Comprehensive Physiology Wiley Online Library

Cell Biology and Physiology of CLC Chloride Channels and Transporters

Full Article on Wiley Online Library



Abstract

Proteins of the CLC gene family assemble to homo‐ or sometimes heterodimers and either function as Cl channels or as Cl/H+‐exchangers. CLC proteins are present in all phyla. Detailed structural information is available from crystal structures of bacterial and algal CLCs. Mammals express nine CLC genes, four of which encode Cl channels and five 2Cl/H+‐exchangers. Two accessory β‐subunits are known: (1) barttin and (2) Ostm1. ClC‐Ka and ClC‐Kb Cl channels need barttin, whereas Ostm1 is required for the function of the lysosomal ClC‐7 2Cl/H+‐exchanger. ClC‐1, ‐2, ‐Ka and ‐Kb Cl channels reside in the plasma membrane and function in the control of electrical excitability of muscles or neurons, in extra‐ and intracellular ion homeostasis, and in transepithelial transport. The mainly endosomal/lysosomal Cl/H+‐exchangers ClC‐3 to ClC‐7 may facilitate vesicular acidification by shunting currents of proton pumps and increase vesicular Cl concentration. ClC‐3 is also present on synaptic vesicles, whereas ClC‐4 and ‐5 can reach the plasma membrane to some extent. ClC‐7/Ostm1 is coinserted with the vesicular H+‐ATPase into the acid‐secreting ruffled border membrane of osteoclasts. Mice or humans lacking ClC‐7 or Ostm1 display osteopetrosis and lysosomal storage disease. Disruption of the endosomal ClC‐5 Cl/H+‐exchanger leads to proteinuria and Dent's disease. Mouse models in which ClC‐5 or ClC‐7 is converted to uncoupled Cl conductors suggest an important role of vesicular Cl accumulation in these pathologies. The important functions of CLC Cl channels were also revealed by human diseases and mouse models, with phenotypes including myotonia, renal loss of salt and water, deafness, blindness, leukodystrophy, and male infertility. © 2012 American Physiological Society. Compr Physiol 2:1701‐1744, 2012.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

The mammalian CLC family of chloride channels and transporters. The CLC family comprises nine members in mammals. This overview depicts their tissue expression (and of the appropriate β‐subunits (in red)), cellular function, and known human and mouse pathologies. The members of the first branch of the CLC family, ClC‐1, ‐2, ‐Ka, and ‐Kb, are plasma membrane Cl channels. By contrast, the members of the second (ClC‐3, ‐4, and ‐5) and third (ClC‐6 and ‐7) subfamilies are Cl/H+‐exchangers that localize predominantly to intracellular compartments of the endosomal/lysosomal pathway.

Figure 2. Figure 2.

Spongiform vacuolation in the white matter of ClC‐2 knockout (KO) mice. Semithin brain sections of the middle cerebellar peduncle of 2‐, 5‐, and 14‐month‐old wildtype (WT) and ClC‐2 KO mice show abundant vacuoles (asterisks) in the cerebellar white matter of 5‐ and 14‐month‐old KO but not WT animals. C, capillaries; scale bar, 20 μm. [Image adapted from, reference (), with permission.]

Figure 3. Figure 3.

Roles of ClC‐K/barttin in transepithelial transport. (A) Schematic representation of renal NaCl reabsorption in the thick ascending limb (TAL) of Henle. Active transport by the basolateral Na,K‐ATPase drives NaCl uptake by the apical NKCC2 transporter. Cotransported K+ is recycled through the apical ROMK channel and Cl leaves the cell through basolateral ClC‐Kb/barttin. (B) Schematic representation of K+ secretion in the stria vascularis of the cochlea. K+ is taken up by the basolateral NKCC1 transporter and the Na,K‐ATPase. While K+ exits through the apical KCNQ1/KCNE1 channel, Cl is recycled by basolateral ClC‐Ka/barttin and ClC‐Kb/barttin channels.

Figure 4. Figure 4.

ClC‐K/barttin in the cochlea. (A) Model of potassium recycling in the cochlea of the inner ear. The endolymph in the cavity of the scala media displays a high K+ concentration of 140 mmol/L and a positive potential of +100 mV. Both the high [K+] and the potential are established by the stria vascularis (light blue). Both parameters are important for the depolarizing K+ current through mechanosensitive channels in the apical membrane of inner (red) and outer (green) hair cells. K+ leaves these sensory cells basolaterally into the perilymph, which displays the zero potential and low [K+] of normal extracellular space. While the perilymph is separated from the endolymph by tight junctions, potassium is transported back to the stria vascularis through a gap junction system. (B) The scheme represents a model of how potassium is secreted into the endolymph through the stria vascularis. In this multilayered epithelium, a layer of marginal cells, which are connected by tight junctions and apically face the endolymph, and a layer of basal cells, also connected by tight junctions, isolate an intrastrial space with a low K+ concentration. K+ enters this space through Kir4.1 from intermediate cells, which can receive K+ through a system of gap junctions, and it is taken up by marginal cells that secrete it into the endolymph. Cl exits the marginal cells through basolateral ClC‐K/barttin channels. The presence of another, unidentified Cl channel on the basolateral side is suggested by the normal endocochlear K+ concentration upon inner‐ear‐specific barttin deletion. [Models modified from, reference (), with permission.]

Figure 5. Figure 5.

ClC‐K/barttin in the cochlea. (A) Model of potassium recycling in the cochlea of the inner ear. The endolymph in the cavity of the scala media displays a high K+ concentration of 140 mmol/L and a positive potential of +100 mV. Both the high [K+] and the potential are established by the stria vascularis (light blue). Both parameters are important for the depolarizing K+ current through mechanosensitive channels in the apical membrane of inner (red) and outer (green) hair cells. K+ leaves these sensory cells basolaterally into the perilymph, which displays the zero potential and low [K+] of normal extracellular space. While the perilymph is separated from the endolymph by tight junctions, potassium is transported back to the stria vascularis through a gap junction system. (B) The scheme represents a model of how potassium is secreted into the endolymph through the stria vascularis. In this multilayered epithelium, a layer of marginal cells, which are connected by tight junctions and apically face the endolymph, and a layer of basal cells, also connected by tight junctions, isolate an intrastrial space with a low K+ concentration. K+ enters this space through Kir4.1 from intermediate cells, which can receive K+ through a system of gap junctions, and it is taken up by marginal cells that secrete it into the endolymph. Cl exits the marginal cells through basolateral ClC‐K/barttin channels. The presence of another, unidentified Cl channel on the basolateral side is suggested by the normal endocochlear K+ concentration upon inner‐ear‐specific barttin deletion. [Models modified from, reference (), with permission.]

Figure 6. Figure 6.

Localization of the intracellular CLC proteins to the endosomal/lysosomal pathway. The scheme illustrates the proposed subcellular localizations of the members of the second and third CLC subfamilies. While ClC‐5 localizes to early compartments of the endocytic pathway, ClC‐3 and ‐6 localize on late endosomes. The localization of ClC‐4 is less clear, and ClC‐7/Ostm1 is the only lysosomal CLC protein. The ATP‐consuming proton pump acidifies the compartments, from the extracellular pH 7.4 to pH 4.5 in lysosomes. At least in early endosomal compartments, the shunt current is provided by the CLC proteins. For all intracellular CLCs except ClC‐3, a Cl/H+‐exchange activity has been shown. For ClC‐7, this activity has been shown to accumulate chloride in lysosomes.

Figure 7. Figure 7.

Neuronal degeneration in ClC‐3 KO mice. (A) Nissl‐stained frontal brain sections show severe neuronal cell loss that leads to a complete loss of the hippocampus in adult ClC‐3 KO mice. (B) Retinal sections of P28 WT and ClC‐3 KO mice reveal a complete degeneration of photoreceptors, with a loss of the photoreceptor outer segment (OS) as well as the nuclei that form the outer nuclear layer (ONL). RPE, retinal pigment epithelium; IS, photoreceptor inner segments; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. [Images adapted from, reference (), with permission.]

Figure 8. Figure 8.

Basic electrophysiological properties of ClC‐4. (A) Two‐electrode voltage‐clamp traces of ClC‐4 expressed in Xenopus oocytes show strongly outwardly rectifying chloride currents which a rapidly activated at positive voltages. (B) Neutralizing the “gating glutamate” in ClC‐4 converts the Cl/H+‐exchanger into a pure Cl conductor which results in significant currents also in the negative voltage range. [Traces taken from, reference (), with permission.]

Figure 9. Figure 9.

Proximal tubule endocytosis defect in ClC‐5 KO mice. Fluorescently labeled lactoglobulin (in blue) was injected into female Clcn5+/– mice. Due to random X‐chromosomal inactivation in females, proximal tubular cells (PTCs) either express (ClC‐5 stained in red) or lack ClC‐5 (indicated by arrows). Cells expressing ClC‐5 accumulated substantial amounts of lactoglobulin below the brush border while neighboring ClC‐5 KO cells had taken up much less protein indicating a reduced receptor‐mediated endocytosis in a cell‐autonomous manner. [Images modified from, reference (), with permission.]

Figure 10. Figure 10.

Model for renal pathology caused by an impaired proximal tubular endocytosis as observed in ClC‐5 KO mice and in patients with Dent's disease. (A) Events in the early proximal tubule: After the small peptide PTH (parathyroid hormone) and various forms of vitamin D have passed the glomerular filter, loss of ClC‐5 results in an impaired megalin‐mediated endocytosis of PTH that would have been normally degraded in lysosomes. The uptake of 1,25(OH)2‐ and 25(OH)‐vitaminD3 together with their binding protein DBP, which requires binding to megalin, is also impaired (indicated by red minus symbols). Under normal conditions 1,25‐VitD reaches VitD receptors that regulate the transcription of nuclear target genes (not shown) and 25‐VitD is metabolized by mitochondrial enzymes: 1α‐hydroxylase (1α‐HYD) converts the precursor 25(OH)‐vitaminD3 to the active hormone 1,25(OH)2‐vitaminD3 (1,25‐VitD), whereas the 24‐hydroxylase (24‐HYD) inactivates 1,25‐VitD. (B) Events in the late proximal tubule: The defect in ClC‐5‐dependent endocytosis results in an increased luminal PTH concentration which leads to an enhanced stimulation of apical PTH receptors (indicated by green plus symbols). The enhanced stimulation of PTH receptors together with the decreased uptake of 1,25(OH)2‐vitaminD3 enhances the transcription of the mitochondrial enzyme 1α‐hydroxylase that converts the precursor 25(OH)‐vitaminD3 into the active metabolite 1,25(OH)2‐vitaminD3, while decreasing transcription of the catabolizing enzyme 24‐hydroxylase. However, 25(OH)‐vitaminD3 megalin‐dependent endocytosis to reach the enzyme is impaired, thus both 1,25(OH)2‐ and 25(OH)‐vitaminD3 are lost into the urine. There is a balance between the changed transcription of enzymes that cooperate to increase active vitamin D3, and the loss of the precursor and active form into the urine. Depending on the outcome (increased or decreased concentration of active vitamin D3 in serum), this leads to different clinical phenotypes. (C) Events in the distal tubule: In contrast to proximal tubules, 1,25(OH)2‐vitaminD3 enters distal tubular cells mainly by diffusion of the free hormone over the membrane and binds to the vitamin D3 receptor which activates the transcription of 1,25(OH)2‐vitaminD3 dependent genes after heterodimerization with the retinoid X receptor (RXR). As the concentration of 1,25(OH)2‐vitaminD3 is increased in the lumen of ClC‐5 KO kidneys, renal 1,25(OH)2‐vitaminD3 target genes are selectively affected. VDR, vitamin D receptor; RXR, retinoid X receptor; PTH‐R, parathyroid hormone receptor. [Model adapted from, reference (), with permission.]

Figure 11. Figure 11.

Models for endosomal acidification. According to the classical model (A), Cl channels provide the electrical shunt for the proton‐pumping V‐ATPase in endosomes. But in reality, the Cl/H+‐exchanger ClC‐5 performs this role (B). Neutralizing its “gating glutamate” uncouples the Cl conductance from H+ countertransport, which results in a pure Cl conductor (C), going back to “classics” (A). [Model adapted from, reference (), with permission.]

Figure 12. Figure 12.

Renal endosomal acidification of mice converting ClC‐5 into a chloride conductor. (A) Averaged traces of acridine orange fluorescence comparing ATP‐driven acidification of endosomal fractions from renal cortex of WT (green) and ClC‐5unc (red) (left panel) and WT and Clcn5 (black) mice (right panel). Acidification of WT and ClC‐5unc vesicles occurred with similar efficiency but was severely reduced with endosomes from mice in which ClC‐5 was lacking. (B) Fluorescently labeled dextran, a marker for fluid‐phase endocytosis (green), was injected into female Clcn5+/unc mice. Cells expressing ClC‐5unc accumulated much less dextran than neighboring cells expressing the 2Cl/H+‐exchanger ClC‐5 (for details, see ()). [Images taken from, reference (), with permission.]

Figure 13. Figure 13.

Minimal mathematical model for ATP‐dependent vesicle acidification. Mathematical modeling for the ATP‐dependent acidification of a minimal vesicle containing just an H+ pump, an H+ leak, and either no Cl conductance (−/−; black traces), a 2Cl/H+‐exchanger (+/+; green traces) or a Cl channel (unc/unc; red traces). For details, see (). (A) Simulations predict a more efficient vesicular acidification with the exchanger despite H+ efflux due to Cl/H+ antiport compared to the acidification predicted with a Cl channel. There is no acidification without any Cl conductance. (B) Upon acidification an inside‐positive potential is predicted with a Cl channel whereas the lumen becomes negative with a Cl/H+‐exchanger. (C) The calculated intravesicular Cl concentration is higher with a Cl/H+‐exchanger than with a Cl channel. The initial conditions were: pHi = 7.2; pHo = 7.2; [cation+]i = 140 mmol/L; [cation+]o = 140 mmol/L; [Cl]i = 50 mmol/L; [Cl]o = 50 mmol/L; U = 0 mV. [Graphs adapted from, reference (), with permission.]

Figure 14. Figure 14.

Neuronal storage material in ClC‐6 and ClC‐7 KO mice. Electron micrography shows the accumulation of electron‐dense deposits (arrows) in ClC‐6‐deficient hippocampal neurons and in cortical neurons of ClC‐7 KO mice. The localization of storage material is restricted to the initial axon segment in ClC‐6‐deficient neurons, whereas it is scattered through the entire soma of ClC‐7 KO neurons. nuc, nucleus; scale bars, 2 μm. [Images modified from, references () (left panel) and () (right panel) , with permission.]

Figure 15. Figure 15.

Subcellular localization of ClC‐7 and Ostm1 in mouse fibroblasts. Top panel: Costaining for ClC‐7 (green) and the lysosomal marker lamp‐1 (red) revealed localization of ClC‐7 on lysosomal compartments in mouse fibroblasts. Lower panel: Immunofluorescence of ClC‐7 (green) and its β‐subunit Ostm1 (red) showed colocalization of the two subunits. [Images modified from, reference (), with permission.]

Figure 16. Figure 16.

Bone phenotype of ClC‐7 mouse models. Microcomputed tomography images of tibiae show increasing severity of osteopetrosis from Clcn7unc/unc to Clcn7–/– mice, which even lack the bone marrow cavity. [Images adapted from, reference (), with permission.]

Figure 17. Figure 17.

Enlarged late endosomal/lysosomal compartments in ClC‐7‐deficient PTCs. Kidney sections from mice with a chimeric ClC‐7 deletion in renal proximal tubules were immunostained for ClC‐7 (green), the late endosomal/lysosomal protein lamp‐1 (red) and the proximal tubule marker villin (blue). Lamp‐1‐positive vesicles are drastically enlarged in ClC‐7‐deficient cells (KO) compared to their appearance in ClC‐7‐expressing cells (WT). [Images modified from, reference (), with permission.]

Figure 18. Figure 18.

Lysosomal transport characterization. carbonyl cyanide 3‐chlorophenylhydrazone (CCCP)

‐induced alkalinization assay of lysosomes that were preloaded with the ratiometric pH indicator Oregon Green‐dextran. The protononophore rapidly dissipated lysosomal pH in Clcn7+/+ (green), Clcn7unc/unc (red), and Clcn7–/– (black) fibroblasts, demonstrating the presence of countercurrents. Lysosomes of Clcn7unc/unc mice reached a more alkaline pH than Clcn7–/– lysosomes, suggesting that the uncoupled transporter (ClC‐7unc) mediates a Cl conductance. However, Clcn7unc/unc lysosomes reached a less alkaline steady‐state pH than WT lysosomes. Since the steady‐state pH is determined by voltage, which depends on the Cl diffusion potential, the difference in lysosomal pH suggests higher lysosomal chloride concentration in WT than in Clcn7unc/unc lysosomes. Alkalinization of Clcn7–/– lysosomes by protonophore treatment argues for lysosomal conductances in addition to ClC‐7 most likely by a so far unknown cation conductance. Mathematical modeling of such an experiment (on the lower right) confirms the plausibility of the conclusions (for details, see ()). The simulated vesicle contains either a Cl/H+‐exchange activity, or a Cl conductance or none of these, corresponding to the three genotypes (same color code as in the experimental data). In addition, the vesicle contains a cation conductance and a large proton conductance simulating CCCP. The initial conditions were: pHi = 4.75; pHo = 6.4; [cation+]i = 100 mmol/L; [cation+]o = 10 mmol/L; [Cl]i = 120 or 80 mmol/L as indicated; [Cl]o = 20 mmol/L. With the same initial [Cl], the luminal pH of vesicles containing a Cl/H+‐exchange activity or a Cl conductance reaches the same value. Lower initial luminal [Cl] in vesicles with a Cl conductance may explain the different final pH values. [Graphs taken from, reference (), with permission.]



