Comprehensive Physiology Wiley Online Library

Ion Channels in the Heart: Cellular and Molecular Properties of Cardiac Na, Ca, and K Channels

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Calcium Channels
2 Sodium Channels
2.1 Primary Structure of the Voltage‐Gated Na+ Channel
2.2 Molecular Pharmacology of Na+ Channels
2.3 Molecular Pharmacology of an Inherited Disease
3 Potassium Channels
3.1 Voltage‐Dependent K+ Channels
3.2 Inward Rectifier K Channels
4 Summary
Figure 1. Figure 1.

Predicted topology for the α1 subunit of voltage‐gated potassium (A), and sodium or calcium (B) channels.

From Keating and Sanguinetti , with permission
Figure 2. Figure 2.

Schematic representation of the subunit composition of L‐type skeletal (left) and cardiac (right) calcium channels. Note that predicted PKA phosphorylation sites are indicated as solid squares.

From Hosey et al., with permission
Figure 3. Figure 3.

The response of L‐type calcium channels to β‐AR stimulation changes with development. Response of currents measured in single murine embryonic cells to isoproterenol in early stage (a) and late stage (b) embryonic heart. The currents in the late, but not early, stage cells are enhanced by isoproterenol and this effect is due to an increase in intracellular cAMP.

From An et al., with permission
Figure 4. Figure 4.

Recombinant channels formed by α1 subunits reconstitute voltage‐ and calcium‐dependent properties of native channels. Recordings from mammalian cells transfected with cDNA encoding the α1 subunit of smooth muscle L‐type calcium channels (α1c–b) (right‐hand panel) compared with L‐type channel activity measured in guinea pig ventricular myocytes (left‐hand panel). The rows compare current when barium (lower) or calcium (upper) is the charge carrier.

From Welling et al., , with permission
Figure 5. Figure 5.

Domain interface model of high‐affinity phenylalkylamine block of L‐type calcium channels. Location of pore region glutamates (A) and key amino acid residues in domains IIIS6 and IVS6 (white symbols on black circles) that, when mutated, disrupt block of channel activity by the charged phenylalkylamine (−)‐D888. Proposed model to explain block of channels postulates that convergence of the pore region of domains III and IV with key residues of IIIS6 forms the binding site for this drug.

From Hockerman et al. , with permission
Figure 6. Figure 6.

An inherited deletion mutation (KPQ) of the human sodium channel α subunit (hH1) promotes maintained current in response to prolonged depolarization. Currents measured from cells transfected with wild‐type (hH1) or mutant (KPQ) Na channel α subunits are shown for peak (left) and maintained (right) current. The KPQ mutation, which causes one form of the long QT syndrome, promotes additional maintained current (right), but does not affect peak currents.

From An et al. , with permission
Figure 7. Figure 7.

Simplified gating states for model Na channel. Transitions are allowed between rested (R), open (O), fast inactivated (IF) and slow inactivated (IS) states. Not indicated here are intermediate inactivated states of the channel as well as multiple open states. However, upper arrows indicate direct transitions between rested and inactivated states of the channel.

Figure 8. Figure 8.

Schematic of sequence of voltage‐gated Na channel alpha subunit. Note four homologous domains, each of which contains six helical transmembrane fragments. C‐ and N‐termini are intracellular.

Figure 9. Figure 9.

The local anesthetic drug lidocaine blocks maintained current through mutant LQT‐3 (KPQ) Na channels more potently than peak currents of either hH1 (wild‐type) or KPQ channels. Plotted is the fraction of current blocked for each channel construct in response to 100 μM lidocaine. These results strongly suggested that this type of drug might be useful in specifically treating the inherited arrhythmia LQT‐3 caused by this gene mutation.

From An et al. , with permission
Figure 10. Figure 10.

Multiple potassium channels in the developing mouse heart. Patch‐clamp recordings of murine embryonic ventricular cells reveals rapidly activating K channel current that inactivates rapidly (A), slowly (B), or not at all (C). These components in the mouse heart reflect Ito (left and center) and Iur (right).

From Davies et al. , with permission
Figure 11. Figure 11.

Two components of delayed rectifier potassium current are revealed by differential sensitivity to block by class III antiarrhythmic agents, Action potentials and membrane currents recorded in the absence (Curve C) and presence (Curve E) of 5 μM E‐4031. Difference currents (DIF) reveal the properties of the current blocked by the drug, which is called IKr. Lower panel shows the voltage‐dependence of activation of total delayed rectifier current (IK) as well as the two components: IKr (open circles) and IKs (open squares).

From Sanguinetti and Jurkiewicz , with permission
Figure 12. Figure 12.

Single‐channel recordings from inward rectifier channels indicate that rectification (the tendency to pass more current in one direction than another) occurs at the single‐channel level.

From Sakmann and Trube , with permission
Figure 13. Figure 13.

Reconstitution of IKATP. Co‐expression of inward rectifier subunit (Kir6.2) with, a the sulfonylurea receptor (SUR2A) encodes channel activity that demonstrates conductance, permeation, and ATP‐sensitivity of native IKATP channels

from Inagaki et al , with permission


Figure 1.

Predicted topology for the α1 subunit of voltage‐gated potassium (A), and sodium or calcium (B) channels.

From Keating and Sanguinetti , with permission


Figure 2.

Schematic representation of the subunit composition of L‐type skeletal (left) and cardiac (right) calcium channels. Note that predicted PKA phosphorylation sites are indicated as solid squares.

From Hosey et al., with permission


Figure 3.

The response of L‐type calcium channels to β‐AR stimulation changes with development. Response of currents measured in single murine embryonic cells to isoproterenol in early stage (a) and late stage (b) embryonic heart. The currents in the late, but not early, stage cells are enhanced by isoproterenol and this effect is due to an increase in intracellular cAMP.

From An et al., with permission


Figure 4.

Recombinant channels formed by α1 subunits reconstitute voltage‐ and calcium‐dependent properties of native channels. Recordings from mammalian cells transfected with cDNA encoding the α1 subunit of smooth muscle L‐type calcium channels (α1c–b) (right‐hand panel) compared with L‐type channel activity measured in guinea pig ventricular myocytes (left‐hand panel). The rows compare current when barium (lower) or calcium (upper) is the charge carrier.

From Welling et al., , with permission


Figure 5.

