
 199. Hess P, Tsien RW. Mechanism of ion permeation through calcium channels. Nature 309: 453‐456, 1984.
 200. Hessa T, White SH, von Heijne G. Membrane insertion of a potassium‐channel voltage sensor. Science 307: 1427, 2005.
 201. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang‐Lazdunski L, Widmann C, Zanzouri M, Romey G, Lazdunski M. TREK‐1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23: 2684‐2695, 2004.
 202. Hibino H, Fujita A, Iwai K, Yamada M, Kurachi Y. Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. J Biol Chem 279: 44065‐44073, 2004.
 203. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: Their structure, function, and physiological roles. Physiol Rev 90: 291‐366, 2010.
 204. Hibino H, Kurachi Y. Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology (Bethesda) 21: 336‐345, 2006.
 205. Hibino H, Nin F, Tsuzuki C, Kurachi Y. How is the highly positive endocochlear potential formed? The specific architecture of the stria vascularis and the roles of the ion‐transport apparatus. Pflugers Arch 459: 521‐533, 2010.
 206. Hicks GA, Marrion NV. Ca2+‐dependent inactivation of large conductance Ca2+‐activated K+ (BK) channels in rat hippocampal neurones produced by pore block from an associated particle. J Physiol 508(Pt 3): 721‐734, 1998.
 207. Ho IH, Murrell‐Lagnado RD. Molecular determinants for sodium‐dependent activation of G protein‐gated K+ channels. J Biol Chem 274: 8639‐8648, 1999.
 208. Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol 116: 449‐472, 1952a.
 209. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117: 500‐544, 1952b.
 210. Hodgkin AL, Keynes RD. The potassium permeability of a giant nerve fibre. J Physiol 128: 61‐88, 1955.
 211. Holmgren M, Shin KS, Yellen G. The activation gate of a voltage‐gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron 21: 617‐621, 1998.
 212. Holmgren M, Smith PL, Yellen G. Trapping of organic blockers by closing of voltage‐dependent K+ channels: Evidence for a trap door mechanism of activation gating. J Gen Physiol 109: 527‐535, 1997.
 213. Honore E. The neuronal background K2P channels: Focus on TREK1. Nat Rev Neurosci 8: 251‐261, 2007.
 214. Honore E, Maingret F, Lazdunski M, Patel AJ. An intracellular proton sensor commands lipid‐ and mechano‐gating of the K(+) channel TREK‐1. EMBO J 21: 2968‐2976, 2002.
 215. Horn R. Electrifying phosphatases. Sci STKE 2005: pe50, 2005.
 216. Horrigan FT, Aldrich RW. Allosteric voltage gating of potassium channels II. Mslo channel gating charge movement in the absence of Ca(2+). J Gen Physiol 114: 305‐336, 1999.
 217. Horrigan FT, Aldrich RW. Coupling between voltage sensor activation, Ca2+ binding and channel opening in large conductance (BK) potassium channels. J Gen Physiol 120: 267‐305, 2002.
 218. Horrigan FT, Cui J, Aldrich RW. Allosteric voltage gating of potassium channels I. Mslo ionic currents in the absence of Ca(2+). J Gen Physiol 114: 277‐304, 1999.
 219. Hoshi T, Zagotta WN, Aldrich RW. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250: 533‐538, 1990.
 220. Hoshi T, Zagotta WN, Aldrich RW. Shaker potassium channel gating. I: Transitions near the open state. J Gen Physiol 103: 249‐278, 1994.
 221. Hoshi T, Zagotta WN, Aldrich RW. Two types of inactivation in Shaker K+ channels: Effects of alterations in the carboxy‐terminal region. Neuron 7: 547‐556, 1991.
 222. Hu H, Shao LR, Chavoshy S, Gu N, Trieb M, Behrens R, Laake P, Pongs O, Knaus HG, Ottersen OP, Storm JF. Presynaptic Ca2+‐activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J Neurosci 21: 9585‐9597, 2001.
 223. Huang CL, Feng S, Hilgemann DW. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature 391: 803‐806, 1998.
 224. Hugnot JP, Salinas M, Lesage F, Guillemare E, de Weille J, Heurteaux C, Mattei MG, Lazdunski M. Kv8.1, a new neuronal potassium channel subunit with specific inhibitory properties towards Shab and Shaw channels. EMBO J 15: 3322‐3331, 1996.
 225. Ilan N, Goldstein SA. Kcnko: Single, cloned potassium leak channels are multi‐ion pores. Biophys J 80: 241‐253, 2001.
 226. Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar‐Bryan L, Bryan J, Seino S. A family of sulfonylurea receptors determines the pharmacological properties of ATP‐sensitive K+ channels. Neuron 16: 1011‐1017, 1996.
 227. Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, Aguilar‐Bryan L, Seino S, Bryan J. Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science 270: 1166‐1170, 1995.
 228. Ishii TM, Maylie J, Adelman JP. Determinants of apamin and d‐tubocurarine block in SK potassium channels. J Biol Chem 272: 23195‐23200, 1997.
 229. Islas LD, Sigworth FJ. Voltage sensitivity and gating charge in Shaker and Shab family potassium channels. J Gen Physiol 114: 723‐742, 1999.
 230. Islas LD, Sigworth FJ. Electrostatics and the gating pore of Shaker potassium channels. J Gen Physiol 117: 69‐89, 2001.
 231. Ivanina T, Rishal I, Varon D, Mullner C, Frohnwieser‐Steinecke B, Schreibmayer W, Dessauer CW, Dascal N. Mapping the Gbetagamma‐binding sites in GIRK1 and GIRK2 subunits of the G protein‐activated K+ channel. J Biol Chem 278: 29174‐29183, 2003.
 232. Iwanir S, Reuveny E. Adrenaline‐induced hyperpolarization of mouse pancreatic islet cells is mediated by G protein‐gated inwardly rectifying potassium (GIRK) channels. Pflugers Arch 456: 1097‐1108, 2008.
 233. Jaggar JH, Porter VA, Lederer WJ, Nelson MT. Calcium sparks in smooth muscle. Am J Physiol Cell Physiol 278: C235‐C256, 2000.
 234. Jelacic TM, Kennedy ME, Wickman K, Clapham DE. Functional and biochemical evidence for G‐protein‐gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3. J Biol Chem 275: 36211‐36216, 2000.
 235. Jiang X, Bett GC, Li X, Bondarenko VE, Rasmusson RL. C‐type inactivation involves a significant decrease in the intracellular aqueous pore volume of Kv1.4 K+ channels expressed in Xenopus oocytes. J Physiol 549: 683‐695, 2003.
 236. Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R. Crystal structure and mechanism of a calcium‐gated potassium channel. Nature 417: 515‐522, 2002a.
 237. Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R. The open pore conformation of potassium channels. Nature 417: 523‐526, 2002b.
 238. Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R. X‐ray structure of a voltage‐dependent K+ channel. Nature 423: 33‐41, 2003.
 239. Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R. Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel. Neuron 29: 593‐601, 2001.
 240. Jiang Y, Ruta V, Chen J, Lee A, MacKinnon R. The principle of gating charge movement in a voltage‐dependent K+ channel. Nature 423: 42‐48, 2003.
 241. Jin W, Lu Z. A novel high‐affinity inhibitor for inward‐rectifier K+ channels. Biochemistry 37: 13291‐13299, 1998.
 242. Jin W, Lu Z. Synthesis of a stable form of tertiapin: A high‐affinity inhibitor for inward‐rectifier K+ channels. Biochemistry 38: 14286‐14293, 1999.
 243. Jogini V, Roux B. Dynamics of the Kv1.2 voltage‐gated K+ channel in a membrane environment. Biophys J 93: 3070‐3082, 2007.
 244. Johansson AC, Lindahl E. Amino‐acid solvation structure in transmembrane helices from molecular dynamics simulations. Biophys J 91: 4450‐4463, 2006.
 245. Johnson SW, Seutin V. Bicuculline methiodide potentiates NMDA‐dependent burst firing in rat dopamine neurons by blocking apamin‐sensitive Ca2+‐activated K+ currents. Neurosci Lett 231: 13‐16, 1997.
 246. Joiner WJ, Khanna R, Schlichter LC, Kaczmarek LK. Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+‐activated K+ channels. J Biol Chem 276: 37980‐37985, 2001.
 247. Joiner WJ, Tang MD, Wang LY, Dworetzky SI, Boissard CG, Gan L, Gribkoff VK, Kaczmarek LK. Formation of intermediate‐conductance calcium‐activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci 1: 462‐469, 1998.
 248. Jones EM, Laus C, Fettiplace R. Identification of Ca(2+)‐activated K+ channel splice variants and their distribution in the turtle cochlea. Proc Bioll Sci 265: 685‐692, 1998.
 249. Kalman K, Pennington MW, Lanigan MD, Nguyen A, Rauer H, Mahnir V, Paschetto K, Kem WR, Grissmer S, Gutman GA, Christian EP, Cahalan MD, Norton RS, Chandy KG. ShK‐Dap22, a potent Kv1.3‐specific immunosuppressive polypeptide. J Biol Chem 273: 32697‐32707, 1998.
 250. Kamb A, Iverson LE, Tanouye MA. Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel. Cell 50: 405‐413, 1987.
 251. Kameyama M, Kakei M, Sato R, Shibasaki T, Matsuda H, Irisawa H. Intracellular Na+ activates a K +channel in mammalian cardiac cells. Nature 309: 354‐356, 1984.
 252. Kane GC, Liu XK, Yamada S, Olson TM, Terzic A. Cardiac KATP channels in health and disease. J Mol Cell Cardiol 38: 937‐943, 2005.
 253. Kang D, Choe C, Kim D. Thermosensitivity of the two‐pore domain K+ channels TREK‐2 and TRAAK. J Physiol 564: 103‐116, 2005.
 254. Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D. Discovery of a small molecule activator of the human ether‐a‐go‐go‐related gene (HERG) cardiac K+ channel. Mol Pharmacol 67: 827‐836, 2005.
 255. Katz B. Les constantes electriques de la membrane du muscle. Arch Sci Physiol 3: 285‐299, 1949.
 256. Keen JE, Khawaled R, Farrens DL, Neelands T, Rivard A, Bond CT, Janowsky A, Fakler B, Adelman JP, Maylie J. Domains responsible for constitutive and Ca(2+)‐dependent interactions between calmodulin and small conductance Ca(2+)‐activated potassium channels. J Neurosci 19: 8830‐8838, 1999.
 257. Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, Goldstein SA. A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem. Nature 376: 690‐695, 1995.
 258. Keynes RD, Rojas E. Kinetics and steady‐state properties of the charged system controlling sodium conductance in the squid giant axon. J Physiol 239: 393‐434, 1974.
 259. Kihira Y, Hermanstyne TO, Misonou H. Formation of heteromeric Kv2 channels in mammalian brain neurons. J Biol Chem 285: 15048‐15055.