Figure 1.

The mammalian CLC family of chloride channels and transporters. The CLC family comprises nine members in mammals. This overview depicts their tissue expression (and of the appropriate β‐subunits (in red)), cellular function, and known human and mouse pathologies. The members of the first branch of the CLC family, ClC‐1, ‐2, ‐Ka, and ‐Kb, are plasma membrane Cl channels. By contrast, the members of the second (ClC‐3, ‐4, and ‐5) and third (ClC‐6 and ‐7) subfamilies are Cl/H+‐exchangers that localize predominantly to intracellular compartments of the endosomal/lysosomal pathway.



Figure 2.

Spongiform vacuolation in the white matter of ClC‐2 knockout (KO) mice. Semithin brain sections of the middle cerebellar peduncle of 2‐, 5‐, and 14‐month‐old wildtype (WT) and ClC‐2 KO mice show abundant vacuoles (asterisks) in the cerebellar white matter of 5‐ and 14‐month‐old KO but not WT animals. C, capillaries; scale bar, 20 μm. [Image adapted from, reference (), with permission.]



Figure 3.

Roles of ClC‐K/barttin in transepithelial transport. (A) Schematic representation of renal NaCl reabsorption in the thick ascending limb (TAL) of Henle. Active transport by the basolateral Na,K‐ATPase drives NaCl uptake by the apical NKCC2 transporter. Cotransported K+ is recycled through the apical ROMK channel and Cl leaves the cell through basolateral ClC‐Kb/barttin. (B) Schematic representation of K+ secretion in the stria vascularis of the cochlea. K+ is taken up by the basolateral NKCC1 transporter and the Na,K‐ATPase. While K+ exits through the apical KCNQ1/KCNE1 channel, Cl is recycled by basolateral ClC‐Ka/barttin and ClC‐Kb/barttin channels.



Figure 4.

ClC‐K/barttin in the cochlea. (A) Model of potassium recycling in the cochlea of the inner ear. The endolymph in the cavity of the scala media displays a high K+ concentration of 140 mmol/L and a positive potential of +100 mV. Both the high [K+] and the potential are established by the stria vascularis (light blue). Both parameters are important for the depolarizing K+ current through mechanosensitive channels in the apical membrane of inner (red) and outer (green) hair cells. K+ leaves these sensory cells basolaterally into the perilymph, which displays the zero potential and low [K+] of normal extracellular space. While the perilymph is separated from the endolymph by tight junctions, potassium is transported back to the stria vascularis through a gap junction system. (B) The scheme represents a model of how potassium is secreted into the endolymph through the stria vascularis. In this multilayered epithelium, a layer of marginal cells, which are connected by tight junctions and apically face the endolymph, and a layer of basal cells, also connected by tight junctions, isolate an intrastrial space with a low K+ concentration. K+ enters this space through Kir4.1 from intermediate cells, which can receive K+ through a system of gap junctions, and it is taken up by marginal cells that secrete it into the endolymph. Cl exits the marginal cells through basolateral ClC‐K/barttin channels. The presence of another, unidentified Cl channel on the basolateral side is suggested by the normal endocochlear K+ concentration upon inner‐ear‐specific barttin deletion. [Models modified from, reference (), with permission.]



Figure 5.

ClC‐K/barttin in the cochlea. (A) Model of potassium recycling in the cochlea of the inner ear. The endolymph in the cavity of the scala media displays a high K+ concentration of 140 mmol/L and a positive potential of +100 mV. Both the high [K+] and the potential are established by the stria vascularis (light blue). Both parameters are important for the depolarizing K+ current through mechanosensitive channels in the apical membrane of inner (red) and outer (green) hair cells. K+ leaves these sensory cells basolaterally into the perilymph, which displays the zero potential and low [K+] of normal extracellular space. While the perilymph is separated from the endolymph by tight junctions, potassium is transported back to the stria vascularis through a gap junction system. (B) The scheme represents a model of how potassium is secreted into the endolymph through the stria vascularis. In this multilayered epithelium, a layer of marginal cells, which are connected by tight junctions and apically face the endolymph, and a layer of basal cells, also connected by tight junctions, isolate an intrastrial space with a low K+ concentration. K+ enters this space through Kir4.1 from intermediate cells, which can receive K+ through a system of gap junctions, and it is taken up by marginal cells that secrete it into the endolymph. Cl exits the marginal cells through basolateral ClC‐K/barttin channels. The presence of another, unidentified Cl channel on the basolateral side is suggested by the normal endocochlear K+ concentration upon inner‐ear‐specific barttin deletion. [Models modified from, reference (), with permission.]



Figure 6.

Localization of the intracellular CLC proteins to the endosomal/lysosomal pathway. The scheme illustrates the proposed subcellular localizations of the members of the second and third CLC subfamilies. While ClC‐5 localizes to early compartments of the endocytic pathway, ClC‐3 and ‐6 localize on late endosomes. The localization of ClC‐4 is less clear, and ClC‐7/Ostm1 is the only lysosomal CLC protein. The ATP‐consuming proton pump acidifies the compartments, from the extracellular pH 7.4 to pH 4.5 in lysosomes. At least in early endosomal compartments, the shunt current is provided by the CLC proteins. For all intracellular CLCs except ClC‐3, a Cl/H+‐exchange activity has been shown. For ClC‐7, this activity has been shown to accumulate chloride in lysosomes.



Figure 7.

Neuronal degeneration in ClC‐3 KO mice. (A) Nissl‐stained frontal brain sections show severe neuronal cell loss that leads to a complete loss of the hippocampus in adult ClC‐3 KO mice. (B) Retinal sections of P28 WT and ClC‐3 KO mice reveal a complete degeneration of photoreceptors, with a loss of the photoreceptor outer segment (OS) as well as the nuclei that form the outer nuclear layer (ONL). RPE, retinal pigment epithelium; IS, photoreceptor inner segments; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. [Images adapted from, reference (), with permission.]



Figure 8.

Basic electrophysiological properties of ClC‐4. (A) Two‐electrode voltage‐clamp traces of ClC‐4 expressed in Xenopus oocytes show strongly outwardly rectifying chloride currents which a rapidly activated at positive voltages. (B) Neutralizing the “gating glutamate” in ClC‐4 converts the Cl/H+‐exchanger into a pure Cl conductor which results in significant currents also in the negative voltage range. [Traces taken from, reference (), with permission.]



Figure 9.

Proximal tubule endocytosis defect in ClC‐5 KO mice. Fluorescently labeled lactoglobulin (in blue) was injected into female Clcn5+/– mice. Due to random X‐chromosomal inactivation in females, proximal tubular cells (PTCs) either express (ClC‐5 stained in red) or lack ClC‐5 (indicated by arrows). Cells expressing ClC‐5 accumulated substantial amounts of lactoglobulin below the brush border while neighboring ClC‐5 KO cells had taken up much less protein indicating a reduced receptor‐mediated endocytosis in a cell‐autonomous manner. [Images modified from, reference (), with permission.]



Figure 10.

Model for renal pathology caused by an impaired proximal tubular endocytosis as observed in ClC‐5 KO mice and in patients with Dent's disease. (A) Events in the early proximal tubule: After the small peptide PTH (parathyroid hormone) and various forms of vitamin D have passed the glomerular filter, loss of ClC‐5 results in an impaired megalin‐mediated endocytosis of PTH that would have been normally degraded in lysosomes. The uptake of 1,25(OH)2‐ and 25(OH)‐vitaminD3 together with their binding protein DBP, which requires binding to megalin, is also impaired (indicated by red minus symbols). Under normal conditions 1,25‐VitD reaches VitD receptors that regulate the transcription of nuclear target genes (not shown) and 25‐VitD is metabolized by mitochondrial enzymes: 1α‐hydroxylase (1α‐HYD) converts the precursor 25(OH)‐vitaminD3 to the active hormone 1,25(OH)2‐vitaminD3 (1,25‐VitD), whereas the 24‐hydroxylase (24‐HYD) inactivates 1,25‐VitD. (B) Events in the late proximal tubule: The defect in ClC‐5‐dependent endocytosis results in an increased luminal PTH concentration which leads to an enhanced stimulation of apical PTH receptors (indicated by green plus symbols). The enhanced stimulation of PTH receptors together with the decreased uptake of 1,25(OH)2‐vitaminD3 enhances the transcription of the mitochondrial enzyme 1α‐hydroxylase that converts the precursor 25(OH)‐vitaminD3 into the active metabolite 1,25(OH)2‐vitaminD3, while decreasing transcription of the catabolizing enzyme 24‐hydroxylase. However, 25(OH)‐vitaminD3 megalin‐dependent endocytosis to reach the enzyme is impaired, thus both 1,25(OH)2‐ and 25(OH)‐vitaminD3 are lost into the urine. There is a balance between the changed transcription of enzymes that cooperate to increase active vitamin D3, and the loss of the precursor and active form into the urine. Depending on the outcome (increased or decreased concentration of active vitamin D3 in serum), this leads to different clinical phenotypes. (C) Events in the distal tubule: In contrast to proximal tubules, 1,25(OH)2‐vitaminD3 enters distal tubular cells mainly by diffusion of the free hormone over the membrane and binds to the vitamin D3 receptor which activates the transcription of 1,25(OH)2‐vitaminD3 dependent genes after heterodimerization with the retinoid X receptor (RXR). As the concentration of 1,25(OH)2‐vitaminD3 is increased in the lumen of ClC‐5 KO kidneys, renal 1,25(OH)2‐vitaminD3 target genes are selectively affected. VDR, vitamin D receptor; RXR, retinoid X receptor; PTH‐R, parathyroid hormone receptor. [Model adapted from, reference (), with permission.]



Figure 11.

Models for endosomal acidification. According to the classical model (A), Cl channels provide the electrical shunt for the proton‐pumping V‐ATPase in endosomes. But in reality, the Cl/H+‐exchanger ClC‐5 performs this role (B). Neutralizing its “gating glutamate” uncouples the Cl conductance from H+ countertransport, which results in a pure Cl conductor (C), going back to “classics” (A). [Model adapted from, reference (), with permission.]



Figure 12.

Renal endosomal acidification of mice converting ClC‐5 into a chloride conductor. (A) Averaged traces of acridine orange fluorescence comparing ATP‐driven acidification of endosomal fractions from renal cortex of WT (green) and ClC‐5unc (red) (left panel) and WT and Clcn5 (black) mice (right panel). Acidification of WT and ClC‐5unc vesicles occurred with similar efficiency but was severely reduced with endosomes from mice in which ClC‐5 was lacking. (B) Fluorescently labeled dextran, a marker for fluid‐phase endocytosis (green), was injected into female Clcn5+/unc mice. Cells expressing ClC‐5unc accumulated much less dextran than neighboring cells expressing the 2Cl/H+‐exchanger ClC‐5 (for details, see ()). [Images taken from, reference (), with permission.]



Figure 13.

Minimal mathematical model for ATP‐dependent vesicle acidification. Mathematical modeling for the ATP‐dependent acidification of a minimal vesicle containing just an H+ pump, an H+ leak, and either no Cl conductance (−/−; black traces), a 2Cl/H+‐exchanger (+/+; green traces) or a Cl channel (unc/unc; red traces). For details, see (). (A) Simulations predict a more efficient vesicular acidification with the exchanger despite H+ efflux due to Cl/H+ antiport compared to the acidification predicted with a Cl channel. There is no acidification without any Cl conductance. (B) Upon acidification an inside‐positive potential is predicted with a Cl channel whereas the lumen becomes negative with a Cl/H+‐exchanger. (C) The calculated intravesicular Cl concentration is higher with a Cl/H+‐exchanger than with a Cl channel. The initial conditions were: pHi = 7.2; pHo = 7.2; [cation+]i = 140 mmol/L; [cation+]o = 140 mmol/L; [Cl]i = 50 mmol/L; [Cl]o = 50 mmol/L; U = 0 mV. [Graphs adapted from, reference (), with permission.]



Figure 14.

Neuronal storage material in ClC‐6 and ClC‐7 KO mice. Electron micrography shows the accumulation of electron‐dense deposits (arrows) in ClC‐6‐deficient hippocampal neurons and in cortical neurons of ClC‐7 KO mice. The localization of storage material is restricted to the initial axon segment in ClC‐6‐deficient neurons, whereas it is scattered through the entire soma of ClC‐7 KO neurons. nuc, nucleus; scale bars, 2 μm. [Images modified from, references () (left panel) and () (right panel) , with permission.]



Figure 15.

Subcellular localization of ClC‐7 and Ostm1 in mouse fibroblasts. Top panel: Costaining for ClC‐7 (green) and the lysosomal marker lamp‐1 (red) revealed localization of ClC‐7 on lysosomal compartments in mouse fibroblasts. Lower panel: Immunofluorescence of ClC‐7 (green) and its β‐subunit Ostm1 (red) showed colocalization of the two subunits. [Images modified from, reference (), with permission.]



Figure 16.

Bone phenotype of ClC‐7 mouse models. Microcomputed tomography images of tibiae show increasing severity of osteopetrosis from Clcn7unc/unc to Clcn7–/– mice, which even lack the bone marrow cavity. [Images adapted from, reference (), with permission.]



Figure 17.

Enlarged late endosomal/lysosomal compartments in ClC‐7‐deficient PTCs. Kidney sections from mice with a chimeric ClC‐7 deletion in renal proximal tubules were immunostained for ClC‐7 (green), the late endosomal/lysosomal protein lamp‐1 (red) and the proximal tubule marker villin (blue). Lamp‐1‐positive vesicles are drastically enlarged in ClC‐7‐deficient cells (KO) compared to their appearance in ClC‐7‐expressing cells (WT). [Images modified from, reference (), with permission.]



Figure 18.

Lysosomal transport characterization. carbonyl cyanide 3‐chlorophenylhydrazone (CCCP)

‐induced alkalinization assay of lysosomes that were preloaded with the ratiometric pH indicator Oregon Green‐dextran. The protononophore rapidly dissipated lysosomal pH in Clcn7+/+ (green), Clcn7unc/unc (red), and Clcn7–/– (black) fibroblasts, demonstrating the presence of countercurrents. Lysosomes of Clcn7unc/unc mice reached a more alkaline pH than Clcn7–/– lysosomes, suggesting that the uncoupled transporter (ClC‐7unc) mediates a Cl conductance. However, Clcn7unc/unc lysosomes reached a less alkaline steady‐state pH than WT lysosomes. Since the steady‐state pH is determined by voltage, which depends on the Cl diffusion potential, the difference in lysosomal pH suggests higher lysosomal chloride concentration in WT than in Clcn7unc/unc lysosomes. Alkalinization of Clcn7–/– lysosomes by protonophore treatment argues for lysosomal conductances in addition to ClC‐7 most likely by a so far unknown cation conductance. Mathematical modeling of such an experiment (on the lower right) confirms the plausibility of the conclusions (for details, see ()). The simulated vesicle contains either a Cl/H+‐exchange activity, or a Cl conductance or none of these, corresponding to the three genotypes (same color code as in the experimental data). In addition, the vesicle contains a cation conductance and a large proton conductance simulating CCCP. The initial conditions were: pHi = 4.75; pHo = 6.4; [cation+]i = 100 mmol/L; [cation+]o = 10 mmol/L; [Cl]i = 120 or 80 mmol/L as indicated; [Cl]o = 20 mmol/L. With the same initial [Cl], the luminal pH of vesicles containing a Cl/H+‐exchange activity or a Cl conductance reaches the same value. Lower initial luminal [Cl] in vesicles with a Cl conductance may explain the different final pH values. [Graphs taken from, reference (), with permission.]

