Gene Symbol: Clcn3
Description: chloride channel, voltage-sensitive 3
Alias: Clc3, H(+)/Cl(-) exchange transporter 3, chloride channel 3, chloride channel protein 3, chloride transporter ClC-3, clC-3
Species: mouse
Products:     Clcn3

Top Publications

  1. Arreola J, Begenisich T, Nehrke K, Nguyen H, Park K, Richardson L, et al. Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene. J Physiol. 2002;545:207-16 pubmed
    ..We found that cells isolated from mice with targeted disruption of the Clcn3 gene undergo regulatory volume decrease in a fashion similar to cells from wild-type littermates...
  2. Mohammad Panah R, Wellhauser L, Steinberg B, Wang Y, Huan L, Liu X, et al. An essential role for ClC-4 in transferrin receptor function revealed in studies of fibroblasts derived from Clcn4-null mice. J Cell Sci. 2009;122:1229-37 pubmed publisher
    ..These observations provide direct evidence supporting an essential role for ClC-4 in the modulation of Tfn receptor accessibility at the cell surface through its role in endosomal acidification. ..
  3. Okamoto F, Kajiya H, Toh K, Uchida S, Yoshikawa M, Sasaki S, et al. Intracellular ClC-3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts. Am J Physiol Cell Physiol. 2008;294:C693-701 pubmed publisher
    ..Mouse osteoclasts lacking ClC-3 Cl(-) channels (ClC-3(-/-) osteoclasts) derived from ClCN3 gene-deficient mice (ClC-3(-/-)) showed lower bone resorption activity compared with ClC-3+/+ osteoclasts derived ..
  4. Dickerson L, Bonthius D, Schutte B, Yang B, Barna T, Bailey M, et al. Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC-3 voltage-gated chloride channels. Brain Res. 2002;958:227-50 pubmed
    Mice lacking ClC-3 chloride channels, encoded by the Clcn3 gene, undergo neurodegeneration of the hippocampal formation and retina [Neuron, 29 (2001) 185-196; Genes Cells, 7 (2002) 597-605]...
  5. Xiong D, Heyman N, Airey J, Zhang M, Singer C, Rawat S, et al. Cardiac-specific, inducible ClC-3 gene deletion eliminates native volume-sensitive chloride channels and produces myocardial hypertrophy in adult mice. J Mol Cell Cardiol. 2010;48:211-9 pubmed publisher
    ..doxycycline diet to preserve ClC-3 expression; removal of doxycycline activates Cre recombinase to inactivate the Clcn3 gene...
  6. Stobrawa S, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik A, et al. Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron. 2001;29:185-96 pubmed
    ..Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills. ..
  7. Yoshikawa M, Uchida S, Ezaki J, Rai T, Hayama A, Kobayashi K, et al. CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis. Genes Cells. 2002;7:597-605 pubmed
    ..To determine the physiological role of CLC-3, we generated CLC-3-deficient mice (Clcn3-/- ) by targeted gene disruption...
  8. Wang X, Deriy L, Foss S, Huang P, Lamb F, Kaetzel M, et al. CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons. Neuron. 2006;52:321-33 pubmed
    ..By increasing postsynaptic potentials in a Cl(-) dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons. ..
  9. Maritzen T, Keating D, Neagoe I, Zdebik A, Jentsch T. Role of the vesicular chloride transporter ClC-3 in neuroendocrine tissue. J Neurosci. 2008;28:10587-98 pubmed publisher
    ..This observation points to an indirect influence of ClC-3 on LDCV exocytosis in chromaffin cells, possibly by affecting an intracellular trafficking step. ..

More Information


  1. Schenck S, Wojcik S, Brose N, Takamori S. A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles. Nat Neurosci. 2009;12:156-62 pubmed publisher
  2. Chu X, Filali M, Stanic B, Takapoo M, Sheehan A, BHALLA R, et al. A critical role for chloride channel-3 (CIC-3) in smooth muscle cell activation and neointima formation. Arterioscler Thromb Vasc Biol. 2011;31:345-51 pubmed publisher
    ..These findings identify ClC-3 as a novel target for the prevention of inflammatory and proliferative vascular diseases. ..
  3. Deriy L, Gomez E, Jacobson D, Wang X, Hopson J, Liu X, et al. The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab. 2009;10:316-23 pubmed publisher
    ..In this study, immuno-EM of beta cells revealed colocalization of ClC-3 and insulin on secretory granules. Clcn3(-/-) mice as well as isolated islets demonstrate impaired insulin secretion; Clcn3(-/-) beta cells are defective ..