Domain interface model of high‐affinity phenylalkylamine block of L‐type calcium channels. Location of pore region glutamates (A) and key amino acid residues in domains IIIS6 and IVS6 (white symbols on black circles) that, when mutated, disrupt block of channel activity by the charged phenylalkylamine (−)‐D888. Proposed model to explain block of channels postulates that convergence of the pore region of domains III and IV with key residues of IIIS6 forms the binding site for this drug.

From Hockerman et al. , with permission


Figure 6.

An inherited deletion mutation (KPQ) of the human sodium channel α subunit (hH1) promotes maintained current in response to prolonged depolarization. Currents measured from cells transfected with wild‐type (hH1) or mutant (KPQ) Na channel α subunits are shown for peak (left) and maintained (right) current. The KPQ mutation, which causes one form of the long QT syndrome, promotes additional maintained current (right), but does not affect peak currents.

From An et al. , with permission


Figure 7.

Simplified gating states for model Na channel. Transitions are allowed between rested (R), open (O), fast inactivated (IF) and slow inactivated (IS) states. Not indicated here are intermediate inactivated states of the channel as well as multiple open states. However, upper arrows indicate direct transitions between rested and inactivated states of the channel.



Figure 8.

Schematic of sequence of voltage‐gated Na channel alpha subunit. Note four homologous domains, each of which contains six helical transmembrane fragments. C‐ and N‐termini are intracellular.



Figure 9.

The local anesthetic drug lidocaine blocks maintained current through mutant LQT‐3 (KPQ) Na channels more potently than peak currents of either hH1 (wild‐type) or KPQ channels. Plotted is the fraction of current blocked for each channel construct in response to 100 μM lidocaine. These results strongly suggested that this type of drug might be useful in specifically treating the inherited arrhythmia LQT‐3 caused by this gene mutation.

From An et al. , with permission


Figure 10.

Multiple potassium channels in the developing mouse heart. Patch‐clamp recordings of murine embryonic ventricular cells reveals rapidly activating K channel current that inactivates rapidly (A), slowly (B), or not at all (C). These components in the mouse heart reflect Ito (left and center) and Iur (right).

From Davies et al. , with permission


Figure 11.

Two components of delayed rectifier potassium current are revealed by differential sensitivity to block by class III antiarrhythmic agents, Action potentials and membrane currents recorded in the absence (Curve C) and presence (Curve E) of 5 μM E‐4031. Difference currents (DIF) reveal the properties of the current blocked by the drug, which is called IKr. Lower panel shows the voltage‐dependence of activation of total delayed rectifier current (IK) as well as the two components: IKr (open circles) and IKs (open squares).

From Sanguinetti and Jurkiewicz , with permission


Figure 12.

Single‐channel recordings from inward rectifier channels indicate that rectification (the tendency to pass more current in one direction than another) occurs at the single‐channel level.

From Sakmann and Trube , with permission


Figure 13.

Reconstitution of IKATP. Co‐expression of inward rectifier subunit (Kir6.2) with, a the sulfonylurea receptor (SUR2A) encodes channel activity that demonstrates conductance, permeation, and ATP‐sensitivity of native IKATP channels