References
 1. Accardi A, Ferrera L, Pusch M. Drastic reduction of the slow gate of human muscle chloride channel (ClC‐1) by mutation C277S. J physiol 534: 745‐752, 2001.
 2. Accardi A, Miller C. Secondary active transport mediated by a prokaryotic homologue of ClC Cl‐ channels. Nature 427: 803‐807, 2004.
 3. Accardi A, Picollo A. CLC channels and transporters: Proteins with borderline personalities. Biochim Biophys Acta 1798: 1457‐1464, 2010.
 4. Accardi A, Pusch M. Fast and slow gating relaxations in the muscle chloride channel CLC‐1. J Gen Physiol 116: 433‐444, 2000.
 5. Adachi S, Uchida S, Ito H, Hata M, Hiroe M, Marumo F, Sasaki S. Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts of rat kidney. J Biol Chem 269: 17677‐17683, 1994.
 6. Adler DA, Rugarli EI, Lingenfelter PA, Tsuchiya K, Poslinski D, Liggitt HD, Chapman VM, Elliott RW, Ballabio A, Disteche CM. Evidence of evolutionary up‐regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus. Proc Natl Acad Sci U S A 94: 9244‐9248, 1997.
 7. Akizuki N, Uchida S, Sasaki S, Marumo F. Impaired solute accumulation in inner medully of Clcnk1‐/‐ mice kidney. Am J Physiol 280: F79‐F87, 2001.
 8. Alekov AK, Fahlke C. Channel‐like slippage modes in the human anion/proton exchanger ClC‐4. J Gen Physiol 133: 485‐496, 2009.
 9. Alex P, Ye M, Zachos NC, Sipes J, Nguyen T, Suhodrev M, Gonzales L, Arora Z, Zhang T, Centola M, Guggino SE, Li X. Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium‐induced colitis. J Immunol 184: 3988‐3996, 2010.
 10. Alroy J, Pfannl R, Ucci A, Lefranc G, Frattini A, Megarbane A. Electron microscopic findings in skin biopsies from patients with infantile osteopetrosis and neuronal storage disease. Ultrastruct Pathol 31: 333‐338, 2007.
 11. Ambizas EM, Ginzburg R. Lubiprostone: A chloride channel activator for treatment of chronic constipation. Ann Pharmacother 41: 957‐964, 2007.
 12. 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.
 13. Ao M, Venkatasubramanian J, Boonkaewwan C, Ganesan N, Syed A, Benya RV, Rao MC. Lubiprostone activates Cl‐ secretion via cAMP signaling and increases membrane CFTR in the human colon carcinoma cell line, T84. Dig Dis Sci 56: 339‐351, 2011.
 14. Aromataris EC, Astill DS, Rychkov GY, Bryant SH, Bretag AH, Roberts ML. Modulation of the gating of CIC‐1 by S‐(‐) 2‐(4‐chlorophenoxy) propionic acid. Br J Pharmacol 126: 1375‐1382, 1999.
 15. Aromataris EC, Rychkov GY, Bennetts B, Hughes BP, Bretag AH, Roberts ML. Fast and slow gating of CLC‐1: Differential effects of 2‐(4‐chlorophenoxy) propionic acid and dominant negative mutations. Mol Pharmacol 60: 200‐208, 2001.
 16. Arreola J, Begenisich T, Melvin JE. Conformation‐dependent regulation of inward rectifier chloride channel gating by extracellular protons. J Physiol 541: 103‐112, 2002.
 17. Arreola J, Begenisch T, Nehrke K, Nguyen HV, Park K, Richardson L, Yang B, Schutte BC, Lamb FS, Melvin JE. Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl‐ channel gene. J Physiol 545(1): 207‐216, 2002.
 18. Barg S, Huang P, Eliasson L, Nelson DJ, Obermüller S, Rorsman P, Thevenod F, Renström E. Priming of insulin granules for exocytosis by granular Cl‐ uptake and acidification. J Cell Sci 114: 2145‐2154, 2001.
 19. Barlassina C, Dal Fiume C, Lanzani C, Manunta P, Guffanti G, Ruello A, Bianchi G, Del Vecchio L, Macciardi F, Cusi D. Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt‐sensitive hypertension. Hum Mol Genet 16: 1630‐1638, 2007.
 20. Bassil AK, Borman RA, Jarvie EM, McArthur‐Wilson RJ, Thangiah R, Sung EZ, Lee K, Sanger GJ. Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon. Br J Pharmacol 154: 126‐135, 2008.
 21. Bauer CK, Steinmeyer K, Schwarz JR, Jentsch TJ. Completely functional double‐barreled chloride channel expressed from a single Torpedo cDNA. Proc Natl Acad Sci U S A 88: 11052‐11056, 1991.
 22. Beck CL, Fahlke C, George AL, Jr. Molecular basis for decreased muscle chloride conductance in the myotonic goat. Proc Natl Acad Sci U S A 93: 11248‐11252, 1996.
 23. Belgardt BF, Bruning JC. CNS leptin and insulin action in the control of energy homeostasis. Ann N Y Acad Sci 1212: 97‐113, 2010.
 24. Bellocchio EE, Reimer RJ, Fremeau RT, Jr., Edwards RH. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289: 957‐960, 2000.
 25. Bennetts B, Parker MW, Cromer BA. Inhibition of skeletal muscle CLC‐1 chloride channels by low intracellular pH and ATP. J Biol Chem 282: 32780‐32791, 2007.
 26. Bennetts B, Roberts ML, Bretag AH, Rychkov GY. Temperature dependence of human muscle ClC‐1 chloride channel. J Physiol 535: 83‐93, 2001.
 27. Bennetts B, Rychkov GY, Ng HL, Morton CJ, Stapleton D, Parker MW, Cromer BA. Cytoplasmic ATP‐sensing domains regulate gating of skeletal muscle ClC‐1 chloride channels. J Biol Chem 280: 32452‐32458, 2005.
 28. Bergler T, Stoelcker B, Jeblick R, Reinhold SW, Wolf K, Riegger GA, Kramer BK. High osmolality induces the kidney‐specific chloride channel CLC‐K1 by a serum and glucocorticoid‐inducible kinase 1 MAPK pathway. Kidney Int 74: 1170‐1177, 2008.
 29. Bergsdorf EY, Zdebik AA, Jentsch TJ. Residues important for nitrate/proton coupling in plant and mammalian CLC transporters. J Biol Chem 284: 11184‐11193, 2009.
 30. Besbas N, Draaken M, Ludwig M, Deren O, Orhan D, Bilginer Y, Ozaltin F. A novel CLCN7 mutation resulting in a most severe form of autosomal recessive osteopetrosis. European journal of pediatrics 168: 1449‐1454, 2009.
 31. Bijvelds MJ, Bot AG, Escher JC, De Jonge HR. Activation of intestinal Cl‐ secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology 137: 976‐985, 2009.
 32. Bircan Z, Harputluoglu F, Jeck N. Deletion of exons 2‐4 in the BSND gene causes severe antenatal Bartter syndrome. Pediatric nephrology (Berlin, Germany) 24: 841‐844, 2009.
 33. Birkenhäger R, Otto E, Schürmann MJ, Vollmer M, Ruf EM, Maier‐Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NVAM, Antignac C, Sudbrack R, Kispert A, Hildebrandt F. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29: 310‐314, 2001.
 34. Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245: 855‐857, 1989.
 35. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, Jentsch TJ. Leukoencephalopathy upon disruption of the chloride channel ClC‐2. J Neurosci 27: 6581‐6589, 2007.
 36. Boettger T, Hübner CA, Maier H, Rust MB, Beck FX, Jentsch TJ. Deafness and renal tubular acidosis in mice lacking the K‐Cl co‐transporter Kcc4. Nature 416: 874‐878, 2002.
 37. Borsani G, Rugarli EI, Taglialatela M, Wong C, Ballabio A. Characterization of a human and murine gene (CLCN3) sharing similarities to voltage‐gated chloride channels and to a yeast integral membrane protein. Genomics 27: 131‐141, 1995.
 38. Bösl MR, Stein V, Hübner C, Zdebik AA, Jordt SE, Mukhophadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ. Male germ cells and photoreceptors, both depending on close cell‐cell interactions, degenerate upon ClC‐2 Cl‐‐channel disruption. EMBO J 20: 1289‐1299, 2001.
 39. Bouyer G, Egee S, Thomas SL. Toward a unifying model of malaria‐induced channel activity. Proc Natl Acad Sci U S A, 104: 11044‐11049, 2007.
 40. Brandt S, Jentsch TJ. ClC‐6 and ClC‐7 are two novel broadly expressed members of the CLC chloride channel family. FEBS letters 377: 15‐20, 1995.
 41. Braun NA, Morgan B, Dick TP, Schwappach B. The yeast CLC protein counteracts vesicular acidification during iron starvation. J Cell Sci 123: 2342‐2350, 2010.
 42. Bretag AH. Muscle chloride channels. Physiol Rev 67: 618‐724, 1987.
 43. Brown CL, Maier KC, Stauber T, Ginkel LM, Wordeman L, Vernos I, Schroer TA. Kinesin‐2 is a motor for late endosomes and lysosomes. Traffic 6: 1114‐1124, 2005.
 44. Bryant SH, Morales‐Aguilera A. Chloride conductance in normal and myotonic muscle fibres and the action of monocarboxylic aromatic acids. J Physiol 219: 367‐383, 1971.
 45. Buyse G, Trouet D, Voets T, Missiaen L, Droogmans G, Nilius B, Eggermont J. Evidence for the intracellular location of chloride channel (ClC)‐type proteins: Co‐localization of ClC‐6a and ClC‐6c with the sarco/endoplasmic‐reticulum Ca2+ pump SERCA2b. Biochem J 330: 1015‐1021, 1998.
 46. Buyse G, Voets T, Tytgat J, De Greef C, Droogmans G, Nilius B, Eggermont J. Expression of human pICln and ClC‐6 in Xenopus oocytes induces an identical endogenous chloride conductance. J Biol Chem 272: 3615‐3621, 1997.
 47. Bykova EA, Zhang XD, Chen TY, Zheng J. Large movement in the C‐terminus of CLC‐0 chloride channel during slow gating. Nat Struct Mol Bio 13: 1115‐1119, 2006.
 48. Camilleri M, Bharucha AE, Ueno R, Burton D, Thomforde GM, Baxter K, McKinzie S, Zinsmeister AR. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol 290: G942‐G947, 2006.
 49. Campos‐Xavier AB, Saraiva JM, Ribeiro LM, Munnich A, Cormier‐Daire V. Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Hum Genet 112: 186‐189, 2003.
 50. Capasso G, Rizzo M, Garavaglia ML, Trepiccione F, Zacchia M, Mugione A, Ferrari P, Paulmichl M, Lang F, Loffing J, Carrel M, Damiano S, Wagner CA, Bianchi G, Meyer G. Upregulation of apical sodium‐chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt‐sensitive hypertension. Am J Physiol 295: F556‐F567, 2008.
 51. Cappola TP, Matkovich SJ, Wang W, van Booven D, Li M, Wang X, Qu L, Sweitzer NK, Fang JC, Reilly MP, Hakonarson H, Nerbonne JM, Dorn GW, 2nd. Loss‐of‐function DNA sequence variant in the CLCNKA chloride channel implicates the cardio‐renal axis in interindividual heart failure risk variation. Proc Natl Acad Sci U S A 108: 2456‐2461, 2011.
 52. Carew MA, Thorn P. Identification of ClC‐2‐like chloride currents in pig pancreatic acinar cells. Pflügers Arch 433: 84‐90, 1996.
 53. Castellano Chiodo D, DiRocco M, Gandolfo C, Morana G, Buzzi D, Rossi A. Neuroimaging findings in malignant infantile osteopetrosis due to OSTM1 mutations. Neuropediatrics 38: 154‐156, 2007.
 54. Catalán M, Cornejo I, Figueroa CD, Niemeyer MI, Sepúlveda FV, Cid LP. ClC‐2 in guinea pig colon: mRNA, immunolabeling, and functional evidence for surface epithelium localization. Am J Physiol Gastrointest Liver Physiol 283: G1004‐G1013, 2002.
 55. Catalán M, Niemeyer MI, Cid LP, Sepúlveda FV. Basolateral ClC‐2 chloride channels in surface colon epithelium: Regulation by a direct effect of intracellular chloride. Gastroenterology 126: 1104‐1114, 2004.
 56. Cederholm JM, Rychkov GY, Bagley CJ, Bretag AH. Inter‐subunit communication and fast gate integrity are important for common gating in hClC‐1. Int J Biochem Cell Biol 42: 1182‐1188, 2010.
 57. Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J. Grey‐lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9: 399‐406, 2003.
 58. Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle‐specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10: 45‐53, 2002.
 59. Chen TY, Miller C. Nonequilibrium gating and voltage dependence of the ClC‐0 Cl‐ channel. J Gen Physiol 108: 237‐250, 1996.
 60. Christensen EI, Devuyst O, Dom G, Nielsen R, Van der Smissen P, Verroust P, Leruth M, Guggino WB, Courtoy PJ. Loss of chloride channel ClC‐5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci U S A 100: 8472‐8477, 2003.
 61. Chu K, Snyder R, Econs MJ. Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. J Bone Miner Res 21: 1089‐1097, 2006.
 62. Chu X, Filali M, Stanic B, Takapoo M, Sheehan A, Bhalla R, Lamb FS, Miller FJ, Jr. A critical role for chloride channel‐3 (CIC‐3) in smooth muscle cell activation and neointima formation. Arterioscler Thromb Vasc Biol 31: 345‐351, 2011.
 63. Cigić B, Pain RH. Location of the binding site for chloride ion activation of cathepsin C. Eur J Biochem 264: 944‐951, 1999.
 64. Clark S, Jordt SE, Jentsch TJ, Mathie A. Characterization of the hyperpolarization‐activated chloride current in dissociated rat sympathetic neurons. J Physiol (London) 506: 665‐678, 1998.
 65. Cleiren E, Benichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, deVernejoul MC, Van Hul W. Albers‐Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10: 2861‐2867, 2001.
 66. Comes N, Abad E, Morales M, Borras T, Gual A, Gasull X. Identification and functional characterization of ClC‐2 chloride channels in trabecular meshwork cells. Exp Eye Res 83: 877‐889, 2006.
 67. Cornejo I, Niemeyer MI, Zuniga L, Yusef YR, Sepulveda FV, Cid LP. Rapid recycling of ClC‐2 chloride channels between plasma membrane and endosomes: Role of a tyrosine endocytosis motif in surface retrieval. J Cell Physiol 221: 650‐657, 2009.
 68. Cortez MA, Li C, Whitehead SN, Dhani SU, D'Antonio C, Huan LJ, Bennett SA, Snead OC, 3rd, Bear CE. Disruption of ClC‐2 expression is associated with progressive neurodegeneration in aging mice. Neuroscience 167: 154‐162, 2010.
 69. Cuddapah VA, Sontheimer H. Molecular interaction and functional regulation of ClC‐3 by Ca2+/calmodulin‐dependent protein kinase II (CaMKII) in human malignant glioma. J Biol Chem 285: 11188‐11196, 2010.
 70. Cunningham R, Esmaili A, Brown E, Biswas RS, Murtazina R, Donowitz M, Dijkman HB, van der Vlag J, Hogema BM, De Jonge HR, Shenolikar S, Wade JB, Weinman EJ. Urine electrolyte, mineral, and protein excretion in NHERF‐2 and NHERF‐1 null mice. Am J Physiol Renal Physiol 294: F1001‐F1007, 2008.
 71. Cuppoletti J, Malinowska DH, Tewari KP, Li QJ, Sherry AM, Patchen ML, Ueno R. SPI‐0211 activates T84 cell Cl‐ transport and recombinant human ClC‐2 Cl‐ currents. Am J Physiol: C1173‐C1183, 2004.
 72. Cuthbert AW. Lubiprostone targets prostanoid EP receptors in ovine airways. Br J Pharmacol 162: 508‐520, 2011.
 73. D'Souza S, Garcia‐Cabado A, Yu F, Teter K, Lukacs G, Skorecki K, Moore HP, Orlowski J, Grinstein S. The epithelial sodium‐hydrogen antiporter Na+/H+ exchanger 3 accumulates and is functional in recycling endosomes. J Biol Chem 273: 2035‐2043, 1998.
 74. De Angeli A, Monachello D, Ephritikhine G, Frachisse JM, Thomine S, Gambale F, Barbier‐Brygoo H. The nitrate/proton antiporter AtCLCa mediates nitrate accumulation in plant vacuoles. Nature 442: 939‐942, 2006.
 75. De Lisle RC, Mueller R, Roach E. Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype. BMC gastroenterology 10: 107, 2010.
 76. Del Greco MF, Pattaro C, Luchner A, Pichler I, Winkler T, Hicks AA, Fuchsberger C, Franke A, Melville SA, Peters A, Wichmann HE, Schreiber S, Heid IM, Krawczak M, Minelli C, Wiedermann CJ, Pramstaller PP. Genome‐wide association analysis and fine mapping of NT‐proBNP level provide novel insight into the role of the MTHFR‐CLCN6‐NPPA‐NPPB gene cluster. Hum Mol Genet, 20: 1660‐1671, 2011.
 77. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na‐K‐2Cl co‐transporter. Nat Genet 22: 192‐195, 1999.
 78. Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, Zhang G, Bindokas VP, Philipson LH, Nelson DJ. The granular chloride channel ClC‐3 is permissive for insulin secretion. Cell metabolism 10: 316‐323, 2009.
 79. Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV. Intra‐renal and subcellular distribution of the human chloride channel, CLC‐5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet 8: 247‐257, 1999.
 80. Dhani SU, Mohammad‐Panah R, Ahmed N, Ackerley C, Ramjeesingh M, Bear CE. Evidence for a functional interaction between the ClC‐2 chloride channel and the retrograde motor dynein complex. J Biol Chem 278: 16262‐16270, 2003.
 81. Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443: 651‐657, 2006.