  4. Tao R, Lau C, Tse H, Li G. Functional ion channels in mouse bone marrow mesenchymal stem cells. Am J Physiol Cell Physiol. 2007;293:C1561-7 pubmed
    ..The corresponding ion channel genes and proteins, KCa3.1 for I(KCa), Kir2.1 for I(Kir), and Clcn3 for I(Cl), were confirmed by RT-PCR and Western immunoblotting analysis in mouse MSCs...
  5. Crawshaw L, Wallace H, Christensen R, Crabbe J. Influence of ethanol on thermoregulation: mapping quantitative trait loci. Physiol Genomics. 2001;7:159-69 pubmed
    ..To our knowledge, this is the first report of QTLs that underlie changes in regulation as well as the disruption of a physiological regulatory system. ..
  6. Wang H, Mao Y, Zhang B, Wang T, Li F, Fu S, et al. Chloride channel ClC-3 promotion of osteogenic differentiation through Runx2. J Cell Biochem. 2010;111:49-58 pubmed publisher
    ..The data from the current study suggest that the function of ClC-3 in osteodifferentiation may be through the Runx2 pathway. ..
  7. Bozeat N, Xiang S, Ye L, Yao T, Duan M, Burkin D, et al. Activation of volume regulated chloride channels protects myocardium from ischemia/reperfusion damage in second-window ischemic preconditioning. Cell Physiol Biochem. 2011;28:1265-78 pubmed publisher
    ..Thus, ClC-3 knockout (Clcn3(-/-)) mice and their age-matched heterozygous (Clcn3(+/-)) and wild-type (Clcn3(+/+)) littermates were used to ..
  8. McCloskey D, Doherty L, Dai Y, Miller L, Hume J, Yamboliev I. Hypotonic activation of short ClC3 isoform is modulated by direct interaction between its cytosolic C-terminal tail and subcortical actin filaments. J Biol Chem. 2007;282:16871-7 pubmed
    Short ClC3 isoform (sClC3) functions as a volume-sensitive outwardly rectifying anion channel (VSOAC) in some cell types...
  9. Tao J, Liu C, Yang J, Xie Z, Ma M, Li X, et al. ClC-3 deficiency prevents atherosclerotic lesion development in ApoE-/- mice. J Mol Cell Cardiol. 2015;87:237-47 pubmed publisher
    ..Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation. ..
  10. Lu X, Ding Y, Niu Q, Xuan S, Yang Y, Jin Y, et al. ClC-3 chloride channel mediates the role of parathyroid hormone [1-34] on osteogenic differentiation of osteoblasts. PLoS ONE. 2017;12:e0176196 pubmed publisher
    ..From the above data, we conclude that the expression of ClC-3 chloride channels in osteoblasts helps them respond to PTH stimulation, which mediates osteogenic differentiation. ..
  11. Li C, Huang D, Tang J, Chen M, Lu Q, Li H, et al. ClC-3 chloride channel is involved in isoprenaline-induced cardiac hypertrophy. Gene. 2018;642:335-342 pubmed publisher
  12. Yang H, Huang L, Zeng D, Huang E, Liang S, Tang Y, et al. Decrease of intracellular chloride concentration promotes endothelial cell inflammation by activating nuclear factor-?B pathway. Hypertension. 2012;60:1287-93 pubmed publisher
  13. Yan Y, Ding Y, Ming B, Du W, Kong X, Tian L, et al. Increase in hypotonic stress-induced endocytic activity in macrophages via ClC-3. Mol Cells. 2014;37:418-25 pubmed publisher
    ..Our findings suggest that hypotonic stress can induce endocytosis in BMDMs and that ClC-3 plays a central role in the endocytic process. ..
  14. Pang R, Xie M, Yang J, Shen K, Chen X, Su Y, et al. Downregulation of ClC-3 in dorsal root ganglia neurons contributes to mechanical hypersensitivity following peripheral nerve injury. Neuropharmacology. 2016;110:181-189 pubmed publisher
    ..Downregulation of ClC-3 by peripheral nerve injury is critical for mechanical hypersensitivity. Our findings suggest that ClC-3 is a novel therapeutic target for treating neuropathic pain. ..
  15. Mills K, Mathews K, Scherpbier Heddema T, Schelper R, Schmalzel R, Bailey H, et al. Genetic mapping near the myd locus on mouse chromosome 8. Mamm Genome. 1995;6:278-80 pubmed
    ..The mutation maps between D8Mit30 and D8Mit75, an interval that is flanked by genes with human homologs at distal 4q. These results are consistent with the possibility that myd is the mouse homolog of FSHD. ..