from Inagaki et al , with permission
References
 1. Alpert, L. A., H. A. Fozzard, D. A. Hanck, and J. C. Makielski. Is there a second external lidocaine binding site on mammalian cardiac cells?. Am. J. Physiol. 257 (Heart Circ. Physiol.): H79–H84, 1989.
 2. Ahlijanian, M. K., R. E. Westenbroek, and W. A. Catterall. Subunit structure and localization of dihydropyridine‐sensitive calcium channels in mammalian brain, spinal cord, and retina. Neuron 4: 819–832, 1990.
 3. An, R.‐H., B. Heath, W. J. Koch, R. J. Lefkowitz, and R. S. Kass. Targeting of cAMP‐dependent increases In L‐type Ca (ICa) over delayed K channel (IKs) activity by overexpression of the beta2‐adrenergic receptor in the developing mouse heart. Biophys. J. 74: A35 (Abstract), 1998.
 4. An, R. H., R. Bangalore, S. Z. Rosero, and R. S. Kass. Lidocaine block of LQT‐3 mutant human Na channels. Circ. Res. 79, 103–108, 1996.
 5. Attali, B., F. Lesage, P. Ziliani, E. Guillemare, E. Honore, R. Waldmann, M. G. Mattei, M. Lazdunski, and J. Barhanin. Multiple mRNA isoforms encoding the mouse cardiac Kv1–5 delayed rectifier K+ channel. J. Biol. Chem. 268, 24283–24289, 1993.
 6. Attwell, D., I. Cohen, D. Eisner, M. Ohba, and C. Ojeda. The steady state TTX‐sensitive (“window”) sodium current in cardiac Purkinje fibres. Pflugers Arch. 379, 137–142, 1979.
 7. Balke, C. W., W. C. Rose, B. O'Rourke, R. Mejia‐Alvarez, P. Backx, and E. Marban. Biophysics and physiology of cardiac calcium channels. Circulation 87 (Suppl. 7): VII49–VII53, 1993.
 8. Bangalore, R., G. Mehrke, K. Gingrich, F. Hofmann, and R. S. Kass. Influence of the L‐type Ca‐channel 2/Δ subunit on ionic and gating current in transiently‐transfected HEK 293 cells. Am. J. Physiol. 270 (Heart Circ. Physiol. 39), H1521–H1528. 1996.
 9. Barhanin, J., F. Lesage, E. Guillemare, M. Fink, M. Lazdunski, and G. Romey. K(V)LQT1 and ISK (MINK) proteins associate to form the i‐ks cardiac potassium current. Nature 384: 78–80, 1996.
 10. Bean, B. P. (1985). Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology. Journal of General Physiology 86, 1–30.
 11. Bean, B. P. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol. 51: 367–384, 1989.
 12. Beeler, G. W., Jr. and H. Reuter. Membrane calcium current in ventricular myocardial fibres. J. Physiol. (Lond.) 207: 191–209, 1970.
 13. Beeler, G. W., Jr. and H. Reuter. The relation between membrane potential, membrane currents and activation of contraction in ventricular myocardial fibres. J. Physiol. (Lond.) 207: 211–229, 1970.
 14. Bennett, P. B., K. Yazawa, N. Makita, and A. L. George. Molecular mechanism for an iniherited cardiac arrhythmia. Nature 376: 683–685, 1995.
 15. Birnbaumer, L., K. P. Campbell, W. A. Catterall, M. M. Harpold, F. Hofmann, W. A. Horne, Y. Mori, A. Schwartz, T. P. Snutch, T. Tanabe, et al. The naming of voltage‐gated calcium channels. Neuron 13: 505–506, 1994.
 16. Brahmajothi, M. V., M. J. Morales, S. Liu, R. L. Rasmusson, D. L. Campbell, and H. C. Strauss. In situ hybridization reveals extensive diversity of K+ channel mRNA in isolated ferret cardiac myocytes. Circ. Res. 78: 1083–1089, 1996.
 17. Bryan, J. and L. Aguilar‐Bryan. The ABCs of ATP‐sensitive potassium channels: more pieces of the puzzle. Curr. Opin. Cell Biol. 9: 553–559, 1997.
 18. Cachelin, A. B., J. E. De Peyer, S. Kokubun, and H. Reuter. Ca channel modulation by 8‐bromocyclic AMP in cultured heart cells. Nature 304: 462–464, 1983.
 19. Cannell, M. B., H. Cheng, and W.J. Lederer. Spatial nonuniformities in [Ca2+]i during excitation‐contraction coupling in cardiac myocytes. Biophys. J. 67: 1942–1956, 1994.
 20. Cannell, M. B., H. Cheng, and W. J. Lederer. The control of calcium release in heart muscle. Science 268: 1045–1049, 1995.
 21. Carmeliet, E. Voltage‐ and time‐dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J. Pharmacol. Exp. Ther. 262: 809–817, 1992.
 22. Carmeliet, E., P. Busselen, F. Verdonck, and J. Vereecke. Ca ions and excitation‐contraction coupling in heart muscle. Verh. K. Acad. Geneeskd. Belg. 35: 181–222, 1973.
 23. Carmeliet, E. and P. P. van Bogaert. Strontium action potentials in cardiac Purkinje fibers. Reunion de Liège, Societé Belge de Physiologie et de Pharmacologie, 1969: 134–135.
 24. Catterall, W. and P. N. Epstein. Ion channels. [Review]. Diabetologia 35 (Suppl 2): S23–33, 1992.
 25. Catterall, W. A. Structure and function of voltage‐gated ion channels. [Review]. Trends Neurosci. 16: 500–506, 1993.
 26. Catterall, W. A. Molecular properties of a superfamily of plasma‐membrane cation channels. [Review]. Curr. Opin. Cell Biol. 6: 607–615, 1994.
 27. Catterall, W. A. Ion channels in plasma membrane signal transduction. J. Bioenerg. Biomembr. 28: 217–218, 1996.
 28. Catterall, W. A. Molecular properties of sodium and calcium channels. J. Bioenerg. Biomembr. 28: 219–230, 1996.
 29. Catterall, W. A., T. Scheuer, W. Thomsen, and S. Rossie. Structure and modulation of voltage‐gated ion channels. Ann. N.Y. Acad. Sci. 625: 174–180, 1991.
 30. Catterall, W. A., M. J. Seagar, and M. Takahashi. Molecular properties of dihydropyridine‐sensitive calcium channels in skeletal muscle. J. Biol. Chem. 263: 3535–3538, 1988.
 31. Catterall, W. A. and J. Striessnig. Receptor sites for Ca channel antagonists. TIPS 13: 256–262, 1992.
 32. Catterall, W. A., V. Trainer, and D. G. Baden. Molecular properties of the sodium channel: a receptor for multiple neurotoxins. Bull. Soc. Pathol. Exot. 85: 481–485, 1992.
 33. Chu, A., M. Fill, M. L. Entman, and E. Stefani. Different Ca2+ sensitivity of the ryanodine‐sensitive Ca2+ release channels of cardiac and skeletal muscle sarcoplasmic reticulum. Biophys. J. 59: 102a–102a, 1991.