 82. DiCiccio JE, Steinberg BE. Lysosomal pH and analysis of the counter ion pathways that support acidification. J Gen Physiol, 137(4): 385‐390, 2011.
 83. Dickerson LW, Bonthius DJ, Schutte BC, Yang B, Barna TJ, Bailey MC, Nehrke K, Williamson RA, Lamb FS. Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC‐3 voltage‐gated chloride channels. Brain Res 958: 227‐250, 2002.
 84. Diewald L, Rupp J, Dreger M, Hucho F, Gillen C, Nawrath H. Activation by acidic pH of CLC‐7 expressed in oocytes from Xenopus laevis. Biochem Biophys Res Commun 291: 421‐424, 2002.
 85. DiFranco M, Herrera A, Vergara JL. Chloride currents from the transverse tubular system in adult mammalian skeletal muscle fibers. J Gen Physiol 137: 21‐41, 2010.
 86. Duan D, Winter C, Cowley S, Hume JR, Horowitz B. Molecular identification of a volume‐regulated chloride channel. Nature 390: 417‐421, 1997.
 87. Duffield M, Rychkov G, Bretag A, Roberts M. Involvement of helices at the dimer interface in ClC‐1 common gating. J Gen Physiol 121: 149‐161, 2003.
 88. Duffield MD, Rychkov GY, Bretag AH, Roberts ML. Zinc inhibits human ClC‐1 muscle chloride channel by interacting with its common gating mechanism. J Physiol 568: 5‐12, 2005.
 89. Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, Nicholson GC, Eastell R, Prince RL, Eisman JA, Jones G, Sambrook PN, Reid IR, Dennison EM, Wark J, Richards JB, Uitterlinden AG, Spector TD, Esapa C, Cox RD, Brown SD, Thakker RV, Addison KA, Bradbury LA, Center JR, Cooper C, Cremin C, Estrada K, Felsenberg D, Gluer CC, Hadler J, Henry MJ, Hofman A, Kotowicz MA, Makovey J, Nguyen SC, Nguyen TV, Pasco JA, Pryce K, Reid DM, Rivadeneira F, Roux C, Stefansson K, Styrkarsdottir U, Thorleifsson G, Tichawangana R, Evans DM, Brown MA. Genome‐wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS genetics 7: e1001372, 2011.
 90. Dutzler R. The ClC family of chloride channels and transporters. Curr Opin Struct Biol 16: 439‐446, 2006.
 91. Dutzler R. A structural perspective on ClC channel and transporter function. FEBS letters 581: 2839‐2844, 2007.
 92. Dutzler R, Campbell EB, Cadene M, Chait BT, MacKinnon R. X‐ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature 415: 287‐294, 2002.
 93. Dutzler R, Campbell EB, MacKinnon R. Gating the selectivity filter in ClC chloride channels. Science 300: 108‐112, 2003.
 94. Edwards MM, Marin de Evsikova C, Collin GB, Gifford E, Wu J, Hicks WL, Whiting C, Varvel NH, Maphis N, Lamb BT, Naggert JK, Nishina PM, Peachey NS. Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Invest Ophthalmol Vis Sci 51: 3264‐3272, 2010.
 95. Eggermont J, Buyse G, Voets T, Tytgat J, De Smedt H, Droogmans G, Nilius B. Alternative splicing of ClC‐6 (a member of the CIC chloride‐channel family) transcripts generates three truncated isoforms one of which, ClC‐6c, is kidney‐specific. Biochem J 325: 269‐276, 1997.
 96. Embark HM, Bohmer C, Palmada M, Rajamanickam J, Wyatt AW, Wallisch S, Capasso G, Waldegger P, Seyberth HW, Waldegger S, Lang F. Regulation of CLC‐Ka/barttin by the ubiquitin ligase Nedd4‐2 and the serum‐ and glucocorticoid‐dependent kinases. Kidney Int 66: 1918‐1925, 2004.
 97. Enz R, Ross BJ, Cutting GR. Expression of the voltage‐gated chloride channel ClC‐2 in rod bipolar cells of the rat retina. J Neurosci 19: 9841‐9847, 1999.
 98. Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P. A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell 13: 377‐390, 2007.
 99. Estévez R, Boettger T, Stein V, Birkenhäger R, Otto M, Hildebrandt F, Jentsch TJ. Barttin is a Cl‐‐channel β‐subunit crucial for renal Cl‐‐reabsorption and inner ear K+‐secretion. Nature 414: 558‐561, 2001.
 100. Estévez R, Pusch M, Ferrer‐Costa C, Orozco M, Jentsch TJ. Functional and structural conservation of CBS domains from CLC chloride channels. J Physiol 557: 363‐378, 2004.
 101. Estévez R, Schroeder BC, Accardi A, Jentsch TJ, Pusch M. Conservation of chloride channel structure revealed by an inhibitor binding site in ClC‐1. Neuron 38: 47‐59, 2003.
 102. Fahlke C. Chloride channels take center stage in a muscular drama. J Gen Physiol 137: 17‐19, 2011.
 103. Fahlke C, Yu HT, Beck CL, Rhodes TH, George AL, Jr. Pore‐forming segments in voltage‐gated chloride channels. Nature 390: 529‐532, 1997.
 104. Falin RA, Miyazaki H, Strange K. C. elegans STK39/SPAK ortholog‐mediated inhibition of ClC anion channel activity is regulated by WNK‐independent ERK kinase signaling. Am J Physiol 300: C624‐C635, 2011.
 105. Faundez V, Hartzell HC. Intracellular chloride channels: Determinants of function in the endosomal pathway. Sci STKE 2004: re8, 2004.
 106. Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O. The functional variant of the CLC‐Kb channel T481S is not associated with blood pressure or hypertension in Swedes. J Hypertens 25: 111‐116, 2007.
 107. Feigin ME, Malbon CC. OSTM1 regulates β‐catenin/Lef1 interaction and is required for Wnt/β‐catenin signaling. Cell Signal 20: 949‐957, 2008.
 108. Feng L, Campbell EB, Hsiung Y, MacKinnon R. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science 330: 635‐641, 2011.
 109. Ferroni S, Marchini C, Nobile M, Rapisarda C. Characterization of an inwardly rectifying chloride conductance expressed by cultured rat cortical astrocytes. Glia 21: 217‐227, 1997.
 110. Fischer M, Janssen AG, Fahlke C. Barttin activates ClC‐K channel function by modulating gating. J Am Soc Nephrol 21: 1281‐1289, 2010.
 111. Fischer T, De Vries L, Meerloo T, Farquhar MG. Promotion of Gαi3 subunit down‐regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS‐GAIP. Proc Natl Acad Sci U S A 100: 8270‐8275, 2003.
 112. Fisher SE, Black GC, Lloyd SE, Hatchwell E, Wrong O, Thakker RV, Craig IW. Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X‐linked hereditary nephrolithiasis). Hum Mol Genet 3: 2053‐2059, 1994.
 113. Flores SY, Debonneville C, Staub O. The role of Nedd4/Nedd4‐like dependant ubiquitylation in epithelial transport processes. Pflugers Arch 446: 334‐338, 2003.
 114. Földy C, Lee SH, Morgan RJ, Soltesz I. Regulation of fast‐spiking basket cell synapses by the chloride channel ClC‐2. Nature neuroscience 13: 1047‐1049, 2010.
 115. Fong P, Rehfeldt A, Jentsch TJ. Determinants of slow gating in ClC‐0, the voltage‐gated chloride channel of Torpedo marmorata. Am J Physiol 274: C966‐C973, 1998.
 116. Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25: 343‐346, 2000.
 117. Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res 18: 1740‐1747, 2003.
 118. Frey A, Lampert A, Waldegger S, Jeck N, Waldegger P, Artunc F, Seebohm G, Lang UE, Kupka S, Pfister M, Hoppe J, Gerloff C, Schaeffeler E, Schwab M, Lang F. Influence of gain of function epithelial chloride channel ClC‐Kb mutation on hearing thresholds. Hear Res 214: 68‐75, 2006.
 119. Friedrich T, Breiderhoff T, Jentsch TJ. Mutational analysis demonstrates that ClC‐4 and ClC‐5 directly mediate plasma membrane currents. J Biol Chem 274: 896‐902, 1999.
 120. Fritsch J, Edelman A. Modulation of the hyperpolarization‐activated Cl‐ current in human intestinal T84 epithelial cells by phosphorylation. J Physiol (London) 490: 115‐128, 1996.
 121. Fritsch J, Edelman A. Osmosensitivity of the hyperpolarization‐activated chloride current in human intestinal T84 cells. Am J Physiol 272: C778‐C786, 1997.
 122. Fuchs R, Mâle P, Mellman I. Acidification and ion permeabilities of highly purified rat liver endosomes. J Biol Chem 264: 2212‐2220, 1989.
 123. Fukuyama S, Hiramatsu M, Akagi M, Higa M, Ohta T. Novel mutations of the chloride channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria. J Clin Endocrinol Metab 89: 5847‐5850, 2004.
 124. Furukawa T, Ogura T, Zheng YJ, Tsuchiya H, Nakaya H, Katayama Y, Inagaki N. Phosphorylation and functional regulation of ClC‐2 chloride channels expressed in Xenopus oocytes by M cyclin‐dependent protein kinase. J Physiol 540: 883‐893, 2002.
 125. Gailly P, Jouret F, Martin D, Debaix H, Parreira KS, Nishita T, Blanchard A, Antignac C, Willnow TE, Courtoy PJ, Scheinman SJ, Christensen EI, Devuyst O. A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction. Kidney Int 74: 52‐61, 2008.
 126. Garcia‐Olivares J, Alekov A, Boroumand MR, Begemann B, Hidalgo P, Fahlke C. Gating of human ClC‐2 chloride channels and regulation by carboxy‐terminal domains. J Physiol 586: 5325‐5336, 2008.
 127. Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR. The PDZ‐binding chloride channel ClC‐3B localizes to the Golgi and associates with CFTR‐interacting PDZ proteins. J Biol Chem 278: 6440‐6449, 2003.
 128. George AL, Jr., Crackower MA, Abdalla JA, Hudson AJ, Ebers GC. Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita). Nat Genet 3: 305‐310, 1993.
 129. George AL, Jr., Sloan‐Brown K, Fenichel GM, Mitchell GA, Spiegel R, Pascuzzi RM. Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita. Hum Mol Genet 3: 2071‐2072, 1994.
 130. Goebel HH, Wisniewski KE. Current state of clinical and morphological features in human NCL. Brain Pathol 14: 61‐69, 2004.
 131. Gong W, Xu H, Shimizu T, Morishima S, Tanabe S, Tachibe T, Uchida S, Sasaki S, Okada Y. ClC‐3‐independent, PKC‐dependent activity of volume‐sensitive Cl channel in mouse ventricular cardiomyocytes. Cell Physiol Biochem 14: 213‐224, 2004.
 132. Gradogna A, Babini E, Picollo A, Pusch M. A regulatory calcium‐binding site at the subunit interface of ClC‐K kidney chloride channels. J Gen Physiol 136: 311‐323, 2010.
 133. Grand T, L'Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T, Genete M, Laghmani K, Teulon J, Lourdel S. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat 32: 476‐483, 2011.
 134. Grand T, Mordasini D, L'Hoste S, Pennaforte T, Genete M, Biyeyeme MJ, Vargas‐Poussou R, Blanchard A, Teulon J, Lourdel S. Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney Int 76: 999‐1005, 2009.
 135. Graves AR, Curran PK, Smith CL, Mindell JA. The Cl‐/H+ antiporter ClC‐7 is the primary chloride permeation pathway in lysosomes. Nature 453: 788‐792, 2008.
 136. Greene JR, Brown NH, DiDomenico BJ, Kaplan J, Eide DJ. The GEF1 gene of Saccharomyces cerevisiae encodes an integral membrane protein; mutations in which have effects on respiration and iron‐limited growth. Mol Gen Genet 241: 542‐553, 1993.
 137. Grønborg M, Pavlos NJ, Brunk I, Chua JJ, Münster‐Wandowski A, Riedel D, Ahnert‐Hilger G, Urlaub H, Jahn R. Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein. J Neurosci 30: 2‐12, 2010.
 138. Gründer S, Thiemann A, Pusch M, Jentsch TJ. Regions involved in the opening of CIC‐2 chloride channel by voltage and cell volume. Nature 360: 759‐762, 1992.
 139. Grüneberg H. A new sub‐lethal colour mutation in the house mouse. Proc R Soc Lond B 118: 321‐342, 1935.
 140. Günther W, Lüchow A, Cluzeaud F, Vandewalle A, Jentsch TJ. ClC‐5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci U S A 95: 8075‐8080, 1998.
 141. Günther W, Piwon N, Jentsch TJ. The ClC‐5 chloride channel knock‐out mouse—an animal model for Dent's disease. Pflügers Arch 445: 456‐462, 2003.
 142. Gurnett CA, Kahl SD, Anderson RD, Campbell KP. Absence of the skeletal muscle sarcolemma chloride channel ClC‐1 in myotonic mice. J Biol Chem 270: 9035‐9038, 1995.
 143. Gyömörey K, Yeger H, Ackerley C, Garami E, Bear CE. Expression of the chloride channel ClC‐2 in the murine small intestine epithelium. Am J Physiol 279: C1787‐C1794, 2000.
 144. Habela CW, Olsen ML, Sontheimer H. ClC3 is a critical regulator of the cell cycle in normal and malignant glial cells. J Neurosci 28: 9205‐9217, 2008.
 145. Hara‐Chikuma M, Wang Y, Guggino SE, Guggino WB, Verkman AS. Impaired acidification in early endosomes of ClC‐5 deficient proximal tubule. Biochem Biophys Res Commun 329: 941‐946, 2005.
 146. Hara‐Chikuma M, Yang B, Sonawane ND, Sasaki S, Uchida S, Verkman AS. ClC‐3 chloride channels facilitate endosomal acidification and chloride accumulation. J Biol Chem 280: 1241‐1247, 2005.
 147. Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller‐Newen G, Propping P, Elger CE, Fahlke C, Lerche H. Retraction: Mutations in CLCN2 encoding a voltage‐gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 41: 1043, 2009.
 148. Hayama A, Rai T, Sasaki S, Uchida S. Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 119: 485‐493, 2003.
 149. Hebeisen S, Heidtmann H, Cosmelli D, González C, Poser B, Latorre R, Alvarez O, Fahlke C. Anion permeation in human ClC‐4 channels. Biophys J 84: 2306‐2318, 2003.
 150. Hebert SC. Bartter syndrome. Curr Opin Nephrol Hypertens 12: 527‐532, 2003.
 151. Henriksen K, Gram J, Neutzsky‐Wulff AV, Jensen VK, Dziegiel MH, Bollerslev J, Karsdal MA. Characterization of acid flux in osteoclasts from patients harboring a G215R mutation in ClC‐7. Biochem Biophys Res Commun 378: 804‐809, 2009.
 152. Henriksen K, Sørensen MG, Nielsen RH, Gram J, Schaller S, Dziegiel MH, Everts V, Bollerslev J, Karsdal MA. Degradation of the organic phase of bone by osteoclasts: A secondary role for lysosomal acidification. J Bone Miner Res 21: 58‐66, 2006.
 153. Hibino H, Kurachi Y. Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology 21: 336‐345, 2006.
 154. 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. Pflügers Arch 459: 521‐533, 2010.
 155. Hinzpeter A, Fritsch J, Borot F, Trudel S, Vieu DL, Brouillard F, Baudouin‐Legros M, Clain J, Edelman A, Ollero M. Membrane cholesterol content modulates ClC‐2 gating and sensitivity to oxidative stress. J Biol Chem 282: 2423‐2432, 2007.
 156. Hinzpeter A, Lipecka J, Brouillard F, Baudouin‐Legros M, Dadlez M, Edelman A, Fritsch J. Association between Hsp90 and the ClC‐2 chloride channel upregulates channel function. Am J Physiol 290: C45‐C56, 2005.
 157. Hoffmann EK, Lambert IH, Pedersen SF. Physiology of cell volume regulation in vertebrates. Physiological reviews 89: 193‐277, 2009.
 158. Hohberger B, Enz R. Cereblon is expressed in the retina and binds to voltage‐gated chloride channels. FEBS letters 583: 633‐637, 2009.
 159. Hoopes RR, Jr., Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ. Evidence for genetic heterogeneity in Dent's disease. Kidney Int 65: 1615‐1620, 2004.
 160. Hoopes RR, Jr., Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ. Dent's disease with mutations in OCRL1. Am J Hum Genet 76: 260‐267, 2005.
 161. Hori K, Takahashi Y, Horikawa N, Furukawa T, Tsukada K, Takeguchi N, Sakai H. Is the ClC‐2 chloride channel involved in the Cl‐ secretory mechanism of gastric parietal cells? FEBS letters 575: 105‐108, 2004.
 162. Hryciw DH, Ekberg J, Ferguson C, Lee A, Wang D, Parton RG, Pollock CA, Yun CC, Poronnik P. Regulation of albumin endocytosis by PSD95/Dlg/ZO‐1 (PDZ) scaffolds. Interaction of Na+‐H +exchange regulatory factor‐2 with ClC‐5. J Biol Chem 281: 16068‐16077, 2006.
 163. Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Pollock CA, Poronnik P. Nedd4‐2 functionally interacts with ClC‐5: Involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem 279: 54996‐55007, 2004.
 164. Hryciw DH, Wang Y, Devuyst O, Pollock CA, Poronnik P, Guggino WB. Cofilin interacts with ClC‐5 and regulates albumin uptake in proximal tubule cell lines. J Biol Chem 278: 40169‐40176, 2003.
 165. Huang P, Liu J, Robinson NC, Musch MW, Kaetzel MA, Nelson DJ. Regulation of human ClC‐3 channels by multifunctional Ca2+/calmodulin dependent protein kinase. J Biol Chem 276: 20093‐20100, 2001.