 260. Kim D. Fatty acid‐sensitive two‐pore domain K+ channels. Trends Pharmacol Sci 24: 648‐654, 2003.
 261. Kim D, Clapham DE. Potassium channels in cardiac cells activated by arachidonic acid and phospholipids. Science 244: 1174‐1176, 1989.
 262. Kim D, Fujita A, Horio Y, Kurachi Y. Cloning and functional expression of a novel cardiac two‐pore background K+ channel (cTBAK‐1). Circ Res 82: 513‐518, 1998.
 263. Kim Y, Bang H, Kim D. TASK‐3, a new member of the tandem pore K(+) channel family. J Biol Chem 275: 9340‐9347, 2000.
 264. Kim Y, Gnatenco C, Bang H, Kim D. Localization of TREK‐2 K+ channel domains that regulate channel kinetics and sensitivity to pressure, fatty acids and pHi. Pflugers Arch 442: 952‐960, 2001.
 265. Klement G, Nilsson J, Arhem P, Elinder F. A tyrosine substitution in the cavity wall of a k channel induces an inverted inactivation. Biophys J 94: 3014‐3022, 2008.
 266. Klemic KG, Kirsch GE, Jones SW. U‐type inactivation of Kv3.1 and Shaker potassium channels. Biophys J 81: 814‐826, 2001.
 267. Knaus HG, Folander K, Garcia‐Calvo M, Garcia ML, Kaczorowski GJ, Smith M, Swanson R. Primary sequence and immunological characterization of beta‐subunit of high conductance Ca(2+)‐activated K+ channel from smooth muscle. J Biol Chem 269: 17274‐17278, 1994.
 268. Knot HJ, Zimmermann PA, Nelson MT. Extracellular K(+)‐induced hyperpolarizations and dilatations of rat coronary and cerebral arteries involve inward rectifier K(+) channels. J Physiol 492(Pt 2): 419‐430, 1996.
 269. Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis DE. Receptor‐mediated hydrolysis of plasma membrane messenger PIP2 leads to K+‐current desensitization. Nat Cell Biol 2: 507‐514, 2000.
 270. Kofuji P, Davidson N, Lester HA. Evidence that neuronal G‐protein‐gated inwardly rectifying K+ channels are activated by G beta gamma subunits and function as heteromultimers. Proc Natl Acad Sci U S A 92: 6542‐6546, 1995.
 271. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP. Small‐conductance, calcium‐activated potassium channels from mammalian brain. Science 273: 1709‐1714, 1996.
 272. Kole MH, Ilschner SU, Kampa BM, Williams SR, Ruben PC, Stuart GJ. Action potential generation requires a high sodium channel density in the axon initial segment. Nat Neurosci 11: 178‐186, 2008.
 273. Kollewe A, Lau AY, Sullivan A, Roux B, Goldstein SA. A structural model for K2P potassium channels based on 23 pairs of interacting sites and continuum electrostatics. J Gen Physiol 134: 53‐68, 2009.
 274. Koval OM, Fan Y, Rothberg BS. A role for the S0 transmembrane segment in voltage‐dependent gating of BK channels. J Gen Physiol 129: 209‐220, 2007.
 275. Koyrakh L, Lujan R, Colon J, Karschin C, Kurachi Y, Karschin A, Wickman K. Molecular and cellular diversity of neuronal G‐protein‐gated potassium channels. J Neurosci 25: 11468‐11478, 2005.
 276. Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. The G‐protein‐gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)‐channel proteins. Nature 374: 135‐141, 1995.
 277. Krapivinsky G, Medina I, Eng L, Krapivinsky L, Yang Y, Clapham DE. A novel inward rectifier K+ channel with unique pore properties. Neuron 20: 995‐1005, 1998.
 278. Krepkiy D, Mihailescu M, Freites JA, Schow EV, Worcester DL, Gawrisch K, Tobias DJ, White SH, Swartz KJ. Structure and hydration of membranes embedded with voltage‐sensing domains. Nature 462: 473‐479, 2009.
 279. Kreusch A, Pfaffinger PJ, Stevens CF, Choe S. Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392: 945‐948, 1998.
 280. Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA. International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol Rev 57: 509‐526, 2005.
 281. Kubo Y, Murata Y. Control of rectification and permeation by two distinct sites after the second transmembrane region in Kir2.1 K+ channel. J Physiol 531: 645‐660, 2001.
 282. Kung C. A possible unifying principle for mechanosensation. Nature 436: 647‐654, 2005.
 283. Kunkel MT, Peralta EG. Identification of domains conferring G protein regulation on inward rectifier potassium channels. Cell 83: 443‐449, 1995.
 284. Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA. Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300: 1922‐1926, 2003.
 285. Kurachi Y, Ito H, Sugimoto T, Katada T, Ui M. Activation of atrial muscarinic K+ channels by low concentrations of beta gamma subunits of rat brain G protein. Pflugers Arch 413: 325‐327, 1989.
 286. Kurachi Y, Nakajima T, Sugimoto T. On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: Involvement of GTP‐binding proteins. Pflugers Arch 407: 264‐274, 1986.
 287. Kurata HT, Doerksen KW, Eldstrom JR, Rezazadeh S, Fedida D. Separation of P/C‐ and U‐type inactivation pathways in Kv1.5 potassium channels. J Physiol 568: 31‐46, 2005.
 288. Kwan HY, Leung PC, Huang Y, Yao X. Depletion of intracellular Ca2+ stores sensitizes the flow‐induced Ca2+ influx in rat endothelial cells. Circ Res 92: 286‐292, 2003.
 289. Lagrutta A, Shen KZ, North RA, Adelman JP. Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium‐activated potassium channel. J Biol Chem 269: 20347‐20351, 1994.
 290. Lancaster B, Nicoll RA. Properties of two calcium‐activated hyperpolarizations in rat hippocampal neurones. J Physiol 389: 187‐203, 1987.
 291. Langer P, Grunder S, Rusch A. Expression of Ca2+‐activated BK channel mRNA and its splice variants in the rat cochlea. J Comp Neurol 455: 198‐209, 2003.
 292. Larsen AP, Bentzen BH, Grunnet M. Differential effects of Kv11.1 activators on Kv11.1a, Kv11.1b and Kv11.1a/Kv11.1b channels. Br J Pharmacol 161: 614‐628, 2010.
 293. Larsson HP, Baker OS, Dhillon DS, Isacoff EY. Transmembrane movement of the shaker K+ channel S4. Neuron 16: 387‐397, 1996.
 294. Larsson HP, Elinder F. A conserved glutamate is important for slow inactivation in K+ channels. Neuron 27: 573‐583, 2000.
 295. Latorre R, Morera FJ, Zaelzer C. Allosteric interactions and the modular nature of the voltage‐ and Ca2+‐activated (BK) channel. J Physiol 588: 3141‐3148, 2010.
 296. Latorre R, Vergara C, Hidalgo C. Reconstitution in planar lipid bilayers of a Ca2+‐dependent K +channel from transverse tubule membranes isolated from rabbit skeletal muscle. Proc Natl Acad Sci U S A 79: 805‐809, 1982.
 297. Ledoux J, Werner ME, Brayden JE, Nelson MT. Calcium‐activated potassium channels and the regulation of vascular tone. Physiology (Bethesda) 21: 69‐78, 2006.
 298. Lee K, Dixon AK, Richardson PJ, Pinnock RD. Glucose‐receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir6.1 and SUR1 subunits. J Physiol 515(Pt 2): 439‐452, 1999.
 299. Lee SY, Banerjee A, MacKinnon R. Two separate interfaces between the voltage sensor and pore are required for the function of voltage‐dependent K(+) channels. PLoS Biol 7: e47, 2009.
 300. Lee WS, Ngo‐Anh TJ, Bruening‐Wright A, Maylie J, Adelman JP. Small conductance Ca2+‐activated K +channels and calmodulin: Cell surface expression and gating. J Biol Chem 278: 25940‐25946, 2003.
 301. Lei Q, Talley EM, Bayliss DA. Receptor‐mediated inhibition of G protein‐coupled inwardly rectifying potassium channels involves G(alpha)q family subunits, phospholipase C, and a readily diffusible messenger. J Biol Chem 276: 16720‐16730, 2001.
 302. Leonoudakis D, Gray AT, Winegar BD, Kindler CH, Harada M, Taylor DM, Chavez RA, Forsayeth JR, Yost CS. An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum. J Neurosci 18: 868‐877, 1998.
 303. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, Romey G, Barhanin J, Lazdunski M. Molecular properties of neuronal G‐protein‐activated inwardly rectifying K+ channels. J Biol Chem 270: 28660‐28667, 1995.
 304. Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J. TWIK‐1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J 15: 1004‐1011, 1996.
 305. Lesage F, Lazdunski M. Molecular and functional properties of two‐pore‐domain potassium channels. Am J Physiol Renal Physiol 279: F793‐F801, 2000.
 306. Lesage F, Reyes R, Fink M, Duprat F, Guillemare E, Lazdunski M. Dimerization of TWIK‐1 K+ channel subunits via a disulfide bridge. EMBO J 15: 6400‐6407, 1996.
 307. Li‐Smerin Y, Hackos DH, Swartz KJ. alpha‐helical structural elements within the voltage‐sensing domains of a K(+) channel. J Gen Physiol 115: 33‐50, 2000.
 308. Li M, Jan YN, Jan LY. Specification of subunit assembly by the hydrophilic amino‐terminal domain of the Shaker potassium channel. Science 257: 1225‐1230, 1992.
 309. Li W, Gao SB, Lv CX, Wu Y, Guo ZH, Ding JP, Xu T. Characterization of voltage‐and Ca2+‐activated K+ channels in rat dorsal root ganglion neurons. J Cell Physiol 212: 348‐357, 2007.
 310. Lichter‐Konecki U, Mangin JM, Gordish‐Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia 56: 365‐377, 2008.
 311. Liman ER, Tytgat J, Hess P. Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs. Neuron 9: 861‐871, 1992.
 312. Liu G, Zakharov SI, Yang L, Deng SX, Landry DW, Karlin A, Marx SO. Position and role of the BK channel alpha subunit S0 helix inferred from disulfide crosslinking. J Gen Physiol 131: 537‐548, 2008.
 313. Liu Y, Holmgren M, Jurman ME, Yellen G. Gated access to the pore of a voltage‐dependent K+ channel. Neuron 19: 175‐184, 1997.
 314. Lodge NJ, Li YW. Ion channels as potential targets for the treatment of depression. Curr Opin Drug Discov Devel 11: 633‐641, 2008.
 315. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. The beta gamma subunits of GTP‐binding proteins activate the muscarinic K+ channel in heart. Nature 325: 321‐326, 1987.
 316. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage‐dependent Shaker family K+ channel. Science 309: 897‐903, 2005a.
 317. Long SB, Campbell EB, Mackinnon R. Voltage sensor of Kv1.2: Structural basis of electromechanical coupling. Science 309: 903‐908, 2005b.