 34. Chutkow, W. A., M. C. Simon, M. M. Le Beau, and C. F. Burant. Cloning, tissue expression and chromosomal localization of SUR2, the putative drug‐binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 45: 1439–1445, 1996.
 35. Colatsky, T. J. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit Purkinje fibers. An effect on steady state sodium currents?. Circ. Res. 50: 17–27, 1982.
 36. Coraboeuf, E., E. Deroubaix, and A. Coulombe. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am. J. Physiol. 236: (Heart Circ. Physiol. 5): H561–H567, 1979.
 37. Cribbs, L. L., J. Satin, H. A. Fozzard, and R. B. Rogart. Functional expression of the rat heart I Na+ channel isoform. Demonstration of properties characteristic of native cardiac Na+ channels. FEBS Lett. 275: 195–200, 1990.
 38. Curran, M. E., I., Splawski, K. W., Timothy, G. M., Vincent, E. D. Green, and M. T. Keating. A molecular basis for cardiac arrhythmia:. HERG mutations cause long QT syndrome. Cell 80: 795–803, 1995.
 39. Davies, M. P., R. H. An, P. Doevendans, S. Kubalak, K. R. Chien, R. S. Kass. Developmental Changes in Ionic Channel Activity in the Embryonic Murine Heart. American Heart Assoc., Inc. 1996.
 40. Davis, N. W., N. B. Standen, and P. R. Stanfield. ATP‐dependent potassium channels of muscle cells: their properties, regulation, and possible functions. J. Bioenerg. Biomembr. 23: 509–535, 1991.
 41. Dixon, J. E. and D. McKinnon. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circulation Research 75: 252–260, 1994.
 42. Dixon, J. E., W. Shi, H. S. Wang, C. McDonald, H. Yu, R. S. Wymore, I. S. Cohen, and D. McKinnon. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. [Published erratum appears in. Circ. Res. 1997 Jan, 80:147]. Circ. Res. 79: 659–668, 1996.
 43. England, S. K., V. N. Uebele, J. Kodali, P. B. Bennett, and M. M. Tamkun. A novel K+ channel α‐subunit (hKv 1.3) is produced via alternative mRNA splicing. J. Biol. Chem. 270: 000–000, 1995.
 44. England, S. K., V. N. Uebele, H. Shear, J. Kodali, P. B. Bennett, and M. M. Tamkun. Characterization of a voltage‐gated K+ channel α subunit expressed in human heart. Proc. Natl. Acad. Sci. U.S.A. 92: 6309–6313, 1995.
 45. Fedida, D. and W. R. Giles. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J. Physiol. (Lond) 442: 191–209, 1991.
 46. Fedida, D., B. Wible, Z. Wang, B. Fermini, F. Faust, S. Nattel, and A. M. Brown. Identity of a novel delayed rectifier current from human heart with a cloned K channel current. Circ. Res. 73: 210–216, 1993.
 47. Ficker, E., M. Taglialatela, B. A. Wible, C. M. Henley, and A. M. Brown. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science 266: 1068–1072, 1994.
 48. Findlay, I. The ATP sensitive potassium channel of cardiac muscle and action potential shortening during metabolic stress. Cardiovasc. Res. 28: 760–761, 1994.
 49. Fozzard, H. A. and M. Hiraoka. The positive dynamic current and its inactivation properties in cardiac Purkinje fibres. J. Physiol. (Lond.) 234: 569–586, 1973.
 50. Furberg, C. D. and B. M. Psaty. Should dihydropyridines be used as first‐line drugs in the treatment of hypertension—the con side. Arch. Intern. Med. 155: 2157–2161, 1995.
 51. Gao, T., T. S. Puri, B. L. Gerhardstein, A. J. Chien, R. D. Green, and M. M. Hosey. Identification and subcellular localization of the subunits of L‐type calcium channels and adenylyl cyclase in cardiac myocytes. J. Biol. Chem. 272: 19401–19407, 1997.
 52. Gao, T., A. Yatani, M. L. Dell'Acqua, H. Sako, S. A. Green, N. Dascal, J. D. Scott, and M. M. Hosey. cAMP‐dependent regulation of cardiac L‐type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. Neuron 19: 185–196, 1997.
 53. Gellens, M. E., A. L. George, Jr., L. Q. Chen, M. Chahine, R. Horn, R. L. Barchi, and R. G. Kallen. Primary structure and functional expression of the human cardiac tetrodotoxininsensitive voltage‐dependent sodium channel. Proc. Natl. Acad. Sci. U.S.A. 89: 554–558, 1992.
 54. Gutierrez, L. M., R. M. Brawley, and M. M. Hosey. Dihydropyridine‐sensitive calcium channels from skeletal muscle. I. Roles of subunits in channel activity. J. Biol. Chem. 266: 16387–16394, 1991.
 55. Gutierrez, L. M., X. L. Zhao, and M. M. Hosey. Protein kinase C‐mediated regulation of L‐type Ca channels from skeletal muscle requires phosphorylation of the alpha 1 subunit. Biochem. Biophys. Res. Commun. 202: 857–865, 1994.
 56. Heinemann, S. H., J. Rettig, F. Wunder, and O. Pongs. Molecular and functional characterization of a rat brain Kv beta 3 potassium channel subunit. FEBS Lett. 377: 383–389, 1995.
 57. Hille, B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug‐receptor reaction. J. Gen. Physiol. 69: 497–515, 1977.
 58. Hille, B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug‐receptor reaction. J. Gen. Physiol. 69: 497–515, 1977.
 59. Hille, B. Ionic Channels of Excitable Membranes. Sunderland, MA: Sinauer, 1992.
 60. Hiraoka, M., K. Sawada, and S. Kawano. Effect of quinidine on plateau currents of guinea‐pig ventricular myocytes. J. Mol. Cell. Cardiol. 18: 1097–1106, 1986.
 61. Ho, K., C. G. Nichols, W. J. Lederer, J. Lytton, P. M. Vassilev, M. V. Kanazirska, and S. C. Hebert. Cloning and expression of an inwardly rectifying ATP‐regulated potassium channel. Nature 362: 31–38, 1993.
 62. Hockerman, G. H., B. Z. Peterson, B. D. Johnson, and W. A. Catterall. Molecular determinants of drug binding and action on L‐type calcium channels. Annu. Rev. Pharmacol. Toxicol. 37: 361–396, 1997.
 63. Hockerman, G. H., B. D. Johnson, M. R. Abbott, T. Scheuer, and W. A. Catterall. Molecular determinants of high affinity phenylalkylamine block of L‐type calcium channels in transmembrane segment IIIS6 and the pore region of the alpha 1 subunit. J. Biol. Chem. 272: 18759–18765, 1997.
 64. Hodgkin, A. L. and A. F. Huxley. A quantitive description of membrane current and its application to conduction and excitation in nerve. J. Physiol.(Lond.) 117: 500–544, 1952.