 166. Huber SM, Duranton C, Henke G, Van De Sand C, Heussler V, Shumilina E, Sandu CD, Tanneur V, Brand V, Kasinathan RS, Lang KS, Kremsner PG, Hübner CA, Rust MB, Dedek K, Jentsch TJ, Lang F. Plasmodium induces swelling‐activated ClC‐2 anion channels in the host erythrocyte. J Biol Chem 279: 41444‐41452, 2004.
 167. Ignoul S, Simaels J, Hermans D, Annaert W, Eggermont J. Human ClC‐6 Is a late endosomal glycoprotein that associates with detergent‐resistant lipid domains. PloS One 2: e474, 2007.
 168. Inagaki A, Yamaguchi S, Takahashi‐Iwanaga H, Iwanaga T, Ishikawa T. Functional characterization of a ClC‐2‐like Cl‐ conductance in surface epithelial cells of rat rectal colon. J Membr Biol 235: 27‐41, 2010.
 169. Isnard‐Bagnis C, Da Silva N, Beaulieu V, Yu AS, Brown D, Breton S. Detection of ClC‐3 and ClC‐5 in epididymal epithelium: Immunofluorescence and RT‐PCR after LCM. Am J Physiol 284: C220‐C232, 2003.
 170. Janssen AG, Scholl U, Domeyer C, Nothmann D, Leinenweber A, Fahlke C. Disease‐causing dysfunctions of barttin in Bartter syndrome type IV. J Am Soc Nephrol 20: 145‐153, 2009.
 171. Jeck N, Waldegger P, Doroszewicz J, Seyberth H, Waldegger S. A common sequence variation of the CLCNKB gene strongly activates ClC‐Kb chloride channel activity. Kidney Int 65: 190‐197, 2004.
 172. Jeck N, Waldegger S, Lampert A, Boehmer C, Waldegger P, Lang PA, Wissinger B, Friedrich B, Risler T, Moehle R, Lang UE, Zill P, Bondy B, Schaeffeler E, Asante‐Poku S, Seyberth H, Schwab M, Lang F. Activating mutation of the renal epithelial chloride channel ClC‐Kb predisposing to hypertension. Hypertension 43: 1175‐1181, 2004.
 173. Jentsch TJ. Chloride transport in the kidney: Lessons from human disease and knockout mice. J Am Soc Nephrol 16: 1549‐1561, 2005.
 174. Jentsch TJ. Chloride and the endosomal‐lysosomal pathway: Emerging roles of CLC chloride transporters. J Physiol 578: 633‐640, 2007.
 175. Jentsch TJ. CLC chloride channels and transporters: From genes to protein structure, pathology and physiology. Crit Rev Biochem Mol Biol 43: 3‐36, 2008.
 176. Jentsch TJ, Günther W, Pusch M, Schwappach B. Properties of voltage‐gated chloride channels of the ClC gene family. J Physiol 482: 19S‐25S, 1995.
 177. Jentsch TJ, Maritzen T, Keating DJ, Zdebik AA, Thevenod F. ClC‐3—a granular anion transporter involved in insulin secretion? Cell metabolism 12: 307‐308, 2010.
 178. Jentsch TJ, Poët M, Fuhrmann JC, Zdebik AA. Physiological functions of CLC Cl‐ channels gleaned from human genetic disease and mouse models. Ann Rev Physiol 67: 779‐807, 2005.
 179. Jentsch TJ, Steinmeyer K, Schwarz G. Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348: 510‐514, 1990.
 180. Jordt SE, Jentsch TJ. Molecular dissection of gating in the ClC‐2 chloride channel. EMBO J 16: 1582‐1592, 1997.
 181. Kajiya H, Okamoto F, Ohgi K, Nakao A, Fukushima H, Okabe K. Characteristics of ClC7 Cl‐ channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene‐expressing cells. Pflügers Arch 458: 1049‐1059, 2009.
 182. Kasinathan RS, Foller M, Lang C, Koka S, Lang F, Huber SM. Oxidation induces ClC‐3‐dependent anion channels in human leukaemia cells. FEBS letters 581: 5407‐5412, 2007.
 183. Kasper D, Planells‐Cases R, Fuhrmann JC, Scheel O, Zeitz O, Ruether K, Schmitt A, Poët M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ. Loss of the chloride channel ClC‐7 leads to lysosomal storage disease and neurodegeneration. EMBO J 24: 1079‐1091, 2005.
 184. Kawasaki M, Suzuki M, Uchida S, Sasaki S, Marumo F. Stable and functional expression of the CIC‐3 chloride channel in somatic cell lines. Neuron 14: 1285‐1291, 1995.
 185. Kawasaki M, Uchida S, Monkawa T, Miyawaki A, Mikoshiba K, Marumo F, Sasaki S. Cloning and expression of a protein kinase C‐regulated chloride channel abundantly expressed in rat brain neuronal cells. Neuron 12: 597‐604, 1994.
 186. Kida Y, Uchida S, Miyazaki H, Sasaki S, Marumo F. Localization of mouse ClC‐6 and ClC‐7 mRNA and their functional complementation of yeast CLC gene mutant. Histochem Cell Biol 115: 189‐194, 2001.
 187. Kieferle S, Fong P, Bens M, Vandewalle A, Jentsch TJ. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc Natl Acad Sci U S A 91: 6943‐6947, 1994.
 188. Kleefuss‐Lie A, Friedl W, Cichon S, Haug K, Warnstedt M, Alekov A, Sander T, Ramirez A, Poser B, Maljevic S, Hebeisen S, Kubisch C, Rebstock J, Horvath S, Hallmann K, Dullinger JS, Rau B, Haverkamp F, Beyenburg S, Schulz H, Janz D, Giese B, Muller‐Newen G, Propping P, Elger CE, Fahlke C, Lerche H. CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 41: 954‐955, 2009.
 189. Klocke R, Steinmeyer K, Jentsch TJ, Jockusch H. Role of innervation, excitability, and myogenic factors in the expression of the muscular chloride channel ClC‐1. A study on normal and myotonic muscle. J Biol Chem 269: 27635‐27639, 1994.
 190. Kobayashi K, Uchida S, Mizutani S, Sasaki S, Marumo F. Developmental expression of CLC‐K1 in the postnatal rat kidney. Histochem Cell Biol 116: 49‐56, 2001.
 191. Kobayashi K, Uchida S, Mizutani S, Sasaki S, Marumo F. Intrarenal and cellular localization of CLC‐K2 protein in the mouse kidney. J Am Soc Nephrol 12: 1327‐1334, 2001.
 192. Kobayashi K, Uchida S, Okamura HO, Marumo F, Sasaki S. Human CLC‐KB gene promoter drives the EGFP expression in the specific distal nephron segments and inner ear. J Am Soc Nephrol 13: 1992‐1998, 2002.
 193. Koch MC, Ricker K, Otto M, Wolf F, Zoll B, Lorenz C, Steinmeyer K, Jentsch TJ. Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker). J Med Genet 30: 914‐917, 1993.
 194. Koch MC, Steinmeyer K, Lorenz C, Ricker K, Wolf F, Otto M, Zoll B, Lehmann‐Horn F, Grzeschik KH, Jentsch TJ. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257: 797‐800, 1992.
 195. Kokubo Y, Iwai N, Tago N, Inamoto N, Okayama A, Yamawaki H, Naraba H, Tomoike H. Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population. Circ J 69: 138‐142, 2005.
 196. Konrad M, Vollmer M, Lemmink HH, van den Heuvel LP, Jeck N, Vargas‐Poussou R, Lakings A, Ruf R, Deschenes G, Antignac C, Guay‐Woodford L, Knoers NV, Seyberth HW, Feldmann D, Hildebrandt F. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 11: 1449‐1459, 2000.
 197. Kornak U, Kasper D, Bösl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ. Loss of the ClC‐7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205‐215, 2001.
 198. Kornak U, Ostertag A, Branger S, Benichou O, de Vernejoul MC. Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II. J Clin Endocrinol Metab 91: 995‐1000, 2005.
 199. Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C. Mutations in the a3 subunit of the vacuolar H+‐ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9: 2059‐2063, 2000.
 200. Koty PP, Pegoraro E, Hobson G, Marks HG, Turel A, Flagler D, Cadaldini M, Angelini C, Hoffman EP. Myotonia and the muscle chloride channel: Dominant mutations show variable penetrance and founder effect. Neurology 47: 963‐968, 1996.
 201. Kubisch C, Schmidt‐Rose T, Fontaine B, Bretag AH, Jentsch TJ. ClC‐1 chloride channel mutations in myotonia congenita: Variable penetrance of mutations shifting the voltage dependence. Hum Mol Genet 7: 1753‐1760, 1998.
 202. Lan WZ, Abbas H, Lam HD, Lemay AM, Hill CE. Contribution of a time‐dependent and hyperpolarization‐activated chloride conductance to currents of resting and hypotonically shocked rat hepatocytes. Am J Physiol 288: G221‐G229, 2005.
 203. Landau D, Shalev H, Ohaly M, Carmi R. Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder. Am J Med Genet 59: 454‐459, 1995.
 204. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC. ClC‐7 requires Ostm1 as a β‐subunit to support bone resorption and lysosomal function. Nature 440: 220‐223, 2006.
 205. Leheste JR, Rolinski B, Vorum H, Hilpert J, Nykjaer A, Jacobsen C, Aucouturier P, Moskaug JO, Otto A, Christensen EI, Willnow TE. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol 155: 1361‐1370, 1999.
 206. Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. ClC‐7 is a slowly voltage‐gated 2 Cl–/1H+‐exchanger and requires Ostm1 for transport activity. EMBO J 30: 2140‐2152, 2011.
 207. Letizia C, Taranta A, Migliaccio S, Caliumi C, Diacinti D, Delfini E, D'Erasmo E, Iacobini M, Roggini M, Albagha OM, Ralston SH, Teti A. Type II benign osteopetrosis (Albers‐Schönberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations. Calcif Tissue Int 74: 42‐46, 2004.
 208. Li DQ, Jing X, Salehi A, Collins SC, Hoppa MB, Rosengren AH, Zhang E, Lundquist I, Olofsson CS, Morgelin M, Eliasson L, Rorsman P, Renstrom E. Suppression of sulfonylurea‐ and glucose‐induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC‐3. Cell Metab 10: 309‐315, 2009.
 209. Li X, Shimada K, Showalter LA, Weinman SA. Biophysical properties of ClC‐3 differentiate it from swelling‐activated chloride channels in Chinese Hamster Ovary‐K1 cells. J Biol Chem 275: 35994‐35998, 2000.
 210. Li X, Wang T, Zhao Z, Weinman SA. The ClC‐3 chloride channel promotes acidification of lysosomes in CHO‐K1 and Huh‐7 cells. Am J Physiol 282: C1483‐C1491, 2002.
 211. Li YP, Chen W, Liang Y, Li E, Stashenko P. Atp6i‐deficient mice exhibit severe osteopetrosis due to loss of osteoclast‐mediated extracellular acidification. Nat Genet 23: 447‐451, 1999.
 212. Liantonio A, De Luca A, Pierno S, Didonna MP, Loiodice F, Fracchiolla G, Tortorella P, Antonio L, Bonerba E, Traverso S, Elia L, Picollo A, Pusch M, Conte Camerino D. Structural requisites of 2‐(p‐chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC‐1. Br J Pharmacol 139: 1255‐1264, 2003.
 213. Liantonio A, Giannuzzi V, Picollo A, Babini E, Pusch M, Conte Camerino D. Niflumic acid inhibits chloride conductance of rat skeletal muscle by directly inhibiting the CLC‐1 channel and by increasing intracellular calcium. Br J Pharmacol 150: 235‐247, 2007.
 214. Liantonio A, Picollo A, Babini E, Carbonara G, Fracchiolla G, Loiodice F, Tortorella V, Pusch M, Camerino DC. Activation and inhibition of kidney CLC‐K chloride channels by fenamates. Mol Pharmacol 69: 165‐173, 2006.
 215. Liantonio A, Picollo A, Carbonara G, Fracchiolla G, Tortorella P, Loiodice F, Laghezza A, Babini E, Zifarelli G, Pusch M, Camerino DC. Molecular switch for CLC‐K Cl‐ channel block/activation: Optimal pharmacophoric requirements towards high‐affinity ligands. Proc Natl Acad Sci U S A 105: 1369‐1373, 2008.
 216. Liantonio A, Pusch M, Picollo A, Guida P, De Luca A, Pierno S, Fracchiolla G, Loiodice F, Tortorella P, Conte Camerino D. Investigations of pharmacologic properties of the renal CLC‐K1 chloride channel co‐expressed with barttin by the use of 2‐(p‐Chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride channels blockers. J Am Soc Nephrol 15: 13‐20, 2004.
 217. Lichter‐Konecki U, Farber LW, Cronin JS, Suchy SF, Nussbaum RL. The effect of missense mutations in the RhoGAP‐homology domain on ocrl1 function. Mol Genet Metab 89: 121‐128, 2006.
 218. Lipecka J, Bali M, Thomas A, Fanen P, Edelman A, Fritsch J. Distribution of ClC‐2 chloride channel in rat and human epithelial tissues. Am J Physiol 282: C805‐C816, 2002.
 219. Lipicky RJ, Bryant SH. Sodium, potassium, and chloride fluxes in intercostal muscle from normal goats and goats with hereditary myotonia. J Gen Physiol 50: 89‐111, 1966.
 220. Lipicky RJ, Bryant SH, Salmon JH. Cable parameters, sodium, potassium, chloride, and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita. J Clin Invest 50: 2091‐2103, 1971.
 221. Lisal J, Maduke M. The ClC‐0 chloride channel is a “‘broken” Cl‐/H+ antiporter. Nat Struct Mol Biol 15: 805‐810, 2008.
 222. Lisal J, Maduke M. Review. Proton‐coupled gating in chloride channels. Philos Trans R Soc Lond B Biol Sci 364: 181‐187, 2009.
 223. Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature 379: 445‐449, 1996.
 224. Lloyd SE, Pearce SH, Günther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV. Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J Clin Invest 99: 967‐974, 1997.
 225. Lorenz C, Pusch M, Jentsch TJ. Heteromultimeric CLC chloride channels with novel properties. Proc Natl Acad Sci U S A 93: 13362‐13366, 1996.
 226. Lourdel S, Paulais M, Marvao P, Nissant A, Teulon J. A chloride channel at the basolateral membrane of the distal‐convoluted tubule: A candidate ClC‐K channel. J Gen Physiol 121: 287‐300, 2003.
 227. Ludewig U, Pusch M, Jentsch TJ. Two physically distinct pores in the dimeric ClC‐0 chloride channel. Nature 383: 340‐343, 1996.
 228. Ludwig M, Doroszewicz J, Seyberth HW, Bokenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S. Functional evaluation of Dent's disease‐causing mutations: Implications for ClC‐5 channel trafficking and internalization. Hum Genet 117: 228‐237, 2005.
 229. Lueck JD, Rossi AE, Thornton CA, Campbell KP, Dirksen RT. Sarcolemmal‐restricted localization of functional ClC‐1 channels in mouse skeletal muscle. J Gen Physiol 136: 597‐613, 2010.
 230. Lui VC, Lung SS, Pu JK, Hung KN, Leung GK. Invasion of human glioma cells is regulated by multiple chloride channels including ClC‐3. Anticancer Res 30: 4515‐4524, 2010.
 231. Luzio JP, Bright NA, Pryor PR. The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Biochem Soc Trans 35: 1088‐1091, 2007.
 232. Maehara H, Okamura HO, Kobayashi K, Uchida S, Sasaki S, Kitamura K. Expression of CLC‐KB gene promoter in the mouse cochlea. Neuroreport 14: 1571‐1573, 2003.
 233. Mailänder V, Heine R, Deymeer F, Lehmann‐Horn F. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet 58: 317‐324, 1996.
 234. Majumdar A, Capetillo‐Zarate E, Cruz D, Gouras GK, Maxfield FR. Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC‐7 to lysosomes. Mol Biol Cell 22: 1664‐1676, 2011.
 235. Makara JK, Petheo GL, Toth A, Spat A. pH‐sensitive inwardly rectifying chloride current in cultured rat cortical astrocytes. Glia 34: 52‐58, 2001.
 236. Makara JK, Rappert A, Matthias K, Steinhäuser C, Spat A, Kettenmann H. Astrocytes from mouse brain slices express ClC‐2‐mediated Cl‐ currents regulated during development and after injury. Mol Cell Neurosci 23: 521‐530, 2003.
 237. Malinowska DH, Kupert EY, Bahinski A, Sherry AM, Cuppoletti J. Cloning, functional expression, and characterization of a PKA‐activated gastric Cl‐ channel. Am J Physiol 268: C191‐C200, 1995.
 238. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA. Expanded CUG repeats trigger aberrant splicing of ClC‐1 chloride channel pre‐mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10: 35‐44, 2002.
 239. Mao J, Chen L, Xu B, Wang L, Li H, Guo J, Li W, Nie S, Jacob TJ, Wang L. Suppression of ClC‐3 channel expression reduces migration of nasopharyngeal carcinoma cells. Biochem Pharmacol 75: 1706‐1716, 2008.
 240. Maranda B, Chabot G, Decarie JC, Pata M, Azeddine B, Moreau A, Vacher J. Clinical and cellular manifestations of OSTM1‐related infantile osteopetrosis. J Bone Miner Res 23: 296‐300, 2008.
 241. Marcus DC, Wu T, Wangemann P, Kofuji P. KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol 282: C403‐C407, 2002.
 242. Maritzen T, Keating DJ, Neagoe I, Zdebik AA, Jentsch TJ. Role of the vesicular chloride transporter ClC‐3 in neuroendocrine tissue. J Neurosci 28: 10587‐10598, 2008.
 243. Maritzen T, Lisi S, Botta R, Pinchera A, Fanelli G, Viacava P, Marcocci C, Marino M. ClC‐5 does not affect megalin expression and function in the thyroid. Thyroid 16: 725‐730, 2006.