 318. Long SB, Tao X, Campbell EB, MacKinnon R. Atomic structure of a voltage‐dependent K+ channel in a lipid membrane‐like environment. Nature 450: 376‐382, 2007.
 319. Lopatin AN, Makhina EN, Nichols CG. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372: 366‐369, 1994.
 320. Lopatin AN, Makhina EN, Nichols CG. The mechanism of inward rectification of potassium channels: “Long‐pore plugging” by cytoplasmic polyamines. J Gen Physiol 106: 923‐955, 1995.
 321. Lopatin AN, Nichols CG. [K+] dependence of open‐channel conductance in cloned inward rectifier potassium channels (IRK1, Kir2.1). Biophys J 71: 682‐694, 1996.
 322. Lopes CM, Gallagher PG, Buck ME, Butler MH, Goldstein SA. Proton block and voltage gating are potassium‐dependent in the cardiac leak channel Kcnk3. J Biol Chem 275: 16969‐16978, 2000.
 323. Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel‐PIP2 interactions underlie channelopathies. Neuron 34: 933‐944, 2002.
 324. Lopez‐Barneo J, Hoshi T, Heinemann SH, Aldrich RW. Effects of external cations and mutations in the pore region on C‐type inactivation of Shaker potassium channels. Receptors Channels 1: 61‐71, 1993.
 325. Lu Z. Mechanism of rectification in inward‐rectifier K+ channels. Annu Rev Physiol 66: 103‐129, 2004.
 326. Lu Z, Klem AM, Ramu Y. Ion conduction pore is conserved among potassium channels. Nature 413: 809‐813, 2001.
 327. Lu Z, Klem AM, Ramu Y. Coupling between voltage sensors and activation gate in voltage‐gated K +channels. J Gen Physiol 120: 663‐676, 2002.
 328. Lu Z, MacKinnon R. Electrostatic tuning of Mg2+ affinity in an inward‐rectifier K+ channel. Nature 371: 243‐246, 1994.
 329. Lu Z, MacKinnon R. Probing a potassium channel pore with an engineered protonatable site. Biochemistry 34: 13133‐13138, 1995.
 330. Lujan R, Maylie J, Adelman JP. New sites of action for GIRK and SK channels. Nat Rev Neurosci 10: 475‐480, 2009.
 331. Luscher C, Jan LY, Stoffel M, Malenka RC, Nicoll RA. G protein‐coupled inwardly rectifying K +channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19: 687‐695, 1997.
 332. Luscher C, Slesinger PA. Emerging roles for G protein‐gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 11: 301‐315, 2010.
 333. Lv C, Chen M, Gan G, Wang L, Xu T, Ding J. Four‐turn alpha‐helical segment prevents surface expression of the auxiliary hbeta2 subunit of BK‐type channel. J Biol Chem 283: 2709‐2715, 2008.
 334. Ma D, Tang XD, Rogers TB, Welling PA. An andersen‐Tawil syndrome mutation in Kir2.1 (V302M) alters the G‐loop cytoplasmic K+ conduction pathway. J Biol Chem 282: 5781‐5789, 2007.
 335. Ma M, Koester J. The role of K+ currents in frequency‐dependent spike broadening in Aplysia R20 neurons: A dynamic‐clamp analysis. J Neurosci 16: 4089‐4101, 1996.
 336. Ma Z, Lou XJ, Horrigan FT. Role of charged residues in the S1‐S4 voltage sensor of BK channels. J Gen Physiol 127: 309‐328, 2006.
 337. MacKinnon R. Determination of the subunit stoichiometry of a voltage‐activated potassium channel. Nature 350: 232‐235, 1991.
 338. Mackinnon R. Structural biology. Membrane protein insertion and stability. Science 307: 1425‐1426, 2005.
 339. MacKinnon R, Miller C. Mutant potassium channels with altered binding of charybdotoxin, a pore‐blocking peptide inhibitor. Science 245: 1382‐1385, 1989.
 340. Magleby KL. Gating mechanism of BK (Slo1) channels: So near, yet so far. J Gen Physiol 121: 81‐96, 2003.
 341. Maher BJ, Mackinnon RL II, Bai J, Chapman ER, Kelly PT. Activation of postsynaptic Ca(2+) stores modulates glutamate receptor cycling in hippocampal neurons. J Neurophysiol 93: 178‐188, 2005.
 342. Maingret F, Honore E, Lazdunski M, Patel AJ. Molecular basis of the voltage‐dependent gating of TREK‐1, a mechano‐sensitive K(+) channel. Biochem Biophys Res Commun 292: 339‐346, 2002.
 343. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honore E. TREK‐1 is a heat‐activated background K(+) channel. EMBO J 19: 2483‐2491, 2000.
 344. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E. Lysophospholipids open the two‐pore domain mechano‐gated K(+) channels TREK‐1 and TRAAK. J Biol Chem 275: 10128‐10133, 2000.
 345. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honore E. Mechano‐ or acid stimulation, two interactive modes of activation of the TREK‐1 potassium channel. J Biol Chem 274: 26691‐26696, 1999.
 346. Malin SA, Nerbonne JM. Delayed rectifier K+ currents, IK, are encoded by Kv2 alpha‐subunits and regulate tonic firing in mammalian sympathetic neurons. J Neurosci 22: 10094‐10105, 2002.
 347. Mao J, Wang X, Chen F, Wang R, Rojas A, Shi Y, Piao H, Jiang C. Molecular basis for the inhibition of G protein‐coupled inward rectifier K(+) channels by protein kinase C. Proc Natl Acad Sci U S A 101: 1087‐1092, 2004.
 348. Marcantoni A, Vandael DH, Mahapatra S, Carabelli V, Sinnegger‐Brauns MJ, Striessnig J, Carbone E. Loss of Cav1.3 channels reveals the critical role of L‐type and BK channel coupling in pacemaking mouse adrenal chromaffin cells. J Neurosci 30: 491‐504, 2010.
 349. Marcotti W, Johnson SL, Kros CJ. A transiently expressed SK current sustains and modulates action potential activity in immature mouse inner hair cells. J Physiol 560: 691‐708, 2004.
 350. Marcus DC, Wu T, Wangemann P, Kofuji P. KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol Cell Physiol 282: C403‐C407, 2002.
 351. Marrion NV, Tavalin SJ. Selective activation of Ca2+‐activated K+ channels by co‐localized Ca2 +channels in hippocampal neurons. Nature 395: 900‐905, 1998.
 352. Martin GE, Hendrickson LM, Penta KL, Friesen RM, Pietrzykowski AZ, Tapper AR, Treistman SN. Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol. Proc Natl Acad Sci U S A 105: 17543‐17548, 2008.
 353. Martina M, Yao GL, Bean BP. Properties and functional role of voltage‐dependent potassium channels in dendrites of rat cerebellar Purkinje neurons. J Neurosci 23: 5698‐5707, 2003.
 354. Martinac B. Mechanosensitive ion channels: Molecules of mechanotransduction. J Cell Sci 117: 2449‐2460, 2004.
 355. Martinez‐Lopez P, Santi CM, Trevino CL, Ocampo‐Gutierrez AY, Acevedo JJ, Alisio A, Salkoff LB, Darszon A. Mouse sperm K+ currents stimulated by pH and cAMP possibly coded by Slo3 channels. Biochem Biophys Res Commun 381: 204‐209, 2009.
 356. Marty A. Ca‐dependent K channels with large unitary conductance in chromaffin cell membranes. Nature 291: 497‐500, 1981.
 357. Mathur R, Zheng J, Yan Y, Sigworth FJ. Role of the S3‐S4 linker in Shaker potassium channel activation. J Gen Physiol 109: 191‐199, 1997.
 358. Matsuda H, Saigusa A, Irisawa H. Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+. Nature 325: 156‐159, 1987.
 359. Maylie J, Bond CT, Herson PS, Lee WS, Adelman JP. Small conductance Ca2+‐activated K+ channels and calmodulin. J Physiol 554: 255‐261, 2004.
 360. McCobb DP, Fowler NL, Featherstone T, Lingle CJ, Saito M, Krause JE, Salkoff L. A human calcium‐activated potassium channel gene expressed in vascular smooth muscle. Am J Physiol 269: H767‐H777, 1995.
 361. McManus OB, Blatz AL, Magleby KL. Inverse relationship of the durations of adjacent open and shut intervals for C1 and K channels. Nature 317: 625‐627, 1985.
 362. Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger, II, Pangalos MN. Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Brain Res Mol Brain Res 86: 101‐114, 2001.
 363. Medina I, Krapivinsky G, Arnold S, Kovoor P, Krapivinsky L, Clapham DE. A switch mechanism for G beta gamma activation of I(KACh). J Biol Chem 275: 29709‐29716, 2000.
 364. Meera P, Wallner M, Song M, Toro L. Large conductance voltage‐ and calcium‐dependent K+ channel, a distinct member of voltage‐dependent ion channels with seven N‐terminal transmembrane segments (S0‐S6), an extracellular N terminus, and an intracellular (S9‐S10) C terminus. Proc Natl Acad Sci U S A 94: 14066‐14071, 1997.
 365. Meera P, Wallner M, Toro L. A neuronal beta subunit (KCNMB4) makes the large conductance, voltage‐ and Ca2+‐activated K+ channel resistant to charybdotoxin and iberiotoxin. Proc Natl Acad Sci U S A 97: 5562‐5567, 2000.
 366. Mi H, Deerinck TJ, Jones M, Ellisman MH, Schwarz TL. Inwardly rectifying K+ channels that may participate in K+ buffering are localized in microvilli of Schwann cells. J Neurosci 16: 2421‐2429, 1996.
 367. Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B, Collins RF, Sansom MS, Ford RC, Ashcroft FM. 3‐D structural and functional characterization of the purified KATP channel complex Kir6.2‐SUR1. EMBO J 24: 4166‐4175, 2005.
 368. Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J, Seino S. ATP‐sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4: 507‐512, 2001.
 369. Miller C. See potassium run. Nature 414: 23‐24, 2001.
 370. Miller C, Moczydlowski E, Latorre R, Phillips M. Charybdotoxin, a protein inhibitor of single Ca2+‐activated K+ channels from mammalian skeletal muscle. Nature 313: 316‐318, 1985.
 371. Miranda‐Rottmann S, Kozlov AS, Hudspeth AJ. Highly specific alternative splicing of transcripts encoding BK channels in the chicken's cochlea is a minor determinant of the tonotopic gradient. Mol Cell Biol 30: 3646‐3660, 2010.
 372. Mohapatra DP, Park KS, Trimmer JS. Dynamic regulation of the voltage‐gated Kv2.1 potassium channel by multisite phosphorylation. Biochem Soc Trans 35: 1064‐1068, 2007.