 65. Hofmann, F., M. Biel, E. Bosse, V. Flockerzi, P. Ruth, and A. Welling. Functional expression of cardiac and smooth muscle calcium channels. In Ion Channels in the Cardiovascular System: Function and Dysfunction, edited by A. M. Brown, W. A. Catterrall, G. J. Kaczorowski, P. S. Spooner, and H. C. Strauss, pp. Washington, DC: AAAS Press, 1993.
 66. Hosey, M. M., A. J. Chien, and T. S. Puri. Structure and regulation of L‐type calcium channels—a current assessment of the properties and roles of channel subunits. Trends Cardiovasc. Med. 6: 265–273, 1996.
 67. Hoshi, T., W. N. Zagotta, and R. W. Aldrich. Biophysical and molecular mechanisms of Shaker potassium channel inactivation [see comments]. Science 250: 533–538, 1990.
 68. Inagaki, N., T. Gonoi, J. P. Clement, C. Z. Wang, L. Aguilar‐Bryan, J. Bryan, and S. Seino. A family of sulfonylurea receptors determines the pharmacological properties of ATP‐sensitive K+ channels. Neuron 16: 1011–1017, 1996.
 69. Inagaki, N., Y. Tsuura, N. Namba, K. Masuda, T. Gonoi, M. Horie, Y. Seino, M. Mizuta, and S. Seino. Cloning and functional characterization of a novel ATP‐sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J. Biol. Chem. 270: 5691–5694, 1995.
 70. Irisawa, H. and N. Hagiwara. Ionic current in sinoatrial node cells. J. Cardiovascu. Electrophysiol. 2: 531–540, 1991.
 71. Isacoff, E., D. Papazian, L. Timpe, Y. N. Jan, and L. Y. Jan. Molecular studies of voltage‐gated potassium channels. Cold Spring Harbor Symp. Quant. Biol. 55: 9–17, 1990.
 72. Ishii, K., T. Yamagishi, and N. Taira. Cloning and functional expression of a cardiac inward rectifier K+ channel. FEBS Lett. 338: 107–111, 1994.
 73. Isom, L. L., K. S. De Jongh, and W. A. Catterall. Auxiliary subunits of voltage‐gated ion channels. Neuron 12: 1183–1194, 1994.
 74. Josephson, I. R., J. Sanchez‐Chapula, and A. M. Brown. Early outward current in rat single ventricular cells. Circ. Res. 54: 157–162, 1984.
 75. Kamb, A., L. E. Iverson, and M. A. Tanouye. Molecular characterization of. shaker, a Drosophila gene that encodes a potassium channel. Cell 50: 405–413, 1987.
 76. Kass, R. S. Dihydropyridine modulation of cardiovascular L‐type calcium channels: molecular and cellular pharmacology. In Ion Channels in the Cardiovascular System: Function and Dysfunction, edited by P. M. Spooner, A. M. Brown, W. A. Catterall, G. J. Kaczorowski, and H. C. Strauss. Armonk, NY: Futura Publishing Co., 1994: 425–440.
 77. Kass, R. S. Ionic basis of electrical activity in the heart. In Physiology and Pathophysiology of the Heart, edited by N. Sperelakis, Norwell, MA: Kluwer Academic, 1994.
 78. Kass, R. S. Molecular pharmacology of cardiac L‐type calcuim channels. In Handbook of Membrane Channels: Molecular and Cellular Physiology, edited by C. Peracchia. Orlando, FL: Academic Press, 1994: 187–198.
 79. Kass, R. S. and M. P. Davies. The roles of ion channels in an inherited heart disease: molecular genetics of the long QT syndrome. Cardiovasc. Res. 32: 443–454, 1996.
 80. Kass, R. S. and M. C. Sanguinetti. Calcium channel inactivation in the cardiac Purkinje fiber. Evidence for voltage‐and calcium‐mediated mechanisms. J. Gen. Physiol. 84: 705–726, 1984.
 81. Kass, R. S. and R. W. Tsien. Multiple effects of calcium antagonists on plateau currents in cardiac purkinje fibers. J. Gen. Physiol. 66: 169–192, 1975.
 82. Kass, R. S. and R. W. Tsien. Control of action potential duration by calcium ions in cardiac purkinje fibers. J. Gen. Physiol. 67: 599–617, 1976.
 83. Kass, R. S. and S. E. Wiegers. The ionic basis of concentrationrelated effects of noradrenaline on the action potential of calf cardiac Purkinje fibres. J. Physiol. (Lond.) 322: 541–558, 1982.
 84. Kenyon, J. L. and J. L. Sutko. Calcium‐ and voltage‐activated plateau currents of cardiac Purkinje fibers. J. Gen. Physiol. 89: 921–958, 1987.
 85. Kubo, Y., E. Reuveny, P. A. Slesinger, Y. N. Jan and L. Y. Jan. Primary structure and functional expression of a rat G‐proteincoupled muscarinic potassium channel [see comments]. Nature 364: 802–806, 1993.
 86. Lacerda, A. E., H. S. Kim, P. Ruth, E. Perez‐Reyes, V. Flockerzi, F. Hofmann, L. Birnbaumer, and A. M. Brown. Normalization of current kinetics by interaction between the α 1 and ã subunits of the skeletal muscle dihydropyridine‐sensitive Ca2+ channel. Nature 352: 527, 1991.
 87. Logothetis, D. E., Y. Kurachi, J. Galper, E. J. Neer, and D. E. Clapham. The beta‐gamma subunits of GTP‐binding proteins activate the muscarinic K+ channel in heart. Nature 325: 321–326, 1987.
 88. Lopatin, A. N., E. N. Makhina, and C. G. Nichols. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372: 366–369, 1994.
 89. Lory, P., G. Varadi, D. F. Slish, M. Varadi, and A. Schwartz. Characterization of beta subunit modulation of a rabbit cardiac L‐type Ca2+ channel alpha 1 subunit as expressed in mouse L cells. FEBS Lett. 315: 167–172, 1993.
 90. Ma, J., L. M. Gutierrez, M. M. Hosey, and E. Rios. Dihydropyridine‐sensitive skeletal muscle Ca channels in polarized planar bilayers. 3. Effects of phosphorylation by protein kinase C. Biophys. J. 63: 639–647, 1992.
 91. MacKinnon, R., R. W. Aldrich, and A. W. Lee. Functional stoichiometry of Shaker potassium channel inactivation. Science 262: 757–759, 1993.
 92. MacKinnon, R. and C. Miller. Mutant potassium channels with altered binding of charybdotoxin, a pore‐blocking peptide inhibitor. Science 245: 1382–1384, 1989.
 93. MacKinnon, R. and Yellen, G. Mutations affecting TEA blockade and ion permeation in voltage activated K+ channels. Science 250: 276–279, 1990.