  16. Moreland J, Davis A, Matsuda J, Hook J, Bailey G, Nauseef W, et al. Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3. J Biol Chem. 2007;282:33958-67 pubmed
    ..In summary, NADPH oxidase activation was required for LOS-mediated priming, but basal oxidants kept unstimulated cells from becoming primed. ClC-3 contributes to both of these processes. ..
  17. Jentsch T. Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol. 2007;578:633-40 pubmed
    ..Surprisingly, ClC-4 and ClC-5 (and probably ClC-3) do not function as Cl- channels, but rather as electrogenic Cl--H+ exchangers. This hints at an important role for luminal chloride in the endosomal-lysosomal system. ..
  18. Robinson N, Huang P, Kaetzel M, Lamb F, Nelson D. Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current. J Physiol. 2004;556:353-68 pubmed
  19. Mills K, Mathews K, Scherpbier Heddema T, Buetow K, Baldini A, Ballabio A, et al. Genetic and physical mapping of a voltage-dependent chloride channel gene to human 4q32 and to mouse 8. Genomics. 1996;36:374-6 pubmed
  20. Huang Y, Huang X, Zhao L, Sun F, Chen W, Du J, et al. ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice. Apoptosis. 2014;19:1559-70 pubmed publisher
  21. Guzman R, Miranda Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015;290:25851-62 pubmed publisher
    ..We conclude that alternative splicing of Clcn3 results in proteins with different subcellular localizations, but leaves the transport function of the proteins ..
  22. Wang H, Wang R, Wang Z, Liu Q, Mao Y, Duan X. ClC-3 chloride channel functions as a mechanically sensitive channel in osteoblasts. Biochem Cell Biol. 2015;93:558-65 pubmed publisher
    ..phosphatase (Alp), bone sialoprotein (Bsp), and osteocalcin (Oc), which could be blocked or strengthened by Clcn3 siRNA or overexpressing, and Alp expression was more sensitive to the changes of ClC-3 level...
  23. Salazar G, Love R, Styers M, Werner E, Peden A, Rodriguez S, et al. AP-3-dependent mechanisms control the targeting of a chloride channel (ClC-3) in neuronal and non-neuronal cells. J Biol Chem. 2004;279:25430-9 pubmed
    ..compartments was functionally significant as revealed by increased vesicular zinc transport with increased ClC3 expression...
  24. Rickheit G, Wartosch L, Schaffer S, Stobrawa S, Novarino G, Weinert S, et al. Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation. J Biol Chem. 2010;285:17595-603 pubmed publisher
    ..We conclude that ClC-5 is unique among CLC proteins in being crucial for proximal tubular endocytosis and that PY-motif-dependent ubiquitylation of ClC-5 is dispensable for this role. ..
  25. Moreland J, Davis A, Bailey G, Nauseef W, Lamb F. Anion channels, including ClC-3, are required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration. J Biol Chem. 2006;281:12277-88 pubmed
    ..Mice lacking the anion channel ClC-3 (Clcn3(-/-)) died from presumed sepsis following intravascular catheter placement, whereas Clcn3(+/+) littermates ..
  26. Miller F, Filali M, Huss G, Stanic B, Chamseddine A, Barna T, et al. Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC-3. Circ Res. 2007;101:663-71 pubmed
    ..These data best support a model whereby ClC-3 is required for charge neutralization of the electron flow generated by Nox1 across the membrane of signaling endosomes. ..
  27. Volk A, Heise C, Hougen J, Artman C, Volk K, Wessels D, et al. ClC-3 and IClswell are required for normal neutrophil chemotaxis and shape change. J Biol Chem. 2008;283:34315-26 pubmed publisher
    ..Murine Clcn3(-/-) PMNs and human PMNs treated with anion transporter inhibitors demonstrated impaired chemotaxis in response to ..
  28. Xiang N, Liu J, Liao Y, Huang Y, Wu Z, Bai Z, et al. Abrogating ClC-3 Inhibits LPS-induced Inflammation via Blocking the TLR4/NF-κB Pathway. Sci Rep. 2016;6:27583 pubmed publisher
    ..In sum, we demonstrate that ClC-3 is a pro-inflammatory factor and that inhibition of ClC-3 inhibits inflammatory induction both in vitro and in vivo, suggesting that ClC-3 is a potential anti-inflammatory target. ..
  29. Fan F, Liu T, Wang X, Ren D, Liu H, Zhang P, et al. ClC-3 Expression and Its Association with Hyperglycemia Induced HT22 Hippocampal Neuronal Cell Apoptosis. J Diabetes Res. 2016;2016:2984380 pubmed publisher
    ..To strengthen our understanding of this aforesaid association, we conducted an extensive literature search which is presented in this paper. ..