 373. Molina A, Castellano AG, Lopez‐Barneo J. Pore mutations in Shaker K+ channels distinguish between the sites of tetraethylammonium blockade and C‐type inactivation. J Physiol 499(Pt 2): 361‐367, 1997.
 374. Monaghan AS, Benton DC, Bahia PK, Hosseini R, Shah YA, Haylett DG, Moss GW. The SK3 subunit of small conductance Ca2+‐activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system. J Biol Chem 279: 1003‐1009, 2004.
 375. Morais‐Cabral JH, Zhou Y, MacKinnon R. Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature 414: 37‐42, 2001.
 376. Morrow JP, Zakharov SI, Liu G, Yang L, Sok AJ, Marx SO. Defining the BK channel domains required for beta1‐subunit modulation. Proc Natl Acad Sci U S A 103: 5096‐5101, 2006.
 377. Moulton G, Attwood TK, Parry‐Smith DJ, Packer JC. Phylogenomic analysis and evolution of the potassium channel gene family. Receptors Channels 9: 363‐377, 2003.
 378. Mullins FM, Stepanovic SZ, Desai RR, George AL Jr., Balser JR. Extracellular sodium interacts with the HERG channel at an outer pore site. J Gen Physiol 120: 517‐537, 2002.
 379. Mullmann TJ, Munujos P, Garcia ML, Giangiacomo KM. Electrostatic mutations in iberiotoxin as a unique tool for probing the electrostatic structure of the maxi‐K channel outer vestibule. Biochemistry 38: 2395‐2402, 1999.
 380. Mullner C, Vorobiov D, Bera AK, Uezono Y, Yakubovich D, Frohnwieser‐Steinecker B, Dascal N, Schreibmayer W. Heterologous facilitation of G protein‐activated K(+) channels by beta‐adrenergic stimulation via cAMP‐dependent protein kinase. J Gen Physiol 115: 547‐558, 2000.
 381. Murakoshi H, Trimmer JS. Identification of the Kv2.1 K+ channel as a major component of the delayed rectifier K+ current in rat hippocampal neurons. J Neurosci 19: 1728‐1735, 1999.
 382. Murata Y, Iwasaki H, Sasaki M, Inaba K, Okamura Y. Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature 435: 1239‐1243, 2005.
 383. Murthy SR, Teodorescu G, Nijholt IM, Dolga AM, Grissmer S, Spiess J, Blank T. Identification and characterization of a novel, shorter isoform of the small conductance Ca2+‐activated K+ channel SK2. J Neurochem 106: 2312‐2321, 2008.
 384. Nanou E, El Manira A. A postsynaptic negative feedback mediated by coupling between AMPA receptors and Na+‐activated K+ channels in spinal cord neurones. Eur J Neurosci 25: 445‐450, 2007.
 385. Naranjo D, Latorre R. Ion conduction in substates of the batrachotoxin‐modified Na+ channel from toad skeletal muscle. Biophys J 64: 1038‐1050, 1993.
 386. Nassar‐Gentina V, Pollard HB, Rojas E. Electrical activity in chromaffin cells of intact mouse adrenal gland. Am J Physiol 254: C675‐C683, 1988.
 387. Navarro B, Kirichok Y, Clapham DE. KSper, a pH‐sensitive K+ current that controls sperm membrane potential. Proc Natl Acad Sci U S A 104: 7688‐7692, 2007.
 388. Neusch C, Papadopoulos N, Muller M, Maletzki I, Winter SM, Hirrlinger J, Handschuh M, Bahr M, Richter DW, Kirchhoff F, Hulsmann S. Lack of the Kir4.1 channel subunit abolishes K+ buffering properties of astrocytes in the ventral respiratory group: Impact on extracellular K+ regulation. J Neurophysiol 95: 1843‐1852, 2006.
 389. Newman EA. Regional specialization of retinal glial cell membrane. Nature 309: 155‐157, 1984.
 390. Nichols CG, Lederer WJ. Adenosine triphosphate‐sensitive potassium channels in the cardiovascular system. Am J Physiol 261: H1675‐H1686, 1991.
 391. Niemeyer MI, Gonzalez‐Nilo FD, Zuniga L, Gonzalez W, Cid LP, Sepulveda FV. Neutralization of a single arginine residue gates open a two‐pore domain, alkali‐activated K+ channel. Proc Natl Acad Sci U S A 104: 666‐671, 2007.
 392. Nimigean CM, Magleby KL. Functional coupling of the beta(1) subunit to the large conductance Ca(2+)‐activated K(+) channel in the absence of Ca(2+). Increased Ca(2+) sensitivity from a Ca(2+)‐independent mechanism. J Gen Physiol 115: 719‐736, 2000.
 393. Nin F, Hibino H, Doi K, Suzuki T, Hisa Y, Kurachi Y. The endocochlear potential depends on two K+ diffusion potentials and an electrical barrier in the stria vascularis of the inner ear. Proc Natl Acad Sci U S A 105: 1751‐1756, 2008.
 394. Nishida M, Cadene M, Chait BT, MacKinnon R. Crystal structure of a Kir3.1‐prokaryotic Kir channel chimera. EMBO J 26: 4005‐4015, 2007.
 395. Nishida M, MacKinnon R. Structural basis of inward rectification: Cytoplasmic pore of the G protein‐gated inward rectifier GIRK1 at 1.8 A resolution. Cell 111: 957‐965, 2002.
 396. Niu X, Magleby KL. Stepwise contribution of each subunit to the cooperative activation of BK channels by Ca2+. Proc Natl Acad Sci U S A 99: 11441‐11446, 2002.
 397. Niu X, Qian X, Magleby KL. Linker‐gating ring complex as passive spring and Ca(2+)‐dependent machine for a voltage‐ and Ca(2+)‐activated potassium channel. Neuron 42: 745‐756, 2004.
 398. Noda M, Shimizu S, Tanabe T, Takai T, Kayano T, Ikeda T, Takahashi H, Nakayama H, Kanaoka Y, Minamino N, et al. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312: 121‐127, 1984.
 399. Noma A. ATP‐regulated K+ channels in cardiac muscle. Nature 305: 147‐148, 1983.
 400. Nuwer MO, Picchione KE, Bhattacharjee A. PKA‐induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. J Neurosci 30: 14165‐14172, 2010.
 401. Okamura Y. Biodiversity of voltage sensor domain proteins. Pflugers Arch 454: 361‐371, 2007.
 402. Olcese R, Latorre R, Toro L, Bezanilla F, Stefani E. Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels. J Gen Physiol 110: 579‐589, 1997.
 403. Olesen SP, Munch E, Moldt P, Drejer J. Selective activation of Ca(2+)‐dependent K+ channels by novel benzimidazolone. Eur J Pharmacol 251: 53‐59, 1994.
 404. Oliva C, Gonzalez V, Naranjo D. Slow inactivation in voltage gated potassium channels is insensitive to the binding of pore occluding peptide toxins. Biophys J 89: 1009‐1019, 2005.
 405. Ordway RW, Walsh JV Jr., Singer JJ. Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells. Science 244: 1176‐1179, 1989.
 406. Orio P, Latorre R. Differential effects of beta 1 and beta 2 subunits on BK channel activity. J Gen Physiol 125: 395‐411, 2005.
 407. Orio P, Rojas P, Ferreira G, Latorre R. New disguises for an old channel: MaxiK channel beta‐subunits. News Physiol Sci 17: 156‐161, 2002.
 408. Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ. Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha‐subunits identified in the human genome. Proc Natl Acad Sci U S A 99: 7986‐7991, 2002.
 409. Pallotta BS, Magleby KL, Barrett JN. Single channel recordings of Ca2+‐activated K+ currents in rat muscle cell culture. Nature 293: 471‐474, 1981.
 410. Pantazis A, Gudzenko V, Savalli N, Sigg D, Olcese R. Operation of the voltage sensor of a human voltage‐ and Ca2+‐activated K+ channel. Proc Natl Acad Sci U S A 107: 4459‐4464, 2010.
 411. Pantazis A, Kohanteb AP, Olcese R. Relative motion of transmembrane segments S0 and S4 during voltage sensor activation in the human BK(Ca) channel. J Gen Physiol 136: 645‐657, 2010.
 412. Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237: 749‐753, 1987.
 413. Pardo LA, Suhmer W. Eag1 as a cancer target. Expert Opin Ther Targets 12: 837‐843, 2008.
 414. Park CS, Miller C. Interaction of charybdotoxin with permeant ions inside the pore of a K+ channel. Neuron 9: 307‐313, 1992a.
 415. Park CS, Miller C. Mapping function to structure in a channel‐blocking peptide: Electrostatic mutants of charybdotoxin. Biochemistry 31: 7749‐7755, 1992b.
 416. Park YB. Ion selectivity and gating of small conductance Ca(2+)‐activated K+ channels in cultured rat adrenal chromaffin cells. J Physiol 481(Pt 3): 555‐570, 1994.
 417. Patel AJ, Honore E. Molecular physiology of oxygen‐sensitive potassium channels. Eur Respir J 18: 221‐227, 2001.
 418. Patel AJ, Honore E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M. A mammalian two pore domain mechano‐gated S‐like K+ channel. EMBO J 17: 4283‐4290, 1998.
 419. Patel AJ, Lazdunski M, Honore E. Lipid and mechano‐gated 2P domain K(+) channels. Curr Opin Cell Biol 13: 422‐428, 2001.
 420. Patel SP, Campbell DL. Transient outward potassium current, ‘Ito’, phenotypes in the mammalian left ventricle: Underlying molecular, cellular and biophysical mechanisms. J Physiol 569: 7‐39, 2005.
 421. Pearson WL, Nichols CG. Block of the Kir2.1 channel pore by alkylamine analogues of endogenous polyamines. J Gen Physiol 112: 351‐363, 1998.
 422. Pedarzani P, Kulik A, Muller M, Ballanyi K, Stocker M. Molecular determinants of Ca2+‐dependent K+ channel function in rat dorsal vagal neurones. J Physiol 527(Pt 2): 283‐290, 2000.
 423. Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, Fakler B. Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+‐activated K+ channels. J Biol Chem 276: 9762‐9769, 2001.
 424. Pedarzani P, Stocker M. Molecular and cellular basis of small–and intermediate‐conductance, calcium‐activated potassium channel function in the brain. Cell Mol Life Sci 65: 3196‐3217, 2008.
 425. Pegan S, Arrabit C, Zhou W, Kwiatkowski W, Collins A, Slesinger PA, Choe S. Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci 8: 279‐287, 2005.
 426. Peleg S, Varon D, Ivanina T, Dessauer CW, Dascal N. G(alpha) (i) controls the gating of the G protein‐activated K(+) channel, GIRK. Neuron 33: 87‐99, 2002.
 427. Pennefather P, Lancaster B, Adams PR, Nicoll RA. Two distinct Ca‐dependent K currents in bullfrog sympathetic ganglion cells. Proc Natl Acad Sci U S A 82: 3040‐3044, 1985.