 94. Makielski, J. C., J. T. Limberis, S. Y. Chang, Z. Fan and J. W. Kyle. Coexpression of beta 1 with cardiac sodium channel alpha subunits in oocytes decreases lidocaine block. Mol. Pharmacol. 49: 30–39, 1996.
 95. Marks, A. R. Intracellular calcium‐release channels: regulators of cell life and death. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H597–H605, 1997.
 96. McCall, E., L. V. Hryshko, V. M. Stiffel, D. M. Christensen, and D. M. Bers. Possible functional linkage between the cardiac dihydropyridine and ryanodine receptor: acceleration of rest decay by Bay K 8644. J. Mol. Cell. Cardiol. 28: 79–93, 1996.
 97. McDonald, T. F., S. Pelzer, W. Trautwein, and D. J. Pelzer. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 74: 365–507, 1994.
 98. Mikami, A., K. Imoto, T. Tanabe, T. Niidome, Y. Mori, H. Takeshima, S. Narumiya and S. Numa. Primary structure and functional expression of the cardiac dihydropyridine‐sensitive calcium channel. Nature 340: 230–233, 1989.
 99. Miller, C. Genetic manipulation of ion channels: a new approach to structure and mechanism. Neuron 2: 1195–1205, 1989.
 100. Morad, M. and E. L. Rolett. Relaxing effects of catecholamines on mammalian heart. J. Physiol. (Lond.) 224: 537–558, 1972.
 101. Morad, M. and W. Trautwein. The effect of the duration of the action potential on contraction in the mammalian heart muscle. Pflügers Arch. 299: 66–82, 1968.
 102. Morad, M. and W. Trautwein. The effect of the duration of the action potential on contractions in mammalian heart tissue. Pflugers Arch 299: 66–82, 1968.
 103. Morales, M. J., J. O. Wee, S. Wang, H. C. Strauss, and R. L. Rasmusson. The N‐terminal domain of a K+ channel beta subunit increases the rate of C‐type inactivation from the cytoplasmic side of the channel. Proc. Natl. Acad. Sci. U.S.A. 93: 15119–15123, 1996.
 104. Mori, Y., T. Friedrich, M.‐S. Kim, A. Mikami, J. Nakai, P. Ruth, E. Bosse, F. Hofmann, V. Flockerzi, T. Furuichi, K. Nikoshiba, K. Imoto, T. Tanabe, and S. Numa. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350: 398–402, 1991.
 105. Moss, A. J. and J. L. Robinson. The long‐QT syndrome: genetic considerations. Trends Cardiovasc. Med. 2: 81–83, 1993.
 106. Neely, A., X. Wei, R. Olcese, L. Birnbaumer, and E. Stefani. Potentiation by the beta subunit of the ratio of the ionic current to the charge movement in the cardiac calcium channel. Science 262: 575–578, 1993.
 107. New, W. and W. Trautwein. The ionic nature of slow inward current and its relation to contraction. Pflügers Arch. 334: 24–38, 1972.
 108. Nichols, C. G. and A. N. Lopatin. Inward rectifier potassium channels. Annu. Rev. Physiol. 59: 171–191, 1997.
 109. Nishimura, S., H. Takeshima, F. Hofmann, V. Flockerzi, and K. Imoto. Requirement of the calcium channel beta subunit for functional conformation. FEBS Lett. 324: 283–286, 1993.
 110. Noble, D. and R. W. Tsien. Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J. Physiol. (Lond.) 200: 205–231, 1969.
 111. Noda, M., H. Suzuki, S. Numa, and W. Stuhmer. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett. 259: 213–216, 1989.
 112. Noma, A. ATP‐regulated K+ channels in cardiac muscle. Nature 305: 147–148, 1983.
 113. Nuss, H. B., N. Chiamvimonvat, M. T. Perezgarcia, G. F. Tomaselli, and E. Marban. Functional association of the beta subunit with human cardiac (HH1) and rat skeletal muscle (MU‐1) sodium channel alpha subunits expressed in. Xenopus oocytes. J. Gen. Physiol. 106: 1171–1191, 1995.
 114. Oh, S. T., E. Yedidag, J. L. Conklin, M. Martin, and K. Bielefeldt. Calcium release from intracellular stores and excitationcontraction coupling in intestinal smooth muscle. J. Surg. Res. 71: 79–86, 1997.
 115. Ono, K., H. A. Fozzard, and D. A. Hanck. Mechanism of cAMP‐dependent modulation of cardiac sodium channel current kinetics. Circ. Res. 72: 807–815, 1993.
 116. Ono, K., H. A. Fozzard, and D. A. Hanck. Mechanism of cAMP‐dependent modulation of cardiac sodium channel current kinetics. Circ. Res. 72: 807–815, 1993.
 117. Patlak, J. Molecular kinetics of voltage‐dependent Na+ channels. Physiol. Rev. 71: 1047–1080, 1991.
 118. Perez‐Reyes, E., L. L. Cribbs, A. Daud, A. E. Lacerda, J. Barclay, M. P. Williamson, M. Fox, M. Rees, and J. H. Lee. Molecular characterization of a neuronal low‐voltage‐activated T‐type calcium channel [see comments]. Nature 391: 896–900, 1998.
 119. Piedras‐Renteria, E. S., C. C. Chen, and P. M. Best. Antisense oligonucleotides against rat brain alphalE DNA and its atrial homologue decrease T‐type calcium current in atrial myocytes. Proc. Natl. Acad. Sci. U.S.A. 94: 14936–14941, 1997.
 120. Po, S., S. Roberds, D. J. Snyders, M. M. Tamkun, and P. B. Bennett. Heteromultimeric assembly of human potassium channels: molecular basis of a transient outward current?. Circ. Res. 72: 1326–1336, 1993.
 121. Pragnell, M., K. J. Snay, J. S. Trimmer, N. J. Maclusky, F. Naftolin, L. K. Kaczmarek, and M. B. Boyle. Estrogen induction of a small, putative K channel mRNA in rat uterus. Neuron 4: 807–812, 1990.
 122. Priori, S. G., F. Cantu, and P. J. Schwartz. The long QT syndrome—new diagnostic and therapeutic approach in the era of molecular biology. Schweiz. Med. Wochenschr. 1727–1731, 1996.
 123. Qu, Y., J. Rogers, T. Tanada, T. Scheuer, and W. A. Catterall. Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel. Proc. Natl. Acad. Sci. U.S.A. 92: 11839–11843, 1995.
 124. Raab‐Graham, K. F., C. M. Radeke, and C. A. Vandenberg. Molecular cloning and expression of a human heart inward rectifier potassium channel. NeuroReport 5: 2501–2505, 1994.
 125. Ragsdale, D. S., J. C. McPhee, T. Scheuer, and W. A. Catterall. Molecular determinants of state‐dependent block of Na+ channels by local anesthetics. Science 265: 1724–1728, 1994.
 126. Reuter, H. Slow inactivation of currents in cardiac Purkinje fibres. J. Physiol. 197: 233–253, 1968.