 244. Maritzen T, Rickheit G, Schmitt A, Jentsch TJ. Kidney‐specific upregulation of vitamin D3 target genes in ClC‐5 KO mice. Kidney Int 70: 79‐87, 2006.
 245. Martinez GQ, Maduke M. A cytoplasmic domain mutation in ClC‐Kb affects long‐distance communication across the membrane. PloS One 3: e2746, 2008.
 246. Matsuda JJ, Filali MS, Collins MM, Volk KA, Lamb FS. The ClC‐3 Cl‐/H+ antiporter becomes uncoupled at low extracellular pH. J Biol Chem 285: 2569‐2579, 2010.
 247. Matsuda JJ, Filali MS, Moreland JG, Miller FJ, Lamb FS. Activation of swelling‐activated chloride current by tumor necrosis factor‐alpha requires ClC‐3‐dependent endosomal reactive oxygen production. J Biol Chem 285: 22864‐22873, 2010.
 248. Matsuda JJ, Filali MS, Volk KA, Collins MM, Moreland JG, Lamb FS. Overexpression of ClC‐3 in HEK293T cells yields novel currents that are pH‐dependent. Am J Physiol 294: C251‐C262, 2008.
 249. Matsumura Y, Uchida S, Kondo Y, Miyazaki H, Ko SB, Hayama A, Morimoto T, Liu W, Arisawa M, Sasaki S, Marumo F. Overt nephrogenic diabetes insipidus in mice lacking the CLC‐K1 chloride channel. Nat Genet 21: 95‐98, 1999.
 250. Matulef K, Howery AE, Tan L, Kobertz WR, Du Bois J, Maduke M. Discovery of potent CLC chloride channel inhibitors. ACS Chem Biol 3: 419‐428, 2008.
 251. McCrea HJ, Paradise S, Tomasini L, Addis M, Melis MA, De Matteis MA, De Camilli P. All known patient mutations in the ASH‐RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem Biophys Res Commun 369: 493‐499, 2008.
 252. Meadows NA, Sharma SM, Faulkner GJ, Ostrowski MC, Hume DA, Cassady AI. The expression of Clcn7 and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor. J Biol Chem 282: 1891‐1904, 2007.
 253. Mejia R, Wade JB. Immunomorphometric study of rat renal inner medulla. Am J Physiol Renal Physiol 282: F553‐F557, 2002.
 254. Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55: 663‐700, 1986.
 255. Menichella DM, Goodenough DA, Sirkowski E, Scherer SS, Paul DL. Connexins are critical for normal myelination in the CNS. J Neurosci 23: 5963‐5973, 2003.
 256. Menichella DM, Majdan M, Awatramani R, Goodenough DA, Sirkowski E, Scherer SS, Paul DL. Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J Neurosci 26: 10984‐10991, 2006.
 257. Meyer S, Savaresi S, Forster IC, Dutzler R. Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC‐5. Nat Struct Mol Biol 14: 60‐67, 2007.
 258. Middleton RE, Pheasant DJ, Miller C. Homodimeric architecture of a ClC‐type chloride ion channel. Nature 383: 337‐340, 1996.
 259. Miller C. Open‐state substructure of single chloride channels from Torpedo electroplax. Philos Trans R Soc Lond B Biol Sci 299: 401‐411, 1982.
 260. Miller C. ClC chloride channels viewed through a transporter lens. Nature 440: 484‐489, 2006.
 261. Miller C, White MM. Dimeric structure of single chloride channels from Torpedo electroplax. Proc Natl Acad Sci U S A 81: 2772‐2775, 1984.
 262. Miller FJ, Jr., Filali M, Huss GJ, Stanic B, Chamseddine A, Barna TJ, Lamb FS. Cytokine activation of nuclear factor κB in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC‐3. Circ Res 101: 663‐671, 2007.
 263. Mitchell J, Wang X, Zhang G, Gentzsch M, Nelson DJ, Shears SB. An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC‐3 function. Curr Biol 18: 1600‐1605, 2008.
 264. Miyamura N, Matsumoto K, Taguchi T, Tokunaga H, Nishikawa T, Nishida K, Toyonaga T, Sakakida M, Araki E. Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the β‐subunit for ClC‐Ka and ClC‐Kb chloride channels, Barttin. J Clin Endocrinol Metab 88: 781‐786, 2003.
 265. Mohammad‐Panah R, Ackerley C, Rommens J, Choudhury M, Wang Y, Bear CE. The chloride channel ClC‐4 co‐localizes with cystic fibrosis transmembrane conductance regulator and may mediate chloride flux across the apical membrane of intestinal epithelia. J Biol Chem 277: 566‐574, 2002.
 266. Mohammad‐Panah R, Harrison R, Dhani S, Ackerley C, Huan LJ, Wang Y, Bear CE. The chloride channel ClC‐4 contributes to endosomal acidification and trafficking. J Biol Chem 278: 29267‐29277, 2003.
 267. Mohammad‐Panah R, Wellhauser L, Steinberg BE, Wang Y, Huan LJ, Liu XD, Bear CE. An essential role for ClC‐4 in transferrin receptor function revealed in studies of fibroblasts derived from Clcn4‐null mice. J Cell Sci 122: 1229‐1237, 2009.
 268. Moon IS, Kim HS, Shin JH, Park YE, Park KH, Shin YB, Bae JS, Choi YC, Kim DS. Novel CLCN1 mutations and clinical features of Korean patients with myotonia congenita. J Korean Med Sci 24: 1038‐1044, 2009.
 269. Moreland JG, Davis AP, Bailey G, Nauseef WM, Lamb FS. Anion channels, including ClC‐3, are required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration. J Biol Chem 281: 12277‐12288, 2006.
 270. Moreland JG, Davis AP, Matsuda JJ, Hook JS, Bailey G, Nauseef WM, Lamb FS. Endotoxin priming of neutrophils requires NADPH oxidase generated oxidants and is regulated by the anion transporter ClC‐3. J Biol Chem 282: 33958‐33967, 2007.
 271. Morimoto T, Uchida S, Sakamoto H, Kondo Y, Hanamizu H, Fukui M, Tomino Y, Nagano N, Sasaki S, Marumo F. Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. J Am Soc Nephrol 9: 811‐818, 1998.
 272. Morioka T, Asilmaz E, Hu J, Dishinger JF, Kurpad AJ, Elias CF, Li H, Elmquist JK, Kennedy RT, Kulkarni RN. Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice. J Clin Invest 117: 2860‐2868, 2007.
 273. Murer H, Forster I, Hernando N, Lambert G, Traebert M, Biber J. Posttranscriptional regulation of the proximal tubule NaPi‐II transporter in response to PTH and dietary Pi. Am J Physiol 277: F676‐F684, 1999.
 274. Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D. Bartter's and Gitelman's syndromes: From gene to clinic. Nephron 96: p65‐p78, 2004.
 275. Neagoe I, Stauber T, Fidzinski P, Bergsdorf EY, Jentsch TJ. The late endosomal ClC‐6 mediates proton/chloride countertransport in heterologous plasma membrane expression. J Biol Chem 285: 21689‐21697, 2010.
 276. Nehrke K, Arreola J, Nguyen HV, Pilato J, Richardson L, Okunade G, Baggs R, Shull GE, Melvin JE. Loss of hyperpolarization‐activated Cl‐ current in salivary acinar cells from Clcn2 knockout mice. J Biol Chem 26: 23604‐23611, 2002.
 277. Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci 21: 5429‐5438, 2001.
 278. Neutzsky‐Wulff AV, Karsdal MA, Henriksen K. Characterization of the bone phenotype in ClC‐7‐deficient mice. Calcif Tissue Int 83: 425‐437, 2008.
 279. Neutzsky‐Wulff AV, Sims NA, Supanchart C, Kornak U, Felsenberg D, Poulton IJ, Martin TJ, Karsdal MA, Henriksen K. Severe developmental bone phenotype in ClC‐7 deficient mice. Dev Biol 344: 1001‐1010, 2010.
 280. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange‐Nielsen cardioauditory syndrome. Nat Genet 15: 186‐189, 1997.
 281. Nguitragool W, Miller C. Uncoupling of a CLC Cl‐/H+ exchange transporter by polyatomic anions. J Mol Biol 362: 682‐690, 2006.
 282. Nguyen DK, Yang F, Kaul R, Alkan C, Antonellis A, Friery KF, Zhu B, de Jong PJ, Disteche CM. Clcn4‐2 genomic structure differs between the X locus in Mus spretus and the autosomal locus in Mus musculus: AT motif enrichment on the X. Genome Res 21: 402‐409, 2011.
 283. Niemeyer MI, Cid LP, Sepulveda FV, Blanz J, Auberson M, Jentsch TJ. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 42: 3, 2010.
 284. Niemeyer MI, Cid LP, Yusef YR, Briones R, Sepúlveda FV. Voltage‐dependent and ‐independent titration of specific residues account for complex gating of a ClC chloride channel by extracellular protons. J Physiol, 587: 1387‐1400, 2009.
 285. Niemeyer MI, Cid LP, Zuñiga L, Catalán M, Sepúlveda FV. A conserved pore‐lining glutamate as a voltage‐ and chloride‐dependent gate in the ClC‐2 chloride channel. J Physiol 553: 873‐879, 2003.
 286. Niemeyer MI, Yusef YR, Cornejo I, Flores CA, Sepúlveda FV, Cid LP. Functional evaluation of human ClC‐2 chloride channel mutations associated with idiopathic generalized epilepsies. Physiol Genomics 19: 74‐83, 2004.
 287. 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.
 288. Nishi T, Forgac M. Molecular cloning and expression of three isoforms of the 100‐kDa a subunit of the mouse vacuolar proton‐translocating ATPase. J Biol Chem 275: 6824‐6830, 2000.
 289. Nissant A, Paulais M, Lachheb S, Lourdel S, Teulon J. Similar chloride channels in the connecting tubule and cortical collecting duct of the mouse kidney. Am J Physiol Renal Physiol 290: F1421‐F1429, 2006.
 290. Nobile M, Pusch M, Rapisarda C, Ferroni S. Single‐channel analysis of a ClC‐2‐like chloride conductance in cultured rat cortical astrocytes. FEBS letters 479: 10‐14, 2000.
 291. Novarino G, Weinert S, Rickheit G, Jentsch TJ. Endosomal chloride‐proton exchange rather than chloride conductance is crucial for renal endocytosis. Science 328: 1398‐1401, 2010.
 292. Nozu K, Inagaki T, Fu XJ, Nozu Y, Kaito H, Kanda K, Sekine T, Igarashi T, Nakanishi K, Yoshikawa N, Iijima K, Matsuo M. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet 45: 182‐186, 2008.
 293. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25‐(OH) vitamin D3. Cell 96: 507‐515, 1999.
 294. Ogura T, Furukawa T, Toyozaki T, Yamada K, Zheng YJ, Katayama Y, Nakaya H, Inagaki N. ClC‐3B, a novel ClC‐3 splicing variant that interacts with EBP50 and facilitates expression of CFTR‐regulated ORCC. FASEB J 16: S63‐S65, 2002.
 295. Ohgi K, Okamoto F, Kajiya H, Sakagami R, Okabe K. Antibodies against ClC7 inhibit extracellular acidification‐induced Cl currents and bone resorption activity in mouse osteoclasts. Naunyn Schmiedebergs Arch Pharmacol 383: 79‐90, 2011.
 296. Ohkuma S, Moriyama Y, Takano T. Electrogenic nature of lysosomal proton pump as revealed with a cyanine dye. J Biochem 94: 1935‐1943, 1983.
 297. Okada Y, Sato K, Numata T. Pathophysiology and puzzles of the volume‐sensitive outwardly rectifying anion channel. J Physiol 587: 2141‐2149, 2009.
 298. Okamoto F, Kajiya H, Toh K, Uchida S, Yoshikawa M, Sasaki S, Kido MA, Tanaka T, Okabe K. Intracellular ClC‐3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts. Am J Physiol 294: C693‐C701, 2008.
 299. Okkenhaug H, Weylandt KH, Carmena D, Wells DJ, Higgins CF, Sardini A. The human ClC‐4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N‐terminus. FASEB J 20: 2390‐2392, 2006.
 300. Orhan G, Fahlke C, Alekov AK. Anion‐ and proton‐dependent gating of ClC‐4 anion/proton transporter under uncoupling conditions. Biophys J 100: 1233‐1241, 2011.
 301. Osteen JD, Mindell JA. Insights into the ClC‐4 transport mechanism from studies of Zn2+ inhibition. Biophys J 95: 4668‐4675, 2008.
 302. Palade PT, Barchi RL. On the inhibition of muscle membrane chloride conductance by aromatic carboxylic acids. J Gen Physiol 69: 879‐896, 1977.
 303. Palmada M, Dieter M, Boehmer C, Waldegger S, Lang F. Serum and glucocorticoid inducible kinases functionally regulate ClC‐2 channels. Biochem Biophys Res Commun 321: 1001‐1006, 2004.
 304. Palmer DN, Fearnley IM, Walker JE, Hall NA, Lake BD, Wolfe LS, Haltia M, Martinus RD, Jolly RD. Mitochondrial ATP synthase subunit c storage in the ceroid‐lipofuscinoses (Batten disease). Am J Med Genet 42: 561‐567, 1992.
 305. Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res 21: 1098‐1105, 2006.
 306. Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C. Molecular and clinical heterogeneity in CLCN7‐dependent osteopetrosis: Report of 20 novel mutations. Hum Mutat 31: E1071‐E1080, 2010.
 307. Papponen H, Kaisto T, Myllyla VV, Myllyla R, Metsikko K. Regulated sarcolemmal localization of the muscle‐specific ClC‐1 chloride channel. Exp Neurol 191: 163‐173, 2005.
 308. Park K, Arreola J, Begenisich T, Melvin JE. Comparison of voltage‐activated Cl‐ channels in rat parotid acinar cells with ClC‐2 in a mammalian expression system. J Membr Biol 163: 87‐95, 1998.
 309. Park K, Begenisich T, Melvin JE. Protein kinase A activation phosphorylates the rat ClC‐2 Cl‐ channel but does not change activity. J Membr Biol 182: 31‐37, 2001.
 310. Pata M, Heraud C, Vacher J. OSTM1 bone defect reveals an intercellular hematopoietic crosstalk. J Biol Chem 283: 30522‐30530, 2008.
 311. Pedersen TH, de Paoli F, Nielsen OB. Increased excitability of acidified skeletal muscle: Role of chloride conductance. J Gen Physiol 125: 237‐246, 2005.
 312. Pedersen TH, de Paoli FV, Flatman JA, Nielsen OB. Regulation of ClC‐1 and KATP channels in action potential‐firing fast‐twitch muscle fibers. J Gen Physiol 134: 309‐322, 2009.
 313. Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG. Intracellular acidosis enhances the excitability of working muscle. Science 305: 1144‐1147, 2004.
 314. Peña‐Münzenmayer G, Catalán M, Cornejo I, Figueroa CD, Melvin JE, Niemeyer MI, Cid LP, Sepúlveda FV. Basolateral localization of native ClC‐2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS‐2 domain di‐leucine motif. J Cell Sci 118: 4243‐4252, 2005.
 315. Petheo GL, Molnar Z, Roka A, Makara JK, Spat A. A pH‐sensitive chloride current in the chemoreceptor cell of rat carotid body. J Physiol 535: 95‐106, 2001.
 316. Pettersson U, Albagha OM, Mirolo M, Taranta A, Frattini A, McGuigan FE, Vezzoni P, Teti A, Van Hul W, Reid DM, Villa A, Ralston SH. Polymorphisms of the CLCN7 gene are associated with BMD in women. J Bone Miner Res 20: 1960‐1967, 2005.
 317. Phadke SR, Fischer B, Gupta N, Ranganath P, Kabra M, Kornak U. Novel mutations in Indian patients with autosomal recessive infantile malignant osteopetrosis. Indian J Med Res 131: 508‐514, 2010.
 318. Picollo A, Liantonio A, Babini E, Camerino DC, Pusch M. Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC‐K chloride channels. J Membr Biol 216: 73‐82, 2007.
 319. Picollo A, Liantonio A, Didonna MP, Elia L, Camerino DC, Pusch M. Molecular determinants of differential pore blocking of kidney CLC‐K chloride channels. EMBO reports 5: 584‐589, 2004.
 320. Picollo A, Malvezzi M, Accardi A. Proton block of the CLC‐5 Cl‐/H+ exchanger. J Gen Physiol 135: 653‐659, 2010.
 321. Picollo A, Malvezzi M, Houtman JC, Accardi A. Basis of substrate binding and conservation of selectivity in the CLC family of channels and transporters. Nat Struct Mol Biol 16: 1294‐1301, 2009.
 322. Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC‐4 and ClC‐5. Nature 436: 420‐423, 2005.
 323. Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM. Identification of novel human WW domain‐containing proteins by cloning of ligand targets. J Biol Chem 272: 14611‐14616, 1997.
 324. Piwon N, Günther W, Schwake M, Bösl MR, Jentsch TJ. ClC‐5 Cl‐‐channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 408: 369‐373, 2000.
 325. Plans V, Rickheit G, Jentsch TJ. Physiological roles of CLC Cl‐/H+ exchangers in renal proximal tubules. Pflügers Arch 458: 23‐37, 2009.
 326. Plassart‐Schiess E, Gervais A, Eymard B, Lagueny A, Pouget J, Warter JM, Fardeau M, Jentsch TJ, Fontaine B. Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance. Neurology 50: 1176‐1179, 1998.
 327. Poët M, Kornak U, Schweizer M, Zdebik AA, Scheel O, Hoelter S, Wurst W, Schmitt A, Fuhrmann JC, Planells‐Cases R, Mole SE, Hübner CA, Jentsch TJ. Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC‐6. Proc Natl Acad Sci U S A 103: 13854‐13859, 2006.
 328. Pressey SN, O'Donnell KJ, Stauber T, Fuhrmann JC, Tyynela J, Jentsch TJ, Cooper JD. Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC‐6 or ClC‐7/Ostm1. J Neuropathol Exp Neurol 69: 1228‐1246, 2010.