 428. Perez GJ, Bonev AD, Nelson MT. Micromolar Ca(2+) from sparks activates Ca(2+)‐sensitive K(+) channels in rat cerebral artery smooth muscle. Am J Physiol Cell Physiol 281: C1769‐C1775, 2001.
 429. Pessia M, Imbrici P, D'Adamo MC, Salvatore L, Tucker SJ. Differential pH sensitivity of Kir4.1 and Kir4.2 potassium channels and their modulation by heteropolymerisation with Kir5.1. J Physiol 532: 359‐367, 2001.
 430. Plant LD, Rajan S, Goldstein SA. K2P channels and their protein partners. Curr Opin Neurobiol 15: 326‐333, 2005.
 431. Pluger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, Gollasch M, Haller H, Luft FC, Ehmke H, Pongs O. Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res 87: E53‐E60, 2000.
 432. Pluznick JL, Wei P, Carmines PK, Sansom SC. Renal fluid and electrolyte handling in BKCa‐beta1‐/‐ mice. Am J Physiol Renal Physiol 284: F1274‐F1279, 2003.
 433. Posson DJ, Ge P, Miller C, Bezanilla F, Selvin PR. Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer. Nature 436: 848‐851, 2005.
 434. Power JM, Sah P. Competition between calcium‐activated K+ channels determines cholinergic action on firing properties of basolateral amygdala projection neurons. J Neurosci 28: 3209‐3220, 2008.
 435. Prakriya M, Lingle CJ. BK channel activation by brief depolarizations requires Ca2+ influx through L‐ and Q‐type Ca2+ channels in rat chromaffin cells. J Neurophysiol 81: 2267‐2278, 1999.
 436. Preisig‐Muller R, Schlichthorl G, Goerge T, Heinen S, Bruggemann A, Rajan S, Derst C, Veh RW, Daut J. Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome. Proc Natl Acad Sci U S A 99: 7774‐7779, 2002.
 437. Prole DL, Lima PA, Marrion NV. Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons. J Gen Physiol 122: 775‐793, 2003.
 438. Quirk JC, Reinhart PH. Identification of a novel tetramerization domain in large conductance K(ca) channels. Neuron 32: 13‐23, 2001.
 439. Rajan S, Wischmeyer E, Xin Liu G, Preisig‐Muller R, Daut J, Karschin A, Derst C. TASK‐3, a novel tandem pore domain acid‐sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem 275: 16650‐16657, 2000.
 440. Raman IM, Bean BP. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J Neurosci 19: 1663‐1674, 1999.
 441. Ramanathan K, Michael TH, Jiang GJ, Hiel H, Fuchs PA. A molecular mechanism for electrical tuning of cochlear hair cells. Science 283: 215‐217, 1999.
 442. Ramsey IS, Moran MM, Chong JA, Clapham DE. A voltage‐gated proton‐selective channel lacking the pore domain. Nature 440: 1213‐1216, 2006.
 443. Ramu Y, Xu Y, Lu Z. Enzymatic activation of voltage‐gated potassium channels. Nature 442: 696‐699, 2006.
 444. Rangaraju S, Chi V, Pennington MW, Chandy KG. Kv1.3 potassium channels as a therapeutic target in multiple sclerosis. Expert Opin Ther Targets 13: 909‐924, 2009.
 445. Ravindran A, Kwiecinski H, Alvarez O, Eisenman G, Moczydlowski E. Modeling ion permeation through batrachotoxin‐modified Na+ channels from rat skeletal muscle with a multi‐ion pore. Biophys J 61: 494‐508, 1992.
 446. Rettig J, Heinemann SH, Wunder F, Lorra C, Parcej DN, Dolly JO, Pongs O. Inactivation properties of voltage‐gated K+ channels altered by presence of beta‐subunit. Nature 369: 289‐294, 1994.
 447. Riven I, Kalmanzon E, Segev L, Reuveny E. Conformational rearrangements associated with the gating of the G protein‐coupled potassium channel revealed by FRET microscopy. Neuron 38: 225‐235, 2003.
 448. Roberds SL, Tamkun MM. Cloning and tissue‐specific expression of five voltage‐gated potassium channel cDNAs expressed in rat heart. Proc Natl Acad Sci U S A 88: 1798‐1802, 1991.
 449. Robitaille R, Charlton MP. Presynaptic calcium signals and transmitter release are modulated by calcium‐activated potassium channels. J Neurosci 12: 297‐305, 1992.
 450. Romey G, Hugues M, Schmid‐Antomarchi H, Lazdunski M. Apamin: A specific toxin to study a class of Ca2+‐dependent K+ channels. J Physiol (Paris) 79: 259‐264, 1984.
 451. Rorsman P, Bokvist K, Ammala C, Arkhammar P, Berggren PO, Larsson O, Wahlander K. Activation by adrenaline of a low‐conductance G protein‐dependent K+ channel in mouse pancreatic B cells. Nature 349: 77‐79, 1991.
 452. Rose CR, Konnerth A. NMDA receptor‐mediated Na+ signals in spines and dendrites. J Neurosci 21: 4207‐4214, 2001.
 453. Rosenblatt KP, Sun ZP, Heller S, Hudspeth AJ. Distribution of Ca2+‐activated K+ channel isoforms along the tonotopic gradient of the chicken's cochlea. Neuron 19: 1061‐1075, 1997.
 454. Rosenhouse‐Dantsker A, Sui JL, Zhao Q, Rusinova R, Rodriguez‐Menchaca AA, Zhang Z, Logothetis DE. A sodium‐mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2). Nat Chem Biol 4: 624‐631, 2008.
 455. Rothberg BS, Magleby KL. Gating kinetics of single large‐conductance Ca2+‐activated K+ channels in high Ca2+ suggest a two‐tiered allosteric gating mechanism. J Gen Physiol 114: 93‐124, 1999.
 456. Rothberg BS, Magleby KL. Voltage and Ca2+ activation of single large‐conductance Ca2+‐activated K +channels described by a two‐tiered allosteric gating mechanism. J Gen Physiol 116: 75‐99, 2000.
 457. Ruta V, Chen J, MacKinnon R. Calibrated measurement of gating‐charge arginine displacement in the KvAP voltage‐dependent K+ channel. Cell 123: 463‐475, 2005.
 458. Ruta V, MacKinnon R. Localization of the voltage‐sensor toxin receptor on KvAP. Biochemistry 43: 10071‐10079, 2004.
 459. Sabbadini M, Yost CS. Molecular biology of background K channels: Insights from K(2P) knockout mice. J Mol Biol 385: 1331‐1344, 2009.
 460. Safronov BV, Vogel W. Properties and functions of Na(+)‐activated K+ channels in the soma of rat motoneurones. J Physiol 497(Pt 3): 727‐734, 1996.
 461. Sah P. Role of calcium influx and buffering in the kinetics of Ca(2+)‐activated K+ current in rat vagal motoneurons. J Neurophysiol 68: 2237‐2247, 1992.
 462. Sah P. Ca(2+)‐activated K+ currents in neurones: Types, physiological roles and modulation. Trends Neurosci 19: 150‐154, 1996.
 463. Sailer CA, Hu H, Kaufmann WA, Trieb M, Schwarzer C, Storm JF, Knaus HG. Regional differences in distribution and functional expression of small‐conductance Ca2+‐activated K+ channels in rat brain. J Neurosci 22: 9698‐9707, 2002.
 464. Sailer CA, Kaufmann WA, Marksteiner J, Knaus HG. Comparative immunohistochemical distribution of three small‐conductance Ca2+‐activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain. Mol Cell Neurosci 26: 458‐469, 2004.
 465. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779‐815, 1993.
 466. Salkoff L, Butler A, Ferreira G, Santi C, Wei A. High‐conductance potassium channels of the SLO family. Nat Rev Neurosci 7: 921‐931, 2006.
 467. Salkoff L, Wei AD, Baban B, Butler A, Fawcett G, Ferreira G, Santi CM. Potassium channels in C. elegans. WormBook 1‐15, 2005.
 468. Sandoz G, Thummler S, Duprat F, Feliciangeli S, Vinh J, Escoubas P, Guy N, Lazdunski M, Lesage F. AKAP150, a switch to convert mechano‐, pH‐ and arachidonic acid‐sensitive TREK K(+) channels into open leak channels. EMBO J 25: 5864‐5872, 2006.
 469. Sandtner W, Szendroedi J, Zarrabi T, Zebedin E, Hilber K, Glaaser I, Fozzard HA, Dudley SC, Todt H. Lidocaine: A foot in the door of the inner vestibule prevents ultra‐slow inactivation of a voltage‐gated sodium channel. Mol Pharmacol 66: 648‐657, 2004.
 470. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 384: 80‐83, 1996.
 471. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81: 299‐307, 1995.
 472. Sano Y, Mochizuki S, Miyake A, Kitada C, Inamura K, Yokoi H, Nozawa K, Matsushime H, Furuichi K. Molecular cloning and characterization of Kv6.3, a novel modulatory subunit for voltage‐gated K(+) channel Kv2.1. FEBS Lett 512: 230‐234, 2002.
 473. Santi CM, Butler A, Kuhn J, Wei A, Salkoff L. Bovine and mouse SLO3 K+ channels: Evolutionary divergence points to an RCK1 region of critical function. J Biol Chem 284: 21589‐21598, 2009.
 474. Santi CM, Ferreira G, Yang B, Gazula VR, Butler A, Wei A, Kaczmarek LK, Salkoff L. Opposite regulation of Slick and Slack K+ channels by neuromodulators. J Neurosci 26: 5059‐5068, 2006.
 475. Santi CM, Martinez‐Lopez P, de la Vega‐Beltran JL, Butler A, Alisio A, Darszon A, Salkoff L. The SLO3 sperm‐specific potassium channel plays a vital role in male fertility. FEBS Lett 584: 1041‐1046, 2010.
 476. Sasaki M, Takagi M, Okamura Y. A voltage sensor‐domain protein is a voltage‐gated proton channel. Science 312: 589‐592, 2006.
 477. Sausbier U, Sausbier M, Sailer CA, Arntz C, Knaus HG, Neuhuber W, Ruth P. Ca2+‐activated K+ channels of the BK‐type in the mouse brain. Histochem Cell Biol 125: 725‐741, 2006.
 478. Savalli N, Kondratiev A, Toro L, Olcese R. Voltage‐dependent conformational changes in human Ca(2+)‐ and voltage‐activated K(+) channel, revealed by voltage‐clamp fluorometry. Proc Natl Acad Sci U S A 103: 12619‐12624, 2006.
 479. Scanziani M. GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity. Neuron 25: 673‐681, 2000.
 480. Scuvee‐Moreau J, Boland A, Graulich A, Van Overmeire L, D'Hoedt D, Graulich‐Lorge F, Thomas E, Abras A, Stocker M, Liegeois JF, Seutin V. Electrophysiological characterization of the SK channel blockers methyl‐laudanosine and methyl‐noscapine in cell lines and rat brain slices. Br J Pharmacol 143: 753‐764, 2004.