 127. Reuter, H. Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 301: 569–574, 1983.
 128. Reuter, H. and H. Scholz. The regulation of Ca conductance of cardiac muscle by adrenaline. J. Physiol. (Lond.) 264: 49–62, 1977.
 129. Roberds, S. L. and M. M. Tamkun. Cloning and tissue‐specific expression of five voltage‐gated potassium channel cDNAs expressed in rat heart. Proc. Nat. Acad. Sci. U.S.A. 88: 1798–1802, 1991.
 130. Rogart, R. B., L. L. Cribbs, L. K. Muglia, M. W. Kaiser, and D. D. Kephart. Molecular cloning of a putative tetrodotoxinresistant rat heart Na channel isoform. Proc. Natl. Acad. Sci. U.S.A. 86: 8170–8174, 1989.
 131. Ruth, P., A. Rohrkasten, M. Biel, E. Bosse, S. Regulla, H. E. Meyer, V. Flockerzi, and F. Hofmann. Primary structure of the subunit of the DHP‐sensitive calcium channel from skeletal muscle. Science 245: 1115–1118, 1989.
 132. Sakmann B., and G. Trube. Voltage‐dependent inactivation of inward rectifying single‐channel currents in the guinea‐pig heart cell membrane. J. Physiol 347: 659–683, 1984.
 133. Sanguinetti, M. C., M. E. Curran, P. S. Spector, and M. T. Keating. Spectrum of HERG K+‐channel dysfunction in an inherited cardiac arrythmia. Proc. Nat. Acad. Sci. U.S.A. 93: 8796–8796, 1996.
 134. Sanguinetti, M. C., M. E. Curran, A. Zou, Shen, J. P. S., X. A. D. Spector, and M. T. Keating. Coassembly of K(V)LQT1 and mink (isk) proteins to form cardiac I‐KS potassium channel. Nature 384: 80–83, 1996.
 135. Sanguinetti, M. C., C. Jiang, M. E. Curran, and M. T. Keating. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81: 299–307, 1995.
 136. Sanguinetti, M. C., J. H. Johnson, L. G. Hammerland, P. R. Kelbaugh, R. A. Volkmann, N. A. Saccomano, and A. L. Mueller. Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels. Mole. Pharmacol. 51: 491–498, 1997.
 137. Sanguinetti, M. C. and N. K. Jurkiewicz. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol. 96: 195–215, 1990.
 138. Schneider, T., and F. Hofmann. The bovine cardiac receptor for calcium channel blockers is a 195‐kDa protein. Eur. J. Biochem. 174: 369–375, 1988.
 139. Schonenherr, R., and S. H. Heinemann. Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J. Physiol. (Lond.) 493: 635–642, 1996.
 140. Schwarz, W., P. T. Palade, and B. Hille. Local anesthetics. Effect of pH on use‐dependent block of sodium channels in frog muscle. Biophys. J. 20: 343–368, 1977.
 141. Sculptoreanu, A., E. Rotman, M. Takahashi, T. Scheuer, and W. A. Catterall. Voltage‐dependent potentiation of the activity of cardiac L‐type calcium channel alpha 1 subunits due to phosphorylation by cAMP‐dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 90: 10135–10139, 1993.
 142. Sculptoreanu, A., T. Scheuer, and W. A. Catterall. Voltagedependent potentiation of L‐type Ca2+ channels due to phosphorylation by cAMP‐dependent protein kinase. Nature 364: 240–243, 1993.
 143. Shalaby, F. Y., P. C. Levesque, W. P. Yang, W. A. Little, M. L. Conder, T. Jenkins‐west, and M. A. Blanar. Dominant‐negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome [see comments]. Circulation 96: 1733–1736, 1997.
 144. Sham, J. S., L. Cleemann, and M. Morad. Functional coupling of Ca2+ channels and ryanodine receptors in cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 92: 121–125, 1995.
 145. Singer‐Lahat, D., I. Lotan, M. Biel, V. Flockerzi, F. Hofmann, and N. Dascal. Cardiac calcium channels expressed in. Xenopus oocytes are modulated by dephosphorylation but not by cAMP‐dependent phosphorylation. Receptors Channels 2: 215–226, 1994.
 146. Singer, D., M. Biel, I. Lotan, V. Flockerzi, F. Hofmann, and N. Dascal. The roles of the subunits in the function of the calcium channel. Science 253: 1553–1557, 1991.
 147. Smith P. L., T. Baukrowitz, and G. Yellen. The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379: 833–836, 1996.
 148. Splawski, I., M. Tristani‐Firouzi, M. H. Lehmann, M. C. Sanguinetti, and M. T. Keating. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat. Genet. 17: 338–340, 1997.
 149. Starmer, C. F. and K. R. Courtney. Modeling ion channel blockade at guarded binding sites: application to tertiary drugs. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H848–H856, 1986.
 150. Strichartz, G. Effects of tertiary local anesthetics and their quaternary derivatives on sodium channels of nerve membranes. Biophys. J. 18: 353–354, 1977.
 151. Stuhmer, W., F. Conti, H. Suzuki, X. Wang, M. Noda, N. Yahagi, H. Kubo, and S. Numa. Structural parts involved in activation and inactivation of the sodium channel. Nature 339: 597–603, 1989.
 152. Suzuki, H., S. Beckh, H. Kubo, N. Yahagi, H. Ishida, T. Kayano, M. Noda, and S. Numa. Functional expression of cloned cDNA encoding sodium channel III. FEBS Lett. 228: 195–200, 1988.
 153. Takahashi, M. and W. A. Catterall. Dihydropyridine‐sensitive calcium channels in cardiac and skeletal muscle membranes: studies with antibodies against the alpha subunits. Biochemistry 26: 5518–5526, 1987.
 154. Takahashi, M., M. J. Seagar, J. F. Jones, B. F. X. Reber, and W. Catterall. Subunit structure of dihydropyridine‐sensitive calcium channels from skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 84: 5478–5482, 1987.
 155. Takumi, T., H. Ohkubo, and S. Nakanishi. Cloning of a membrane protein that induces a slow voltage‐gated potassium current. Science 242: 1042–1045, 1988.
 156. Tamkun, M. M., K. M. Knoth, J. A. Walbridge, H. Kroemer, D. M. Roden, and D. M. Glover. Molecular cloning and characterization of two voltage‐gated K+ channel cDNAs from human ventricle. FASEB J. 5: 331–337, 1991.
 157. Toshe, N. Calcium‐sensitive delayed rectifier potassium current in guinea pig ventricular cells. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1200–H1207, 1990.