  30. Deng Z, Peng S, Zheng Y, Yang X, Zhang H, Tan Q, et al. Estradiol activates chloride channels via estrogen receptor-? in the cell membranes of osteoblasts. Am J Physiol Cell Physiol. 2017;313:C162-C172 pubmed publisher
  31. Templin J, Bang S, Soiza Reilly M, Berde C, Commons K. Patterned expression of ion channel genes in mouse dorsal raphe nucleus determined with the Allen Mouse Brain Atlas. Brain Res. 2012;1457:1-12 pubmed publisher
    ..The identified genes likely contribute to unique excitable properties of different groups of neurons in the DR and may include novel pharmacologic targets for affective disorders. ..
  32. Tao R, Lau C, Tse H, Li G. Regulation of cell proliferation by intermediate-conductance Ca2+-activated potassium and volume-sensitive chloride channels in mouse mesenchymal stem cells. Am J Physiol Cell Physiol. 2008;295:C1409-16 pubmed publisher
    ..Knockdown of KCa3.1 or Clcn3 with specific short interference (si)RNAs significantly reduced IK(Ca) or I(Cl...
  33. Ma M, Lin C, Liu C, Gao M, Sun L, Tang Y, et al. Threonine532 phosphorylation in ClC-3 channels is required for angiotensin II-induced Cl(-) current and migration in cultured vascular smooth muscle cells. Br J Pharmacol. 2016;173:529-44 pubmed publisher
    ..ClC-3 protein phosphorylation at Thr(532) by ROCK2 is required for AngII-induced Cl(-) current and VSMC migration that are involved in AngII-induced vascular remodelling in hypertension. ..
  34. Kasper D, Planells Cases R, Fuhrmann J, Scheel O, Zeitz O, Ruether K, et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 2005;24:1079-91 pubmed
    ..There are important medical implications as defects in the H(+)-ATPase and ClC-7 can underlie human osteopetrosis...
  35. Borsani G, Rugarli E, 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. 1995;27:131-41 pubmed
    We describe the isolation and characterization of a human gene (CLCN3) and its murine homologue (Clcn3) sharing significant sequence and structural similarities with all previously identified members of the voltage-gated chloride channel ..
  36. Ohtaki H, Ohara K, Song D, Miyamoto K, Tsumuraya T, Yofu S, et al. Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene-deficient mice. J Neurosci Res. 2012;90:2163-72 pubmed publisher
    ..In this study, we determined the level of ASM in chloride channel 3 (ClC-3) gene-deficient (KO) mice both in response to aging and following mild global ischemia...
  37. Zeng J, Wang X, Ma M, Lv X, Liu J, Zhou J, et al. Integrin ?3 mediates cerebrovascular remodelling through Src/ClC-3 volume-regulated Cl(-) channel signalling pathway. Br J Pharmacol. 2014;171:3158-70 pubmed publisher
    ..ClC-3 knockout significantly attenuated angiotensin II-induced cerebrovascular remodelling. Integrin ?3 mediates cerebrovascular remodelling during hypertension via Src/ClC-3 signalling pathway. ..
  38. Farmer L, Le B, Nelson D. CLC-3 chloride channels moderate long-term potentiation at Schaffer collateral-CA1 synapses. J Physiol. 2013;591:1001-15 pubmed publisher
    ..Thus, CLC-3 confers Cl(-) sensitivity to excitatory synapses, controls the magnitude of long-term potentiation and may provide a protective limit on Ca(2+) influx. ..
  39. Grewal P, Bolland D, Todd L, Hewitt J. High-resolution mapping of mouse chromosome 8 identifies an evolutionary chromosomal breakpoint. Mamm Genome. 1998;9:603-7 pubmed
    ..As well as providing clues about chromosomal evolution, this map of the FSHD syntenic mouse region should prove invaluable in the isolation of candidate genes for this disease. ..
  40. Arnaiz I, Johnson M, Cook D, Day M. Changing expression of chloride channels during preimplantation mouse development. Reproduction. 2013;145:73-84 pubmed publisher
    ..b>CLCN3 protein was detected at low levels in the cytoplasm and plasma membrane in 4-cell embryos and was localized to the ..