 329. Prinetti A, Rocchetta F, Costantino E, Frattini A, Caldana E, Rucci F, Bettiga A, Poliani PL, Chigorno V, Sonnino S. Brain lipid composition in grey‐lethal mutant mouse characterized by severe malignant osteopetrosis. Glycoconj J 26: 623‐633, 2009.
 330. Pusch M. Myotonia caused by mutations in the muscle chloride channel gene CLCN1. Hum Mutat 19: 423‐434, 2002.
 331. Pusch M, Jordt SE, Stein V, Jentsch TJ. Chloride dependence of hyperpolarization‐activated chloride channel gates. J Physiol 515: 341‐353, 1999.
 332. Pusch M, Ludewig U, Rehfeldt A, Jentsch TJ. Gating of the voltage‐dependent chloride channel ClC‐0 by the permeant anion. Nature 373: 527‐531, 1995.
 333. Pusch M, Steinmeyer K, Jentsch TJ. Low single channel conductance of the major skeletal muscle chloride channel, ClC‐1. Biophys J 66: 149‐152, 1994.
 334. Pusch M, Steinmeyer K, Koch MC, Jentsch TJ. Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the ClC‐1 chloride channel. Neuron 15: 1455‐1463, 1995.
 335. Qian Y, Du YH, Tang YB, Lv XF, Liu J, Zhou JG, Guan YY. ClC‐3 chloride channel prevents apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells through mitochondria dependent pathway. Apoptosis 16: 468‐477, 2011.
 336. Quarello P, Forni M, Barberis L, Defilippi C, Campagnoli MF, Silvestro L, Frattini A, Chalhoub N, Vacher J, Ramenghi U. Severe malignant osteopetrosis caused by a GL gene mutation. J Bone Miner Res 19: 1194‐1199, 2004.
 337. Ramírez A, Faupel J, Goebel I, Stiller A, Beyer S, Stockle C, Hasan C, Bode U, Kornak U, Kubisch C. Identification of a novel mutation in the coding region of the grey‐lethal gene OSTM1 in human malignant infantile osteopetrosis. Hum Mutat 23: 471‐476, 2004.
 338. Raposo G Marks MS. Melanosomes–dark organelles enlighten endosomal membrane transport. Nat Rev Mol Cell Biol 8: 786‐797, 2007.
 339. Reed AA, Loh NY, Terryn S, Lippiat JD, Partridge C, Galvanovskis J, Williams SE, Jouret F, Wu FT, Courtoy PJ, Nesbit MA, Rorsman P, Devuyst O, Ashcroft FM, Thakker RV. ClC‐5 and KIF3B interact to facilitate CLC‐5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. Am J Physiol 298: F365‐F380, 2010.
 340. Rhodes TH, Vite CH, Giger U, Patterson DF, Fahlke C, George AL, Jr. A missense mutation in canine ClC‐1 causes recessive myotonia congenita in the dog. FEBS letters 456: 54‐58, 1999.
 341. Riazanski V, Deriy LV, Shevchenko PD, Le B, Gomez EA, Nelson DJ. Presynaptic CLC‐3 determines quantal size of inhibitory transmission in the hippocampus. Nat Neurosci 14: 487‐494, 2011.
 342. Riazuddin S, Anwar S, Fischer M, Ahmed ZM, Khan SY, Janssen AG, Zafar AU, Scholl U, Husnain T, Belyantseva IA, Friedman PL, Riazuddin S, Friedman TB, Fahlke C. Molecular basis of DFNB73: Mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am J Hum Genet 85: 273‐280, 2009.
 343. Rickheit G, Maier H, Strenzke N, Andreescu CE, De Zeeuw CI, Muenscher A, Zdebik AA, Jentsch TJ. Endocochlear potential depends on Cl‐ channels: Mechanism underlying deafness in Bartter syndrome IV. EMBO J 27: 2907‐2917, 2008.
 344. Rickheit G, Wartosch L, Schaffer S, Stobrawa SM, Novarino G, Weinert S, Jentsch TJ. Role of ClC‐5 in renal endocytosis is unique among ClC exchangers and does not require PY‐motif‐dependent ubiquitylation. J Biol Chem 285: 17595‐17603, 2010.
 345. Rinke I, Artmann J, Stein V. ClC‐2 voltage‐gated channels constitute part of the background conductance and assist chloride extrusion. J Neurosci 30: 4776‐4786, 2010.
 346. Romanenko VG, Nakamoto T, Catalan MA, Gonzalez‐Begne M, Schwartz GJ, Jaramillo Y, Sepúlveda FV, Figueroa CD, Melvin JE. Clcn2 encodes the hyperpolarization‐activated chloride channel in the ducts of mouse salivary glands. Am J Physiol 295: G1058‐G1067, 2008.
 347. Rugarli EI, Adler DA, Borsani G, Tsuchiya K, Franco B, Hauge X, Disteche C, Chapman V, Ballabio A. Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice. Nat Genet 10: 466‐471, 1995.
 348. Ryan A, Dallos P. Effect of absence of cochlear outer hair cells on behavioural auditory threshold. Nature 253: 44‐46, 1975.
 349. Rychkov GY, Astill DS, Bennetts B, Hughes BP, Bretag AH, Roberts ML. pH‐dependent interactions of Cd2+ and a carboxylate blocker with the rat ClC‐1 chloride channel and its R304E mutant in the Sf‐9 insect cell line. J Physiol 501: 355‐362, 1997.
 350. Rychkov GY, Pusch M, Astill DS, Roberts ML, Jentsch TJ, Bretag AH. Concentration and pH dependence of skeletal muscle chloride channel ClC‐1. J Physiol 497: 423‐435, 1996.
 351. Rychkov GY, Pusch M, Roberts ML, Bretag AH. Interaction of hydrophobic anions with the rat skeletal muscle chloride channel ClC‐1: Effects on permeation and gating. J Physiol 530: 379‐393, 2001.
 352. Rychkov GY, Pusch M, Roberts ML, Jentsch TJ, Bretag AH. Permeation and block of the skeletal muscle chloride channel, ClC‐1, by foreign anions. J Gen Physiol 111: 653‐665, 1998.
 353. Sage CL, Marcus DC. Immunolocalization of ClC‐K chloride channel in strial marginal cells and vestibular dark cells. Hear Res 160: 1‐9, 2001.
 354. Saito‐Ohara F, Uchida S, Takeuchi Y, Sasaki S, Hayashi A, Marumo F, Ikeuchi T. Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32‐q33 by in situ hybridization. Genomics 36: 372‐374, 1996.
 355. Saito M, Hanson PI, Schlesinger P. Luminal chloride‐dependent activation of endosome calcium channels: Patch clamp study of enlarged endosomes. J Biol Chem 282: 27327‐27333, 2007.
 356. Sakamoto H, Sado Y, Naito I, Kwon TH, Inoue S, Endo K, Kawasaki M, Uchida S, Nielsen S, Sasaki S, Marumo F. Cellular and subcellular immunolocalization of ClC‐5 channel in mouse kidney: Colocalization with H+‐ATPase. Am J Physiol 277: F957‐F965, 1999.
 357. Salazar G, Love R, Styers ML, Werner E, Peden A, Rodriguez S, Gearing M, Wainer BH, Faundez V. AP‐3‐dependent mechanisms control the targeting of a chloride channel (ClC‐3) in neuronal and non‐neuronal cells. J Biol Chem 279: 25430‐25439, 2004.
 358. Sanchez‐Rodriguez JE, De Santiago‐Castillo JA, Arreola J. Permeant anions contribute to voltage dependence of ClC‐2 chloride channel by interacting with the protopore gate. J Physiol 588: 2545‐2556, 2010.
 359. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A. A gene network regulating lysosomal biogenesis and function. Science 325: 473‐477, 2009.
 360. Saviane C, Conti F, Pusch M. The muscle chloride channel ClC‐1 has a double‐barreled appearance that is differentially affected in dominant and recessive myotonia. J Gen Physiol 113: 457‐468, 1999.
 361. Sayer JA, Stewart GS, Boese SH, Gray MA, Pearce SH, Goodship TH, Simmons NL. The voltage‐dependent Cl(‐) channel ClC‐5 and plasma membrane Cl(‐) conductances of mouse renal collecting duct cells (mIMCD‐3). J Physiol 536: 769‐783, 2001.
 362. Scheel O, Zdebik A, Lourdel S, Jentsch TJ. Voltage‐dependent electrogenic chloride proton exchange by endosomal CLC proteins. Nature 436: 424‐427, 2005.
 363. Scheinman SJ. X‐linked hypercalciuric nephrolithiasis: Clinical syndromes and chloride channel mutations. Kidney Int 53: 3‐17, 1998.
 364. Schenck S, Wojcik SM, Brose N, Takamori S. A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles. Nat Neurosci 12: 156‐162, 2009.
 365. Scheper GC, van Berkel CG, Leisle L, de Groot KE, Errami A, Jentsch TJ, Van der Knaap MS. Analysis of CLCN2 as candidate gene for megalencephalic leukoencephalopathy with subcortical cysts. Genet Test Mol Biomarkers 14: 255‐257, 2010.
 366. Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, Waldegger S. Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350: 1314‐1319, 2004.
 367. Scholl U, Hebeisen S, Janssen AG, Müller‐Newen G, Alekov A, Fahlke C. Barttin modulates trafficking and function of ClC‐K channels. Proc Natl Acad Sci U S A 103: 11411‐11416, 2006.
 368. Schonteich E, Wilson GM, Burden J, Hopkins CR, Anderson K, Goldenring JR, Prekeris R. The Rip11/Rab11‐FIP5 and kinesin II complex regulates endocytic protein recycling. J Cell Sci 121: 3824‐3833, 2008.
 369. Schulz P, Werner J, Stauber T, Henriksen K, Fendler K. The G215R mutation in the Cl‐/H+‐antiporter ClC‐7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. PloS One 5: e12585, 2010.
 370. Schulze‐Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, and Funke H. KCNE1 mutations cause Jervell and Lange‐Nielsen syndrome. Nat Genet 17: 267‐268, 1997.
 371. Schwake M, Friedrich T, Jentsch TJ. An internalization signal in ClC‐5, an endosomal Cl‐‐channel mutated in Dent's disease. J Biol Chem 276: 12049‐12054, 2001.
 372. Schwiebert EM, Cid‐Soto LP, Stafford D, Carter M, Blaisdell CJ, Zeitlin PL, Guggino WB, Cutting GR. Analysis of ClC‐2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. Proc Natl Acad Sci U S A 95: 3879‐3884, 1998.
 373. Scimeca JC, Franchi A, Trojani C, Parrinello H, Grosgeorge J, Robert C, Jaillon O, Poirier C, Gaudray P, Carle GF. The gene encoding the mouse homologue of the human osteoclast‐specific 116‐kDa V‐ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone 26: 207‐213, 2000.
 374. Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG. CBS domains form energy‐sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113: 274‐284, 2004.
 375. Seong E, Wainer BH, Hughes ED, Saunders TL, Burmeister M, Faundez V. Genetic analysis of the neuronal and ubiquitous AP‐3 adaptor complexes reveals divergent functions in brain. Mol Biol Cell 16: 128‐140, 2005.
 376. Sethi SK, Ludwig M, Kabra M, Hari P, Bagga A. Vitamin A responsive night blindness in Dent's disease. Pediatric nephrology (Berlin, Germany) 24: 1765‐1770, 2009.
 377. Seyberth HW. An improved terminology and classification of Bartter‐like syndromes. Nat Clin Pract Nephrol 4: 560‐567, 2008.
 378. Shrimpton AE, Hoopes RR, Jr., Knohl SJ, Hueber P, Reed AA, Christie PT, Igarashi T, Lee P, Lehman A, White C, Milford DV, Sanchez MR, Unwin R, Wrong OM, Thakker RV, Scheinman SJ. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron 112: p27‐p36, 2009.
 379. Sik A, Smith RL, Freund TF. Distribution of chloride channel‐2‐immunoreactive neuronal and astrocytic processes in the hippocampus. Neuroscience 101: 51‐65, 2000.
 380. Sile S, Gillani NB, Velez DR, Vanoye CG, Yu C, Byrne LM, Gainer JV, Brown NJ, Williams SM, George AL, Jr. Functional BSND variants in essential hypertension. Am J Hypertens 20: 1176‐1182, 2007.
 381. Sile S, Velez DR, Gillani NB, Narsia T, Moore JH, George AL, Jr., Vanoye CG, Williams SM. CLCNKB‐T481S and essential hypertension in a Ghanaian population. J Hypertens 27: 298‐304, 2009.
 382. Simon DB, Bindra RS, Mansfield TA, Nelson‐Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez‐Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17: 171‐178, 1997.
 383. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na‐K‐2Cl cotransporter NKCC2. Nat Genet 13: 183‐188, 1996.
 384. Simon DB, Karet FE, Rodriguez‐Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152‐156, 1996.
 385. Smith AJ, Lippiat JD. Direct endosomal acidification by the outwardly rectifying CLC‐5 Cl(‐)/H(+) exchanger. J Physiol 588: 2033‐2045, 2010.
 386. Smith AJ, Reed AA, Loh NY, Thakker RV, Lippiat JD. Characterization of Dent's disease mutations of CLC‐5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol 296: F390‐F397, 2009.
 387. Smith RL, Clayton GH, Wilcox CL, Escudero KW, Staley KJ. Differential expression of an inwardly rectifying chloride conductance in rat brain neurons: A potential mechanism for cell‐specific modulation of postsynaptic inhibition. J Neurosci 15: 4057‐4067, 1995.
 388. Sonawane ND, Thiagarajah JR, Verkman AS. Chloride concentration in endosomes measured using a ratioable fluorescent Cl‐ indicator: Evidence for chloride accumulation during acidification. J Biol Chem 277: 5506‐5513, 2002.
 389. Souraty N, Noun P, Djambas‐Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Megarbane A. Molecular study of six families originating from the Middle‐East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet 50: 188‐199, 2007.
 390. Speirs HJ, Wang WY, Benjafield AV, Morris BJ. No association with hypertension of CLCNKB and TNFRSF1B polymorphisms at a hypertension locus on chromosome 1p36. J Hypertens 23: 1491‐1496, 2005.
 391. Staley K. The role of an inwardly rectifying chloride conductance in postsynaptic inhibition. J Neurophysiol 72: 273‐284, 1994.
 392. Staley K, Smith R, Schaack J, Wilcox C, Jentsch TJ. Alteration of GABAA receptor function following gene transfer of the ClC‐2 chloride channel. Neuron 17: 543‐551, 1996.
 393. Stauber T, Jentsch TJ. Sorting motifs of the endosomal/lysosomal CLC chloride transporters. J Biol Chem 285: 34537‐34548, 2010.
 394. Stauber T, Simpson JC, Pepperkok R, Vernos I. A role for kinesin‐2 in COPI‐dependent recycling between the ER and the Golgi complex. Curr Biol 16: 2245‐2251, 2006.
 395. Steinberg BE, Huynh KK, Brodovitch A, Jabs S, Stauber T, Jentsch TJ, Grinstein S. A cation counterflux supports lysosomal acidification. J Cell Biol 189: 1171‐1186, 2010.
 396. Steinberg BE, Touret N, Vargas‐Caballero M, Grinstein S. In situ measurement of the electrical potential across the phagosomal membrane using FRET and its contribution to the proton‐motive force. Proc Natl Acad Sci U S A 104: 9523‐9528, 2007.
 397. Steinmeyer K, Klocke R, Ortland C, Gronemeier M, Jockusch H, Gründer S, Jentsch TJ. Inactivation of muscle chloride channel by transposon insertion in myotonic mice. Nature 354: 304‐308, 1991.
 398. Steinmeyer K, Lorenz C, Pusch M, Koch MC, Jentsch TJ. Multimeric structure of ClC‐1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J 13: 737‐743, 1994.
 399. Steinmeyer K, Ortland C, Jentsch TJ. Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature 354: 301‐304, 1991.
 400. Steinmeyer K, Schwappach B, Bens M, Vandewalle A, Jentsch TJ. Cloning and functional expression of rat CLC‐5, a chloride channel related to kidney disease. J Biol Chem 270: 31172‐31177, 1995.
 401. Steward CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 29: 87‐97, 2003.
 402. Stobrawa SM, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik AA, Bösl MR, Ruether K, Jahn H, Draguhn A, Jahn R, Jentsch TJ. Disruption of ClC‐3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29: 185‐196, 2001.
 403. Suchy SF, Olivos‐Glander IM, Nussabaum RL. Lowe syndrome, a deficiency of phosphatidylinositol 4,5‐bisphosphate 5‐phosphatase in the Golgi apparatus. Hum Mol Genet 4: 2245‐2250, 1995.
 404. Suzuki T, Rai T, Hayama A, Sohara E, Suda S, Itoh T, Sasaki S, Uchida S. Intracellular localization of ClC chloride channels and their ability to form hetero‐oligomers. J Cell Physiol 206: 792‐798, 2006.
 405. Tajima M, Hayama A, Rai T, Sasaki S, Uchida S. Barttin binds to the outer lateral surface of the ClC‐K2 chloride channel. Biochem Biophys Res Commun 362: 858‐864, 2007.
 406. Takeuchi Y, Uchida S, Marumo F, Sasaki S. Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney. Kidney Int 48: 1497‐1503, 1995.
 407. Tanaka K, Terryn S, Geffers L, Garbay S, Pontoglio M, Devuyst O. The transcription factor HNF1‐alpha regulates expression of chloride‐proton exchanger ClC‐5 in the renal proximal tubule. Am J Physiol 299: F1339‐F1347, 2010.
 408. Tang YB, Liu YJ, Zhou JG, Wang GL, Qiu QY, Guan YY. Silence of ClC‐3 chloride channel inhibits cell proliferation and the cell cycle via G/S phase arrest in rat basilar arterial smooth muscle cells. Cell proliferation 41: 775‐785, 2008.