 158. Toshe, N., M. Kameyama, and H. Irasawa. Intracellular Ca and PKC modulate K current in guinea pig heart cells. Am. J. Physiol. 253 (Heart Circ. Physiol. 22): H1321–H1324, 1987.
 159. Tsien, R. W. Effects of epinephrine on the pacemaker potassium current of cardiac Purkinje fibers. J. Gen. Physiol. 64: 293–319, 1977.
 160. Tsien, R. W., P. T. Ellinor, and W. A. Horne. Molecular diversity of voltage‐dependent Ca2+ channels. TIPS 12: 349–354, 1991.
 161. Tucker, S. J., F. M. Gribble, C. Zhao, S. Trapp, and F. M. Ashcroft. Truncation of Kir6.2 produces ATP‐sensitive K+ channels in the absence of the sulphonylurea receptor. Nature 387: 179–183, 1997.
 162. Vandenberg, C. A. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc. Natl. Acad. Sci. USA 84: 2560–2564, 1987.
 163. Varadi, G., P. Lory, D. Schultz, M. Varadi, and A. Schwartz. Acceleration of activation and inactivation by the subunit of the skeletal muscle calcium channel. Nature 352: 159–162, 1991.
 164. Walsh, K. B. and R. S. Kass. Regulation of a heart potassium channel by protein kinase A and C. Science 242: 67–69, 1988.
 165. Walsh, K. B. and R. S. Kass. Distinct voltage‐dependent regulation of a heart‐delayed. IK by protein kinases A and C. Am. J. Physiol. 261 (Cell Physiol. 30): C1081–C1090, 1991.
 166. Wang, D. W., K. Yazawa, N. Makita, A. L. George, and P. B. Bennett. Pharmacological targeting of long QT mutant sodium channels. J. Clin. Invest. 99: 1714–1720, 1997.
 167. Wang, Q., M. E. Curran, I. Splawski, T. C. Burn, J. M. Millholland, T. J. Vanraay, J. Shen, K. W. Timothy, G. M. Vincent, T. Dejager, P. J. Schwartz, J. A. Towbin, A. J. Moss, D. L. Atkinson, G. M. Landes, T. D. Connors, and M. T. Keating. Positional cloning of a novel potassium channel gene—KVLQT1 mutations cause cardiac arrhythmias. Nat. Genet. 12: 17–23, 1996.
 168. Wang, Q., J. Shen, Z. Li, K. Timothy, G. M. Vincent, S. G. Priori, P. J. Schwartz, and M. T. Keating. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum. Mol. Genet. 4: 1603–1607, 1995.
 169. Wang, Q., J. Shen, I. Splawski, D. Atkinson, Z. Li, J. L. Robinson, A. J. Moss, J. A. Towbin, and M. T. Keating. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80: 805–811, 1995.
 170. Wang, Z., B. Fermini, and S. Nattel. Sustained depolarizationinduced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents. Circ. Res. 73: 1061–1076, 1993.
 171. Warmke, J. W. and B. Ganetzky. A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl. Acad. Sci. U.S.A. 91: 3438–3442, 1994.
 172. Welling, A., Y. W. Kwan, E. Bosse, V. Flockerzi, F. Hofmann, and R. S. Kass. Subunit‐dependent modulation of recombinant L‐type calcium channels: molecular basis for dihydropyridine tissue selectivity. Circ. Res. 73: 974–980, 1993.
 173. Wible, B. A., M. De Biasi, K. Majumder, M. Taglialatela, and A. M. Brown. Cloning and functional expression of an inwardly rectifying K+ channel from human atrium. Circ. Res. 76: 343–350, 1995.
 174. Wiechen, K., D. T. Yue, and S. Herzig. Two distinct functional effects of protein phosphatase inhibitors on guinea‐pig cardiac L‐type Ca2+ channels. J. Physiol. (Lond.) 484: 583–592, 1995.
 175. Yamada, M., S. Isomoto, S. Matsumoto, C. Kondo, T. Shindo, Y. Horio, and Y. Kurachi. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea‐sensitive but ATP‐insensitive K+ channel. J. Physiol. (Lond.) 499: 715–720, 1997.
 176. Yamazawa, T., H. Takeshima, M. Shimuta, and M. Iino. A region of the ryanodine receptor critical for excitationcontraction coupling in skeletal muscle. J. Biol. Chem. 272: 8161–8164, 1997.
 177. Yeola, S. W. and D. J. Snyders. Electrophysiological and pharmacological correspondence between Kv4.2 current and rat cardiac transient outward current. Cardiovasc. Res. 33: 540–547, 1997.
 178. Yue, D. T., P. H. Backx, and J. P. Imredy. Calcium‐sensitive inactivation in the gating of single calcium channels. Science 21: 1735–1738, 1990.
 179. Zagotta, W. N., T. Hoshi, and R. W. Aldrich. Restoration of inactivation in mutants of. Shaker potassium channels by a peptide derived from ShB. Science 250: 568–571, 1990.
 180. Zhao, X. L., L. M. Gutierrez, C. F. Chang, and M. M. Hosey. The alpha 1‐subunit of skeletal muscle L‐type Ca channels is the key target for regulation by A‐kinase and protein phosphatase‐1C. Biochemic. Biophys. Res. Commun. 198: 166–173, 1994.
 181. Zhou, Z. and C. T. January. Both T‐ and L‐type Ca2+ channels can contribute to excitation‐contraction coupling in cardiac Purkinje cells. Biophys. J. 74: 1830–1839, 1998.
 182. Zong, X. G., J. Schreieck, G. Mehrke, A. Welling, A. Schuster, E. Bosse, V. Flockerzi, and F. Hofmann. L‐type calcium channels, cAMP‐dependent regulation of calcium channels, transient and stable expression of calcium channels, CHO cells, HEK 293 and cells. on the regulation of the expressed L‐type calcium channel by cAMP‐dependent phosphorylation. Pflugers Arch. 430: 340–347, 1995.
 183. Zygmunt, A. C. Intracellular calcium activates a chloride current in canine ventricular myocytes. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H1984–H1995, 1994.
 184. Zygmunt, A. C., and W. R. Gibbons. Properties of the calcium‐activated chloride current in heart. J. Gen. Physiol. 99: 391–414, 1992.
 185. Zygmunt, A. C., R. J. Goodrow, and C. Antzelevitch. Sodium effects on 4‐aminopyridine‐sensitive transient outward current in canine ventricular cells. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H1–H11, 1997.

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Bronagh Heath, Kevin Gingrich, Robert S. Kass. Ion Channels in the Heart: Cellular and Molecular Properties of Cardiac Na, Ca, and K Channels. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 548-567. First published in print 2002. doi: 10.1002/cphy.cp020114