  41. Zhang X, Zhang Y, Sun H, Jin M, Li G. Functional ion channels and cell proliferation in 3T3-L1 preadipocytes. J Cell Physiol. 2012;227:1972-9 pubmed publisher
    ..vol)). RT-PCR and Western blot analysis revealed the expression of KCa3.1 (for IK(Ca)), Kir2.1 (for I(Kir)), and Clcn3 (for I(Cl.vol)). Blockade of IK(Ca) with TRAM-34 or I(Cl...
  42. Grewal P, van Deutekom J, Mills K, Lemmers R, Mathews K, Frants R, et al. The mouse homolog of FRG1, a candidate gene for FSHD, maps proximal to the myodystrophy mutation on chromosome 8. Mamm Genome. 1997;8:394-8 pubmed
    ..Using a cross segregating the myd mutation and the European Collaborative Interspecific Backcross, we showed that Frg1 maps proximal to the myd locus and to the Clc3 and Ant1 genes.
  43. Okada T, Akita T, Sato Numata K, Islam M, Okada Y. A newly cloned ClC-3 isoform, ClC-3d, as well as ClC-3a mediates Cd-sensitive outwardly rectifying anion currents. Cell Physiol Biochem. 2014;33:539-56 pubmed publisher
    ..We thus conclude that plasmalemmal ClC-3d, like ClC-3a, mediates Cd(2+)-sensitive outwardly rectifying anion currents and that ClC-3d is distinct from the molecular entities of acid- and volume-sensitive anion channels. ..
  44. Zheng L, Li L, Ma M, Liu Y, Wang G, Tang Y, et al. Deficiency of volume-regulated ClC-3 chloride channel attenuates cerebrovascular remodelling in DOCA-salt hypertension. Cardiovasc Res. 2013;100:134-42 pubmed publisher
    ..Our findings suggest that ClC-3 deficiency attenuates cerebrovascular remodelling possibly via the suppression of MMPs/TIMP expression and TGF-?1/Smad3 signalling pathway in this hypertension. ..
  45. Zhang H, Deng Z, Yang L, Luo H, Liu S, Li Y, et al. The AQP-3 water channel is a pivotal modulator of glycerol-induced chloride channel activation in nasopharyngeal carcinoma cells. Int J Biochem Cell Biol. 2016;72:89-99 pubmed publisher
    ..In conclusion, AQP-3 is the pathway for water, glycerol and other small solutes to enter cells, and it may be an essential modulator for the gating of chloride channels. ..
  46. Liu C, Li X, Du R, Gao M, Ma M, Li F, et al. Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells. Circ J. 2016;80:2397-2406 pubmed
    ..Circ J 2016; 80: 2397-2406). ..
  47. Matsuda J, Filali M, Collins M, Volk K, Lamb F. The ClC-3 Cl-/H+ antiporter becomes uncoupled at low extracellular pH. J Biol Chem. 2010;285:2569-79 pubmed publisher
    ..0 ClC-3 behaves as an anion-selective channel. These findings have important implications for the biology of Cl(-)/H(+) antiporters and perhaps for pH regulation in highly acidic intracellular compartments. ..
  48. Li D, Jing X, Salehi A, Collins S, Hoppa M, Rosengren A, et al. Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. Cell Metab. 2009;10:309-15 pubmed publisher
    ..The data establish the importance of granular Cl(-) fluxes in granule priming and provide direct evidence for the involvement of ClC-3 in the process. ..
  49. Riazanski V, Deriy L, Shevchenko P, Le B, Gomez E, Nelson D. Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus. Nat Neurosci. 2011;14:487-94 pubmed publisher
    The absence of the chloride channel CLC-3 in Clcn3(-/-) mice results in hippocampal degeneration with a distinct temporal-spatial sequence that resembles neuronal loss in temporal lobe epilepsy...
  50. Gong W, Xu H, Shimizu T, Morishima S, Tanabe S, Tachibe T, et al. ClC-3-independent, PKC-dependent activity of volume-sensitive Cl channel in mouse ventricular cardiomyocytes. Cell Physiol Biochem. 2004;14:213-24 pubmed
    ..cardiomyocytes, the properties of VSOR Cl- currents in single ventricular myocytes isolated from ClC-3-deficient (Clcn3(-/-)) mice were compared with those of the same currents in ClC-3-expressing wild-type (Clcn3(+/+)) and ..
  51. Hara Chikuma M, Yang B, Sonawane N, Sasaki S, Uchida S, Verkman A. ClC-3 chloride channels facilitate endosomal acidification and chloride accumulation. J Biol Chem. 2005;280:1241-7 pubmed
    ..3 versus 5.9. Our results provide direct evidence for involvement of ClC-3 in endosomal acidification by Cl- shunting of the interior-positive membrane potential created by the vacuolar H+ pump. ..