 409. Teitelbaum SL. Bone resorption by osteoclasts. Science 289: 1504‐1508, 2000.
 410. Thiemann A, Gründer S, Pusch M, Jentsch TJ. A chloride channel widely expressed in epithelial and nonepithelial cells. Nature 356: 57‐60, 1992.
 411. Thompson CH, Fields DM, Olivetti PR, Fuller MD, Zhang ZR, Kubanek J, McCarty NA. Inhibition of ClC‐2 chloride channels by a peptide component or components of scorpion venom. J Membr Biol 208: 65‐76, 2005.
 412. Thompson CH, Olivetti PR, Fuller MD, Freeman CS, McMaster D, French RJ, Pohl J, Kubanek J, McCarty NA. Isolation and characterization of a high affinity peptide inhibitor of ClC‐2 chloride channels. J Biol Chem 284: 26051‐26062, 2009.
 413. Thomsen J. Tonische Krämpfe in willkürlich beweglichen Muskeln in Folge von ererbter psychischer Disposition. Arch Psychiatr Nervenkrankh 6: 702‐718, 1876.
 414. Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med 351: 2839‐2849, 2004.
 415. Tomaszewski M, Debiec R, Braund PS, Nelson CP, Hardwick R, Christofidou P, Denniff M, Codd V, Rafelt S, van der Harst P, Waterworth D, Song K, Vollenweider P, Waeber G, Zukowska‐Szczechowska E, Burton PR, Mooser V, Charchar FJ, Thompson JR, Tobin MD, Samani NJ. Genetic architecture of ambulatory blood pressure in the general population: Insights from cardiovascular gene‐centric array. Hypertension 56: 1069‐1076, 2011.
 416. Tseng PY, Bennetts B, Chen TY. Cytoplasmic ATP inhibition of CLC‐1 is enhanced by low pH. J Gen Physiol 130: 217‐221, 2007.
 417. Tseng PY, Yu WP, Liu HY, Zhang XD, Zou X, Chen TY. Binding of ATP to the CBS domains in the C‐terminal region of CLC‐1. J Gen Physiol 137: 357‐368, 2011.
 418. Tyynelä J, Palmer DN, Baumann M, Haltia M. Storage of saposins A and D in infantile neuronal ceroid‐lipofuscinosis. FEBS letters 330: 8‐12, 1993.
 419. Uchida S, Sasaki S, Furukawa T, Hiraoka M, Imai T, Hirata Y, Marumo F. Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla [published erratum appears in J Biol Chem 1994 Jul 22;269(29):19192]. J Biol Chem 268: 3821‐3824, 1993.
 420. Uchida S, Sasaki S, Nitta K, Uchida K, Horita S, Nihei H, Marumo F. Localization and functional characterization of rat kidney‐specific chloride channel, ClC‐K1. J Clin Invest 95: 104‐113, 1995.
 421. van den Hove MF, Croizet‐Berger K, Jouret F, Guggino SE, Guggino WB, Devuyst O, Courtoy PJ. The loss of the chloride channel, ClC‐5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland. Endocrinology 147: 1287‐1296, 2006.
 422. Van Dyke RW. Acidification of rat liver lysosomes: Quantitation and comparison with endosomes. Am J Physiol 265: C901‐C917, 1993.
 423. Van Slegtenhorst MA, Bassi MT, Borsani G, Wapenaar MC, Ferrero GB, de Conciliis L, Rugarli EI, Grillo A, Franco B, Zoghbi HY, Ballabio A. A gene from the Xp22.3 region shares homology with voltage‐gated chloride channels. Hum Mol Genet 3: 547‐552, 1994.
 424. Vandewalle A, Cluzeaud F, Bens M, Kieferle S, Steinmeyer K, Jentsch TJ. Localization and induction by dehydration of ClC‐K chloride channels in the rat kidney. Am J Physiol 272: F678‐F688, 1997.
 425. Vandewalle A, Cluzeaud F, Peng KC, Bens M, Lüchow A, Günther W, Jentsch TJ. Tissue distribution and subcellular localization of the ClC‐5 chloride channel in rat intestinal cells. Am J Physiol 280: C373‐C381, 2001.
 426. Vanoye CG George AG, Jr. Functional characterization of recombinant human ClC‐4 chloride channels in cultured mammalian cells. J Physiol 539: 373‐383, 2002.
 427. Varela D, Niemeyer MI, Cid LP, Sepúlveda FV. Effect of an N‐terminus deletion on voltage‐dependent gating of the ClC‐ 2 chloride channel. J Physiol 544: 363‐372, 2002.
 428. Varela D, Simon F, Riveros A, Jorgensen F, Stutzin A. NAD(P)H oxidase‐derived H2O2 signals chloride channel activation in cell volume regulation and cell proliferation. J Biol Chem 279: 13301‐13304, 2004.
 429. Vargas‐Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C. Functional characterization of a calcium‐sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter‐like syndrome. J Am Soc Nephrol 13: 2259‐2266, 2002.
 430. Vetter DE, Mann JR, Wangemann P, Liu J, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J. Inner ear defects induced by null mutation of the isk gene. Neuron 17: 1251‐1264, 1996.
 431. Vitzthum H, Castrop H, Meier‐Meitinger M, Riegger GA, Kurtz A, Kramer BK, Wolf K. Nephron‐specific regulation of chloride channel CLC‐K2 mRNA in the rat. Kidney Int 61: 547‐554, 2002.
 432. Volk AP, Heise CK, Hougen JL, Artman CM, Volk KA, Wessels D, Soll DR, Nauseef WM, Lamb FS, Moreland JG. ClC‐3 and IClswell are required for normal neutrophil chemotaxis and shape change. J Biol Chem 283: 34315‐34326, 2008.
 433. von Weikersthal SF, Barrand MA, Hladky SB. Functional and molecular characterization of a volume‐sensitive chloride current in rat brain endothelial cells. J Physiol 516(Pt 1): 75‐84, 1999.
 434. Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: Clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab 92: 771‐778, 2007.
 435. Waguespack SG, Koller DL, White KE, Fishburn T, Carn G, Buckwalter KA, Johnson M, Kocisko M, Evans WE, Foroud T, Econs MJ. Chloride channel 7 (CLCN7) gene mutations and autosomal dominant osteopetrosis, type II. J Bone Miner Res 18: 1513‐1518, 2003.
 436. Waldegger S, Jeck N, Barth P, Peters M, Vitzthum H, Wolf K, Kurtz A, Konrad M, Seyberth HW. Barttin increases surface expression and changes current properties of ClC‐K channels. Pflügers Arch 444: 411‐418, 2002.
 437. Waldegger S, Jentsch TJ. Functional and structural analysis of ClC‐K chloride channels involved in renal disease. J Biol Chem 275: 24527‐24533, 2000.
 438. Wang H, Mao Y, Zhang B, Wang T, Li F, Fu S, Xue Y, Yang T, Wen X, Ding Y, Duan X. Chloride channel ClC‐3 promotion of osteogenic differentiation through Runx2. J Cell Biochem 111: 49‐58, 2010.
 439. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12: 17‐23, 1996.
 440. Wang SS, Devuyst O, Courtoy PJ, Wang XT, Wang H, Wang Y, Thakker RV, Guggino S, Guggino WB. Mice lacking renal chloride channel, ClC‐5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor‐mediated endocytosis. Hum Mol Genet 9: 2937‐2945, 2000.
 441. Wang T, Weinman SA. Involvement of chloride channels in hepatic copper metabolism: ClC‐4 promotes copper incorporation into ceruloplasmin. Gastroenterology 126: 1157‐1166, 2004.
 442. Wang XF, Lin RY, Wang SZ, Zhang LP, Qian J, Lu DR, Wen H, Jin L. Association study of variants in two ion‐channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta 388: 95‐98, 2007.
 443. Wang XQ, Deriy LV, Foss S, Huang P, Lamb FS, Kaetzel MA, Bindokas V, Marks JD, Nelson DJ. CLC‐3 channels modulate excitatory synaptic transmission in hippocampal neurons. Neuron 52: 321‐333, 2006.
 444. Wang Y, Cai H, Cebotaru L, Hryciw DH, Weinman EJ, Donowitz M, Guggino SE, Guggino WB. ClC‐5: Role in endocytosis in the proximal tubule. Am J Physiol Renal Physiol 289: F850‐F862, 2005.
 445. Wartosch L, Fuhrmann JC, Schweizer M, Stauber T, Jentsch TJ. Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC‐7. FASEB J 23: 4056‐4068, 2009.
 446. Wartosch L, Stauber T. A role for chloride transport in lysosomal protein degradation. Autophagy 6: 158‐159, 2010.
 447. Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium‐sensing receptor and Bartter's syndrome. Lancet 360: 692‐694, 2002.
 448. Weinert S, Jabs S, Supanchart C, Schweizer M, Gimber N, Richter M, Rademann J, Stauber T, Kornak U, Jentsch TJ. Lysosomal pathology and osteopetrosis upon loss of H+‐driven lysosomal Cl‐ accumulation. Science 328: 1401‐1403, 2010.
 449. Weinreich F, Jentsch TJ. Pores formed by single subunits in mixed dimers of different CLC chloride channels. J Biol Chem 276: 2347‐2353, 2001.
 450. Wellhauser L, Kuo HH, Stratford FL, Ramjeesingh M, Huan LJ, Luong W, Li C, Deber CM, Bear CE. Nucleotides bind to the C‐terminus of ClC‐5. Biochem J 398: 289‐294, 2006.
 451. Wellhauser L, Luna‐Chavez C, D'Antonio C, Tainer J, Bear CE. ATP induces conformational changes in the carboxyl‐terminal region of ClC‐5. J Biol Chem 286: 6733‐6741, 2011.
 452. Wenk MR, Lucast L, Di Paolo G, Romanelli AJ, Suchy SF, Nussbaum RL, Cline GW, Shulman GI, McMurray W, De Camilli P. Phosphoinositide profiling in complex lipid mixtures using electrospray ionization mass spectrometry. Nat Biotechnol 21: 813‐817, 2003.
 453. Weylandt KH, Nebrig M, Jansen‐Rosseck N, Amey JS, Carmena D, Wiedenmann B, Higgins CF, Sardini A. ClC‐3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. Mol Cancer Ther 6: 979‐986, 2007.
 454. Weylandt KH, Valverde MA, Nobles M, Raguz S, Amey JS, Díaz M, Nastrucci C, Higgins CF, Sardini A. Human ClC‐3 is not the swelling‐activated chloride channel involved in cell volume regulation. J Biol Chem 276: 17461‐17467, 2001.
 455. Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA. Correction of ClC‐1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117: 3952‐3957, 2007.
 456. White MM, Miller C. A voltage‐gated anion channel from the electric organ of Torpedo californica. J Biol Chem 254: 10161‐10166, 1979.
 457. Wright J, Morales MM, Sousa‐Menzes J, Ornellas D, Sipes J, Cui Y, Cui I, Hulamm P, Cebotaru V, Cebotaru L, Guggino WB, Guggino SE. Transcriptional adaptation to Clcn5 knockout in proximal tubules of mouse kidney. Physiol Genomics 33: 341‐354, 2008.
 458. Wrong OM, Norden AG, Feest TG. Dent's disease; A familial proximal renal tubular syndrome with low‐molecular‐weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 87: 473‐493, 1994.
 459. Wu F, Reed AA, Williams SE, Loh NY, Lippiat JD, Christie PT, Large O, Bettinelli A, Dillon MJ, Goldraich NP, Hoppe B, Lhotta K, Loirat C, Malik R, Morel D, Kotanko P, Roussel B, Rubinger D, Schrander‐Stumpel C, Serdaroglu E, Nesbit MA, Ashcroft F, Thakker RV. Mutational analysis of CLC‐5, cofilin and CLC‐4 in patients with Dent's disease. Nephron 112: p53‐p62, 2009.
 460. Wu F, Roche P, Christie PT, Loh NY, Reed AA, Esnouf RM, Thakker RV. Modeling study of human renal chloride channel (hCLC‐5) mutations suggests a structural‐functional relationship. Kidney Int 63: 1426‐1432, 2003.
 461. Xiong D, Heyman NS, Airey J, Zhang M, Singer CA, Rawat S, Ye L, Evans R, Burkin DJ, Tian H, McCloskey DT, Valencik M, Britton FC, Duan D, Hume JR. Cardiac‐specific, inducible ClC‐3 gene deletion eliminates native volume‐sensitive chloride channels and produces myocardial hypertrophy in adult mice. J Mol Cell Cardiol 48: 211‐219, 2010.
 462. Xiong D, Wang GX, Burkin DJ, Yamboliev IA, Singer CA, Rawat S, Scowen P, Evans R, Ye L, Hatton WJ, Tian H, Keller PS, McCloskey DT, Duan D, Hume JR. Cardiac‐specific overexpression of the human short CLC‐3 chloride channel isoform in mice. Clin Exp Pharmacol Physiol 36: 386‐393, 2009.
 463. Xu B, Mao J, Wang L, Zhu L, Li H, Wang W, Jin X, Zhu J, Chen L. ClC‐3 chloride channels are essential for cell proliferation and cell cycle progression in nasopharyngeal carcinoma cells. Acta Biochim Biophys Sin 42: 370‐380, 2010.
 464. Yamamoto‐Mizuma S, Wang GX, Liu LL, Schegg K, Hatton WJ, Duan D, Horowitz B, Lamb FS, Hume JR. Altered properties of volume‐sensitive osmolyte and anion channels (VSOACs) and membrane protein expression in cardiac and smooth muscle myocytes from Clcn3‐/‐ mice. J Physiol 557: 439‐456, 2004.
 465. Yamazaki J, Duan D, Janiak R, Kuenzli K, Horowitz B, Hume JR. Functional and molecular expression of volume‐regulated chloride channels in canine vascular smooth muscle cells. J Physiol 507: 729‐736, 1998.
 466. Yin Z, Tong Y, Zhu H, Watsky MA. ClC‐3 is required for LPA‐activated Cl‐ current activity and fibroblast‐to‐myofibroblast differentiation. Am J Physiol 294: C535‐C542, 2008.
 467. Yoshikawa M, Uchida S, Ezaki J, Rai T, Hayama A, Kobayashi K, Kida Y, Noda M, Koike M, Uchiyama Y, Marumo F, Kominami E, Sasaki S. CLC‐3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis. Genes Cells 7: 597‐605, 2002.
 468. Yoshikawa M, Uchida S, Yamauchi A, Miyai A, Tanaka Y, Sasaki S, Marumo F. Localization of rat CLC‐K2 chloride channel mRNA in the kidney. Am J Physiol 276: F552‐F558, 1999.
 469. Yusef YR, Zuñiga L, Catalán M, Niemeyer MI, Cid LP, Sepúlveda FV. Removal of gating in voltage‐dependent ClC‐2 chloride channel by point mutations affecting the pore and C‐terminus CBS‐2 domain. J Physiol 572: 173‐181, 2006.
 470. Zdebik AA, Cuffe J, Bertog M, Korbmacher C, Jentsch TJ. Additional disruption of the ClC‐2 Cl‐ channel does not exacerbate the cystic fibrosis phenotype of CFTR mouse models. J Biol Chem 279: 22276‐22283, 2004.
 471. Zdebik AA, Wangemann P, Jentsch TJ. Potassium ion movement in the inner ear: insights from genetic disease and mouse models. Physiology 24: 307‐316, 2009.
 472. Zdebik AA, Zifarelli G, Bergsdorf E‐Y, Soliani P, Scheel O, Jentsch TJ, Pusch M. Determinants of anion‐proton coupling in mammalian endosomal CLC proteins. J Biol Chem 283: 4219‐4227, 2008.
 473. Zhang X, Hartz PA, Philip E, Racusen LC, Majerus PW. Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5‐phosphatase and accumulate phosphatidylinositol 4,5‐bisphosphate. J Biol Chem 273: 1574‐1582, 1998.
 474. Zhang X, Jefferson AB, Auethavekiat V, Majerus PW. The protein deficient in Lowe syndrome is a phosphatidylinositol‐4,5‐bisphosphate 5‐phosphatase. Proc Natl Acad Sci U S A 92: 4853‐4856, 1995.
 475. Zhang XD, Tseng PY, Chen TY. ATP inhibition of CLC‐1 is controlled by oxidation and reduction. J Gen Physiol 132: 421‐428, 2008.
 476. Zhang ZL, He JW, Zhang H, Hu WW, Fu WZ, Gu JM, Yu JB, Gao G, Hu YQ, Li M, Liu YJ. Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II). J Bone Miner Metab 27: 444‐451, 2009.
 477. Zhao Z, Li X, Hao J, Winston JH, Weinman SA. The ClC‐3 chloride transport protein traffics through the plasma membrane via interaction of an N‐terminal dileucine cluster with clathrin. J Biol Chem 282: 29022‐29031, 2007.
 478. Zifarelli G, Liantonio A, Gradogna A, Picollo A, Gramegna G, De Bellis M, Murgia AR, Babini E, Camerino DC, Pusch M. Identification of sites responsible for the potentiating effect of niflumic acid on ClC‐Ka kidney chloride channels. Br J Pharmacol 160: 1652‐1661, 2010.
 479. Zifarelli G, Pusch M. CLC chloride channels and transporters: A biophysical and physiological perspective. Rev Physiol Biochem Pharmacol 158: 23‐76, 2007.
 480. Zifarelli G, Pusch M. CLC transport proteins in plants. FEBS letters 584: 2122‐2127, 2010.
 481. Zifarelli G, Pusch M. Conversion of the 2 Cl‐/1 H+ antiporter ClC‐5 in a NO3‐/H+ antiporter by a single point mutation. EMBO J 28: 175‐182, 2009.
 482. Zifarelli G, Pusch M. Intracellular regulation of human ClC‐5 by adenine nucleotides. EMBO reports 10: 1111‐1116, 2009.
 483. Zifarelli G, Pusch M. The muscle chloride channel ClC‐1 is not directly regulated by intracellular ATP. J Gen Physiol 131: 109‐116, 2008.
 484. Zifarelli G, Pusch M. Relaxing messages from the sarcolemma. J Gen Physiol 136: 593‐596, 2010.
 485. Zuñiga L, Niemeyer MI, Varela D, Catalán M, Cid LP, Sepúlveda FV. The voltage‐dependent ClC‐2 chloride channel has a dual gating mechanism. J Physiol 555: 671‐682, 2004.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Tobias Stauber, Stefanie Weinert, Thomas J. Jentsch. Cell Biology and Physiology of CLC Chloride Channels and Transporters. Compr Physiol 2012, 2: 1701-1744. doi: 10.1002/cphy.c110038