 481. Schmidt D, Jiang QX, MacKinnon R. Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444: 775‐779, 2006.
 482. Schoppa NE, McCormack K, Tanouye MA, Sigworth FJ. The size of gating charge in wild‐type and mutant Shaker potassium channels. Science 255: 1712‐1715, 1992.
 483. Schoppa NE, Sigworth FJ. Activation of Shaker potassium channels. III. An activation gating model for wild‐type and V2 mutant channels. J Gen Physiol 111: 313‐342, 1998.
 484. Schreiber M, Wei A, Yuan A, Gaut J, Saito M, Salkoff L. Slo3, a novel pH‐sensitive K+ channel from mammalian spermatocytes. J Biol Chem 273: 3509‐3516, 1998.
 485. Schrempf H, Schmidt O, Kummerlen R, Hinnah S, Muller D, Betzler M, Steinkamp T, Wagner R. A prokaryotic potassium ion channel with two predicted transmembrane segments from Streptomyces lividans. EMBO J 14: 5170‐5178, 1995.
 486. Schumacher MA, Rivard AF, Bachinger HP, Adelman JP. Structure of the gating domain of a Ca2+‐activated K+ channel complexed with Ca2+/calmodulin. Nature 410: 1120‐1124, 2001.
 487. Schwartzkroin PA, Stafstrom CE. Effects of EGTA on the calcium‐activated afterhyperpolarization in hippocampal CA3 pyramidal cells. Science 210: 1125‐1126, 1980.
 488. Schwindt PC, Spain WJ, Foehring RC, Stafstrom CE, Chubb MC, Crill WE. Multiple potassium conductances and their functions in neurons from cat sensorimotor cortex in vitro. J Neurophysiol 59: 424‐449, 1988.
 489. Semenova NP, Abarca‐Heidemann K, Loranc E, Rothberg BS. Bimane fluorescence scanning suggests secondary structure near the S3‐S4 linker of BK channels. J Biol Chem 284: 10684‐10693, 2009.
 490. Seoh SA, Sigg D, Papazian DM, Bezanilla F. Voltage‐sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16: 1159‐1167, 1996.
 491. Seutin V, Johnson SW. Recent advances in the pharmacology of quaternary salts of bicuculline. Trends Pharmacol Sci 20: 268‐270, 1999.
 492. Shakkottai VG, Regaya I, Wulff H, Fajloun Z, Tomita H, Fathallah M, Cahalan MD, Gargus JJ, Sabatier JM, Chandy KG. Design and characterization of a highly selective peptide inhibitor of the small conductance calcium‐activated K+ channel, SkCa2. J Biol Chem 276: 43145‐43151, 2001.
 493. Shao LR, Halvorsrud R, Borg‐Graham L, Storm JF. The role of BK‐type Ca2+‐dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol 521(Pt 1): 135‐146, 1999.
 494. Sharon D, Vorobiov D, Dascal N. Positive and negative coupling of the metabotropic glutamate receptors to a G protein‐activated K+ channel, GIRK, in Xenopus oocytes. J Gen Physiol 109: 477‐490, 1997.
 495. Shen KZ, Lagrutta A, Davies NW, Standen NB, Adelman JP, North RA. Tetraethylammonium block of Slowpoke calcium‐activated potassium channels expressed in Xenopus oocytes: Evidence for tetrameric channel formation. Pflugers Arch 426: 440‐445, 1994.
 496. Shieh RC, Chang JC, Arreola J. Interaction of Ba2+ with the pores of the cloned inward rectifier K+ channels Kir2.1 expressed in Xenopus oocytes. Biophys J 75: 2313‐2322, 1998.
 497. Shin HG, Lu Z. Mechanism of the voltage sensitivity of IRK1 inward‐rectifier K+ channel block by the polyamine spermine. J Gen Physiol 125: 413‐426, 2005.
 498. Shin KS, Maertens C, Proenza C, Rothberg BS, Yellen G. Inactivation in HCN channels results from reclosure of the activation gate: Desensitization to voltage. Neuron 41: 737‐744, 2004.
 499. Shmukler BE, Bond CT, Wilhelm S, Bruening‐Wright A, Maylie J, Adelman JP, Alper SL. Structure and complex transcription pattern of the mouse SK1 K(Ca) channel gene, KCNN1. Biochi Biophys Acta 1518: 36‐46, 2001.
 500. Shyng S, Nichols CG. Octameric stoichiometry of the KATP channel complex. J Gen Physiol 110: 655‐664, 1997.
 501. Sieg A, Su J, Munoz A, Buchenau M, Nakazaki M, Aguilar‐Bryan L, Bryan J, Ullrich S. Epinephrine‐induced hyperpolarization of islet cells without KATP channels. Am J Physiol Endocrinol Metab 286: E463‐E471, 2004.
 502. Sigg D, Bezanilla F. Total charge movement per channel. The relation between gating charge displacement and the voltage sensitivity of activation. J Gen Physiol 109: 27‐39, 1997.
 503. Signorini S, Liao YJ, Duncan SA, Jan LY, Stoffel M. Normal cerebellar development but susceptibility to seizures in mice lacking G protein‐coupled, inwardly rectifying K+ channel GIRK2. Proc Natl Acad Sci U S A 94: 923‐927, 1997.
 504. Slesinger PA, Reuveny E, Jan YN, Jan LY. Identification of structural elements involved in G protein gating of the GIRK1 potassium channel. Neuron 15: 1145‐1156, 1995.
 505. Smith PA, Bokvist K, Arkhammar P, Berggren PO, Rorsman P. Delayed rectifying and calcium‐activated K+ channels and their significance for action potential repolarization in mouse pancreatic beta‐cells. J Gen Physiol 95: 1041‐1059, 1990.
 506. Soh H, Park CS. Inwardly rectifying current‐voltage relationship of small‐conductance Ca2+‐activated K+ channels rendered by intracellular divalent cation blockade. Biophys J 80: 2207‐2215, 2001.
 507. Soh H, Park CS. Localization of divalent cation‐binding site in the pore of a small conductance Ca(2+)‐activated K(+) channel and its role in determining current‐voltage relationship. Biophys J 83: 2528‐2538, 2002.
 508. Solaro CR, Prakriya M, Ding JP, Lingle CJ. Inactivating and noninactivating Ca(2+)‐ and voltage‐dependent K+ current in rat adrenal chromaffin cells. J Neurosci 15: 6110‐6123, 1995.
 509. Stackman RW, Hammond RS, Linardatos E, Gerlach A, Maylie J, Adelman JP, Tzounopoulos T. Small conductance Ca2+‐activated K+ channels modulate synaptic plasticity and memory encoding. J Neurosci 22: 10163‐10171, 2002.
 510. Stanfield PR, Davies NW, Shelton PA, Sutcliffe MJ, Khan IA, Brammar WJ, Conley EC. A single aspartate residue is involved in both intrinsic gating and blockage by Mg2+ of the inward rectifier, IRK1. J Physiol 478(Pt 1): 1‐6, 1994.
 511. Starace DM, Bezanilla F. Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker k+ channel. J Gen Physiol 117: 469‐490, 2001.
 512. Starace DM, Bezanilla F. A proton pore in a potassium channel voltage sensor reveals a focused electric field. Nature 427: 548‐553, 2004.
 513. Starace DM, Stefani E, Bezanilla F. Voltage‐dependent proton transport by the voltage sensor of the Shaker K+ channel. Neuron 19: 1319‐1327, 1997.
 514. Stefani E, Ottolia M, Noceti F, Olcese R, Wallner M, Latorre R, Toro L. Voltage‐controlled gating in a large conductance Ca2+‐sensitive K+channel (hslo). Proc Natl Acad Sci U S A 94: 5427‐5431, 1997.
 515. Stocker M, Hirzel K, D'Hoedt D, Pedarzani P. Matching molecules to function: Neuronal Ca2+‐activated K+ channels and afterhyperpolarizations. Toxicon 43: 933‐949, 2004.
 516. Stocker M, Krause M, Pedarzani P. An apamin‐sensitive Ca2+‐activated K+ current in hippocampal pyramidal neurons. Proc Natl Acad Sci U S A 96: 4662‐4667, 1999.
 517. Storm JF. Action potential repolarization and a fast after‐hyperpolarization in rat hippocampal pyramidal cells. J Physiol 385: 733‐759, 1987.
 518. Strassmaier T, Bond CT, Sailer CA, Knaus HG, Maylie J, Adelman JP. A novel isoform of SK2 assembles with other SK subunits in mouse brain. J Biol Chem 280: 21231‐21236, 2005.
 519. Strobaek D, Hougaard C, Johansen TH, Sorensen US, Nielsen EO, Nielsen KS, Taylor RD, Pedarzani P, Christophersen P. Inhibitory gating modulation of small conductance Ca2+‐activated K+ channels by the synthetic compound (R)‐N‐(benzimidazol‐2‐yl)‐1,2,3,4‐tetrahydro‐1‐naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Mol Pharmacol 70: 1771‐1782, 2006.
 520. Sui JL, Chan KW, Logothetis DE. Na+ activation of the muscarinic K+ channel by a G‐protein‐independent mechanism. J Gen Physiol 108: 381‐391, 1996.
 521. Sui JL, Petit‐Jacques J, Logothetis DE. Activation of the atrial KACh channel by the betagamma subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates. Proc Natl Acad Sci U S A 95: 1307‐1312, 1998.
 522. Swanson WJ, Vacquier VD. The rapid evolution of reproductive proteins. Nat Rev Genet 3: 137‐144, 2002.
 523. Swartz KJ. Towards a structural view of gating in potassium channels. Nat Rev Neurosci 5: 905‐916, 2004.
 524. Swartz KJ. Sensing voltage across lipid membranes. Nature 456: 891‐897, 2008.
 525. Swartz KJ, MacKinnon R. An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula. Neuron 15: 941‐949, 1995.
 526. Sweet TB, Cox DH. Measuring the influence of the BKCa {beta}1 subunit on Ca2+ binding to the BKCa channel. J Gen Physiol 133: 139‐150, 2009.
 527. Swensen AM, Bean BP. Ionic mechanisms of burst firing in dissociated Purkinje neurons. J Neurosci 23: 9650‐9663, 2003.
 528. Taglialatela M, Wible BA, Caporaso R, Brown AM. Specification of pore properties by the carboxyl terminus of inwardly rectifying K+ channels. Science 264: 844‐847, 1994.
 529. Takano K, Yasufuku‐Takano J, Kozasa T, Singer WD, Nakajima S, Nakajima Y. Gq/11 and PLC‐beta 1 mediate the substance P‐induced inhibition of an inward rectifier K+ channel in brain neurons. J Neurophysiol 76: 2131‐2136, 1996.
 530. Takano M, Kuratomi S. Regulation of cardiac inwardly rectifying potassium channels by membrane lipid metabolism. Prog Biophys Mol Biol 81: 67‐79, 2003.
 531. Takeuchi S, Ando M, Kakigi A. Mechanism generating endocochlear potential: Role played by intermediate cells in stria vascularis. Biophys J 79: 2572‐2582, 2000.
 532. Talukder G, Aldrich RW. Complex voltage‐dependent behavior of single unliganded calcium‐sensitive potassium channels. Biophys J 78: 761‐772, 2000.
 533. Talley EM, Lei Q, Sirois JE, Bayliss DA. TASK‐1, a two‐pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25: 399‐410, 2000.
 534. Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA. Cns distribution of members of the two‐pore‐domain (KCNK) potassium channel family. J Neurosci 21: 7491‐7505, 2001.
 535. Tamsett TJ, Picchione KE, Bhattacharjee A. NAD+ activates KNa channels in dorsal root ganglion neurons. J Neurosci 29: 5127‐5134, 2009.
 536. Tanemoto M, Kittaka N, Inanobe A, Kurachi Y. In vivo formation of a proton‐sensitive K+ channel by heteromeric subunit assembly of Kir5. 1 with Kir4.1. J Physiol 525(Pt 3): 587‐592, 2000.
 537. Tang QY, Zhang Z, Xia XM, Lingle CJ. Block of mouse Slo1 and Slo3 K +channels by CTX, IbTX, TEA, 4‐AP and quinidine. Channels (Austin) 4: 22‐41, 2010.
 538. Tang X, Schmidt TM, Perez‐Leighton CE, Kofuji P. Inwardly rectifying potassium channel Kir4.1 is responsible for the native inward potassium conductance of satellite glial cells in sensory ganglia. Neuroscience 166: 397‐407, 2010.
 539. Tao X, Avalos JL, Chen J, MacKinnon R. Crystal structure of the eukaryotic strong inward‐rectifier K+ channel Kir2.2 at 3.1 A resolution. Science 326: 1668‐1674, 2009.
 540. Tiwari‐Woodruff SK, Lin MA, Schulteis CT, Papazian DM. Voltage‐dependent structural interactions in the Shaker K(+) channel. J Gen Physiol 115: 123‐138, 2000.
 541. Tiwari‐Woodruff SK, Schulteis CT, Mock AF, Papazian DM. Electrostatic interactions between transmembrane segments mediate folding of Shaker K+ channel subunits. Biophys J 72: 1489‐1500, 1997.
 542. Tombola F, Pathak MM, Gorostiza P, Isacoff EY. The twisted ion‐permeation pathway of a resting voltage‐sensing domain. Nature 445: 546‐549, 2007.
 543. Tombola F, Pathak MM, Isacoff EY. Voltage‐sensing arginines in a potassium channel permeate and occlude cation‐selective pores. Neuron 45: 379‐388, 2005.
 544. Tomita H, Shakkottai VG, Gutman GA, Sun G, Bunney WE, Cahalan MD, Chandy KG, Gargus JJ. Novel truncated isoform of SK3 potassium channel is a potent dominant‐negative regulator of SK currents: Implications in schizophrenia. Mol Psychiatry 8: 524‐535, 2003.
 545. Topert C, Doring F, Wischmeyer E, Karschin C, Brockhaus J, Ballanyi K, Derst C, Karschin A. Kir2.4: A novel K+ inward rectifier channel associated with motoneurons of cranial nerve nuclei. J Neurosci 18: 4096‐4105, 1998.
 546. Toro L, Wallner M, Meera P, Tanaka Y. Maxi‐K(Ca), a unique member of the voltage‐gated K channel superfamily. News Physiol Sci 13: 112‐117, 1998.
 547. Torres YP, Morera FJ, Carvacho I, Latorre R. A marriage of convenience: Beta‐subunits and voltage‐dependent K+ channels. J Biol Chem 282: 24485‐24489, 2007.
 548. Treistman SN, Martin GE. BK Channels: Mediators and models for alcohol tolerance. Trends Neurosci 32: 629‐637, 2009.
 549. Treptow W, Tarek M. Environment of the gating charges in the Kv1.2 Shaker potassium channel. Biophys J 90: L64‐L66, 2006.
 550. Trimmer JS. Immunological identification and characterization of a delayed rectifier K +channel polypeptide in rat brain. Proc Natl Acad Sci U S A 88: 10764‐10768, 1991.
 551. Tristani‐Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110: 381‐388, 2002.
 552. Tsaur ML, Sheng M, Lowenstein DH, Jan YN, Jan LY. Differential expression of K+ channel mRNAs in the rat brain and down‐regulation in the hippocampus following seizures. Neuron 8: 1055‐1067, 1992.
 553. Tseng‐Crank J, Foster CD, Krause JD, Mertz R, Godinot N, DiChiara TJ, Reinhart PH. Cloning, expression, and distribution of functionally distinct Ca(2+)‐activated K+ channel isoforms from human brain. Neuron 13: 1315‐1330, 1994.
 554. Tzounopoulos T, Stackman R. Enhancing synaptic plasticity and memory: A role for small‐conductance Ca(2+)‐activated K+ channels. Neuroscientist 9: 434‐439, 2003.
 555. Uebele VN, Lagrutta A, Wade T, Figueroa DJ, Liu Y, McKenna E, Austin CP, Bennett PB, Swanson R. Cloning and functional expression of two families of beta‐subunits of the large conductance calcium‐activated K+ channel. J Biol Chem 275: 23211‐23218, 2000.
 556. Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C, Latorre R. Acute activation of Maxi‐K channels (hSlo) by estradiol binding to the beta subunit. Science 285: 1929‐1931, 1999.
 557. Vanderberg C. Inward rectification in a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc Natl Acad Sci U S A 84: 307‐320, 1987.
 558. Vergara C, Moczydlowski E, Latorre R. Conduction, blockade and gating in a Ca‐activated K channel incorporated into planar lipid bilayers. Biophys J 45: 73‐76, 1984.
 559. Villalba‐Galea CA, Miceli F, Taglialatela M, Bezanilla F. Coupling between the voltage‐sensing and phosphatase domains of Ci‐VSP. J Gen Physiol 134: 5‐14, 2009.
 560. Villalba‐Galea CA, Sandtner W, Starace DM, Bezanilla F. S4‐based voltage sensors have three major conformations. Proc Natl Acad Sci U S A 105: 17600‐17607, 2008.
 561. Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 9: 389‐397, 2006.
 562. Wallen P, Robertson B, Cangiano L, Low P, Bhattacharjee A, Kaczmarek LK, Grillner S. Sodium‐dependent potassium channels of a Slack‐like subtype contribute to the slow afterhyperpolarization in lamprey spinal neurons. J Physiol 585: 75‐90, 2007.
 563. Wallner M, Meera P, Toro L. Molecular basis of fast inactivation in voltage and Ca2+‐activated K +channels: A transmembrane beta‐subunit homolog. Proc Natl Acad Sci U S A 96: 4137‐4142, 1999.
 564. Wang B, Rothberg BS, Brenner R. Mechanism of beta4 subunit modulation of BK channels. J Gen Physiol 127: 449‐465, 2006.
 565. Wang L, Sigworth FJ. Structure of the BK potassium channel in a lipid membrane from electron cryomicroscopy. Nature 461: 292‐295, 2009.
 566. Wang WH, Giebisch G. Regulation of potassium (K) handling in the renal collecting duct. Pflugers Arch 458: 157‐168, 2009.
 567. Wang X, Xu R, Abernathey G, Taylor J, Alzghoul MB, Hannon K, Hockerman GH, Pond AL. Kv11.1 channel subunit composition includes MinK and varies developmentally in mouse cardiac muscle. Dev Dyn 237: 2430‐2437, 2008.
 568. Weatherall KL, Goodchild SJ, Jane DE, Marrion NV. Small conductance calcium‐activated potassium channels: From structure to function. Prog Neurobiol 91: 242‐255, 2010.
 569. Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium‐activated potassium channels. Pharmacol Rev 57: 463‐472, 2005.
 570. Wei DS, Mei YA, Bagal A, Kao JP, Thompson SM, Tang CM. Compartmentalized and binary behavior of terminal dendrites in hippocampal pyramidal neurons. Science 293: 2272‐2275, 2001.
 571. Wellman GC, Bevan JA. Barium inhibits the endothelium‐dependent component of flow but not acetylcholine‐induced relaxation in isolated rabbit cerebral arteries. J Pharmacol Exp Ther 274: 47‐53, 1995.
 572. White MM, Bezanilla F. Activation of squid axon K+ channels. Ionic and gating current studies. J Gen Physiol 85: 539‐554, 1985.
 573. Wible BA, Taglialatela M, Ficker E, Brown AM. Gating of inwardly rectifying K+ channels localized to a single negatively charged residue. Nature 371: 246‐249, 1994.
 574. Wickman K, Clapham DE. Ion channel regulation by G proteins. Physiol Rev 75: 865‐885, 1995.
 575. Wittekindt OH, Dreker T, Morris‐Rosendahl DJ, Lehmann‐Horn F, Grissmer S. A novel non‐neuronal hSK3 isoform with a dominant‐negative effect on hSK3 currents. Cell Physiol Biochem 14: 23‐30, 2004.
 576. Wolfart J, Neuhoff H, Franz O, Roeper J. Differential expression of the small‐conductance, calcium‐activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci 21: 3443‐3456, 2001.
 577. Wolfart J, Roeper J. Selective coupling of T‐type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J Neurosci 22: 3404‐3413, 2002.
 578. Womack M, Khodakhah K. Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J Neurosci 22: 10603‐10612, 2002.
 579. Womack MD, Chevez C, Khodakhah K. Calcium‐activated potassium channels are selectively coupled to P/Q‐type calcium channels in cerebellar Purkinje neurons. J Neurosci 24: 8818‐8822, 2004.
 580. Womack MD, Khodakhah K. Somatic and dendritic small‐conductance calcium‐activated potassium channels regulate the output of cerebellar Purkinje neurons. J Neurosci 23: 2600‐2607, 2003.
 581. Woodhull AM. Ionic blockage of sodium channels in nerve. J Gen Physiol 61: 687‐708, 1973.
 582. Wu RS, Marx SO. The BK potassium channel in the vascular smooth muscle and kidney: Alpha‐ and beta‐subunits. Kidney Int 78: 963‐974, 2010.
 583. Wu Y, Yang Y, Ye S, Jiang Y. Structure of the gating ring from the human large‐conductance Ca(2+)‐gated K(+) channel. Nature 466: 393‐397, 2010.
 584. Wynne PM, Puig SI, Martin GE, Treistman SN. Compartmentalized beta subunit distribution determines characteristics and ethanol sensitivity of somatic, dendritic, and terminal large‐conductance calcium‐activated potassium channels in the rat central nervous system. J Pharmacol Exp Ther 329: 978‐986, 2009.
 585. Xia XM, Ding JP, Lingle CJ. Molecular basis for the inactivation of Ca2+‐ and voltage‐dependent BK channels in adrenal chromaffin cells and rat insulinoma tumor cells. J Neurosci 19: 5255‐5264, 1999.
 586. Xia XM, Ding JP, Lingle CJ. Inactivation of BK channels by the NH2 terminus of the beta2 auxiliary subunit: An essential role of a terminal peptide segment of three hydrophobic residues. J Gen Physiol 121: 125‐148, 2003.
 587. Xia XM, Ding JP, Zeng XH, Duan KL, Lingle CJ. Rectification and rapid activation at low Ca2 +of Ca2+‐activated, voltage‐dependent BK currents: Consequences of rapid inactivation by a novel beta subunit. J Neurosci 20: 4890‐4903, 2000.
 588. Xia XM, Fakler B, Rivard A, Wayman G, Johnson‐Pais T, Keen JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S, Maylie J, Adelman JP. Mechanism of calcium gating in small‐conductance calcium‐activated potassium channels. Nature 395: 503‐507, 1998.
 589. Xia XM, Zeng X, Lingle CJ. Multiple regulatory sites in large‐conductance calcium‐activated potassium channels. Nature 418: 880‐884, 2002.
 590. Xia XM, Zhang X, Lingle CJ. Ligand‐dependent activation of Slo family channels is defined by interchangeable cytosolic domains. J Neurosci 24: 5585‐5591, 2004.
 591. Xie J, McCobb DP. Control of alternative splicing of potassium channels by stress hormones. Science 280: 443‐446, 1998.
 592. Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, O'Rourke B. Cytoprotective role of Ca2+‐ activated K+ channels in the cardiac inner mitochondrial membrane. Science 298: 1029‐1033, 2002.
 593. Xu Y, Ramu Y, Lu Z. Removal of phospho‐head groups of membrane lipids immobilizes voltage sensors of K+ channels. Nature 451: 826‐829, 2008.
 594. Xu Y, Shin HG, Szep S, Lu Z. Physical determinants of strong voltage sensitivity of K(+) channel block. Nat Struct Mol Biol 16: 1252‐1258, 2009.
 595. Yang B, Gribkoff VK, Pan J, Damagnez V, Dworetzky SI, Boissard CG, Bhattacharjee A, Yan Y, Sigworth FJ, Kaczmarek LK. Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 51: 896‐906, 2006.
 596. Yang CT, Zeng XH, Xia XM, Lingle CJ. Interactions between beta subunits of the KCNMB family and Slo3: Beta4 selectively modulates Slo3 expression and function. PLoS One 4: e6135, 2009.
 597. Yang H, Shi J, Zhang G, Yang J, Delaloye K, Cui J. Activation of Slo1 BK channels by Mg2+ coordinated between the voltage sensor and RCK1 domains. Nat Struct Mol Biol 15: 1152‐1159, 2008.
 598. Yang J, Jan YN, Jan LY. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel. Neuron 14: 1047‐1054, 1995.
 599. Yang J, Krishnamoorthy G, Saxena A, Zhang G, Shi J, Yang H, Delaloye K, Sept D, Cui J. An epilepsy/dyskinesia‐associated mutation enhances BK channel activation by potentiating Ca2+ sensing. Neuron 66: 871‐883, 2010.
 600. Yang N, George AL Jr., Horn R. Molecular basis of charge movement in voltage‐gated sodium channels. Neuron 16: 113‐122, 1996.
 601. Ye S, Li Y, Chen L, Jiang Y. Crystal structures of a ligand‐free MthK gating ring: Insights into the ligand gating mechanism of K+ channels. Cell 126: 1161‐1173, 2006.
 602. Ye X, Fukushima N, Kingsbury MA, Chun J. Lysophosphatidic acid in neural signaling. Neuroreport 13: 2169‐2175, 2002.
 603. Yellen G. The moving parts of voltage‐gated ion channels. Q Rev Biophys 31: 239‐295, 1998.
 604. Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M, Kurachi Y. Somatostatin induces hyperpolarization in pancreatic islet alpha cells by activating a G protein‐gated K+ channel. FEBS Lett 444: 265‐269, 1999.
 605. Yuan A, Dourado M, Butler A, Walton N, Wei A, Salkoff L. SLO‐2, a K+ channel with an unusual Cl‐ dependence. Nat Neurosci 3: 771‐779, 2000.
 606. Yuan A, Santi CM, Wei A, Wang ZW, Pollak K, Nonet M, Kaczmarek L, Crowder CM, Salkoff L. The sodium‐activated potassium channel is encoded by a member of the Slo gene family. Neuron 37: 765‐773, 2003.
 607. Yuan P, Leonetti MD, Pico AR, Hsiung Y, Mackinnon R. Structure of the Human BK Channel Ca2+‐Activation Apparatus at 3.0 A Resolution. Science 329: 182‐186, 2010.
 608. Yuill KH, Stansfeld PJ, Ashmole I, Sutcliffe MJ, Stanfield PR. The selectivity, voltage‐dependence and acid sensitivity of the tandem pore potassium channel TASK‐1: Contributions of the pore domains. Pflugers Arch 455: 333‐348, 2007.
 609. Yusaf SP, Wray D, Sivaprasadarao A. Measurement of the movement of the S4 segment during the activation of a voltage‐gated potassium channel. Pflugers Arch 433: 91‐97, 1996.
 610. Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R. The RCK2 domain of the human BKCa channel is a calcium sensor. Proc Natl Acad Sci U S A 105: 376‐381, 2008.
 611. Zagha E, Manita S, Ross WN, Rudy B. Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes. J Neurophysiol 103: 3516‐3525.
 612. Zagotta WN, Hoshi T, Aldrich RW. Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB. Science 250: 568‐571, 1990.
 613. Zagotta WN, Hoshi T, Aldrich RW. Shaker potassium channel gating. III: Evaluation of kinetic models for activation. J Gen Physiol 103: 321‐362, 1994.
 614. Zagotta WN, Hoshi T, Dittman J, Aldrich RW. Shaker potassium channel gating. II: Transitions in the activation pathway. J Gen Physiol 103: 279‐319, 1994.
 615. Zarei MM, Song M, Wilson RJ, Cox N, Colom LV, Knaus HG, Stefani E, Toro L. Endocytic trafficking signals in KCNMB2 regulate surface expression of a large conductance voltage and Ca(2+)‐activated K+ channel. Neuroscience 147: 80‐89, 2007.
 616. Zarei MM, Zhu N, Alioua A, Eghbali M, Stefani E, Toro L. A novel MaxiK splice variant exhibits dominant‐negative properties for surface expression. J Biol Chem 276: 16232‐16239, 2001.
 617. Zaritsky JJ, Redell JB, Tempel BL, Schwarz TL. The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol 533: 697‐710, 2001.
 618. Zawar C, Plant TD, Schirra C, Konnerth A, Neumcke B. Cell‐type specific expression of ATP‐sensitive potassium channels in the rat hippocampus. J Physiol 514(Pt 2): 327‐341, 1999.
 619. Zeng XH, Xia XM, Lingle CJ. Redox‐sensitive extracellular gates formed by auxiliary beta subunits of calcium‐activated potassium channels. Nat Struct Biol 10: 448‐454, 2003.
 620. Zeng XH, Xia XM, Lingle CJ. Divalent cation sensitivity of BK channel activation supports the existence of three distinct binding sites. J Gen Physiol 125: 273‐286, 2005.
 621. Zhang BM, Kohli V, Adachi R, Lopez JA, Udden MM, Sullivan R. Calmodulin binding to the C‐terminus of the small‐conductance Ca2+‐activated K+ channel hSK1 is affected by alternative splicing. Biochemistry 40: 3189‐3195, 2001.
 622. Zhang G, Huang SY, Yang J, Shi J, Yang X, Moller A, Zou X, Cui J. Ion sensing in the RCK1 domain of BK channels. Proc Natl Acad Sci U S A 107: 18700‐18705, 2010.
 623. Zhang PC, Keleshian AM, Sachs F. Voltage‐induced membrane movement. Nature 413: 428‐432, 2001.
 624. Zhang X, Bertaso F, Yoo JW, Baumgartel K, Clancy SM, Lee V, Cienfuegos C, Wilmot C, Avis J, Hunyh T, Daguia C, Schmedt C, Noebels J, Jegla T. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci 13: 1056‐1058.
 625. Zhang X, Zeng X, Lingle CJ. Slo3 K+ channels: Voltage and pH dependence of macroscopic currents. J Gen Physiol 128: 317‐336, 2006.
 626. Zhang Y, Gao F, Popov VL, Wen JW, Hamill OP. Mechanically gated channel activity in cytoskeleton‐deficient plasma membrane blebs and vesicles from Xenopus oocytes. J Physiol 523(Pt 1): 117‐130, 2000.
 627. Zheng J, Sigworth FJ. Intermediate conductances during deactivation of heteromultimeric Shaker potassium channels. J Gen Physiol 112: 457‐474, 1998.
 628. Zhou Y, MacKinnon R. The occupancy of ions in the K+ selectivity filter: Charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J Mol Biol 333: 965‐975, 2003.
 629. Zhou Y, Morais‐Cabral JH, Kaufman A, MacKinnon R. Chemistry of ion coordination and hydration revealed by a K+ channel‐Fab complex at 2.0 A resolution. Nature 414: 43‐48, 2001.
 630. Zhou Z, Misler S. Action potential‐induced quantal secretion of catecholamines from rat adrenal chromaffin cells. J Biol Chem 270: 3498‐3505, 1995.
 631. Zilberberg N, Ilan N, Goldstein SA. KCNKO: Opening and closing the 2‐P‐domain potassium leak channel entails “C‐type” gating of the outer pore. Neuron 32: 635‐648, 2001.
 632. Zingman LV, Hodgson DM, Bast PH, Kane GC, Perez‐Terzic C, Gumina RJ, Pucar D, Bienengraeber M, Dzeja PP, Miki T, Seino S, Alekseev AE, Terzic A. Kir6.2 is required for adaptation to stress. Proc Natl Acad Sci U S A 99: 13278‐13283, 2002.
 633. Zobel C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, Backx PH. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: Evidence for heteromeric co‐assembly of Kir2.1 and Kir2.2. J Physiol 550: 365‐372, 2003.
 634. Zou A, Lin Z, Humble M, Creech CD, Wagoner PK, Krafte D, Jegla TJ, Wickenden AD. Distribution and functional properties of human KCNH8 (Elk1) potassium channels. Am J Physiol Cell Physiol 285: C1356‐C1366, 2003.

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Carlos González, David Baez‐Nieto, Ignacio Valencia, Ingrid Oyarzún, Patricio Rojas, David Naranjo, Ramón Latorre. K+ Channels: Function‐Structural Overview. Compr Physiol 2012, 2: 2087-2149. doi: 10.1002/cphy.c110047