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Gene Review

CLCN3  -  chloride channel, voltage-sensitive 3

Homo sapiens

Synonyms: CLC3, Chloride channel protein 3, Chloride transporter ClC-3, ClC-3, H(+)/Cl(-) exchange transporter 3
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Disease relevance of CLCN3

  • In the present study we provide several lines of evidence that glioma Cl- currents are primarily mediated by ClC-2 and ClC-3, two genes that belong to the ClC superfamily [1].
  • Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles co-labeled with the late endosomal/lysosomal marker LAMP-1 [2].
  • These findings indicate that ClC-3 might be involved in modulating vascular remodeling in hypertension and arteriosclerosis [3].
  • Bcl-2-dependent modulation of swelling-activated Cl- current and ClC-3 expression in human prostate cancer epithelial cells [4].
  • They also provide evidence that ClC-3 upregulation may protect against oxidative stress-induced PASMC necrosis, thereby improving PASMC survival and promoting medial hypertrophy [5].

High impact information on CLCN3


Biological context of CLCN3

  • CLCN2 gene expression was predominantly influenced by cell volume regulation while that of CLCN3 was preferentially affected by conditions associated with TM pathology [8].
  • The current canine whole genome sequence assembly was used for gene structure analyses and revealed 13 coding CLCN3 exons in 52 kb of genomic sequence [9].
  • No consistent CLCN3 haplotype was associated with NCL [9].
  • Sequence analysis of the coding exons and flanking intron regions of CLCN3 using six NCL-affected Tibetan terrier dogs and an NCL-affected Polish Owczarek Nizinny (PON) dog, as well as eight healthy Tibetan terrier dogs revealed 13 SNPs [9].
  • We suggest that ClC-2 and ClC-3 channels are specifically upregulated in glioma membranes and endow glioma cells with an enhanced ability to transport Cl-. This may in turn facilitate rapid changes in cell size and shape as cells divide or invade through tortuous extracellular brain spaces [1].

Anatomical context of CLCN3


Associations of CLCN3 with chemical compounds

  • Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein [15].
  • In addition, our findings indicate that ClC-3 and ZnT3 reside in a common vesicle population where they functionally interact to determine vesicle luminal composition [16].
  • In PC-12 cells, ClC-3 was present in transferrin receptor-positive endosomes, where it was targeted to synaptic-like microvesicles (SLMV) by a mechanism sensitive to brefeldin A, a signature of the AP-3-dependent route of SLMV biogenesis [16].
  • ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC(50) in either BON or HEK293 cell lines [2].
  • Accordingly, granule acidification and priming are inhibited by agents that prevent transgranular Cl(-) fluxes, such as 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and an antibody against the ClC-3 channels, but accelerated by increases in the intracellular ATP:ADP ratio or addition of hypoglycemic sulfonylureas [17].

Regulatory relationships of CLCN3


Other interactions of CLCN3

  • DEX treatment markedly down regulated CLCN3 and little, if any, reduced ClC-2 [8].
  • RESULTS: RT-PCR analysis gave positive bands at the predicted size for CLC-3 and CLC-5 from fresh human, rabbit and bovine as well as CBCEC [19].
  • CLCN3 is by far the most abundant CLC channel mRNA in both VSM and ENDO cells [10].
  • The status of the field is reviewed, with particular emphasis on ClC-3, a member of the ClC family which has been recently proposed as the chloride channel involved in cell volume regulation [20].
  • RESULTS: RT-PCR results confirmed the presence of ClC-5 mRNA, and a full-length clone encoding ClC-3 was isolated from a cDNA library for RPE 28 SV4 cells [21].

Analytical, diagnostic and therapeutic context of CLCN3


  1. Expression of voltage-gated chloride channels in human glioma cells. Olsen, M.L., Schade, S., Lyons, S.A., Amaral, M.D., Sontheimer, H. J. Neurosci. (2003) [Pubmed]
  2. ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. Weylandt, K.H., Nebrig, M., Jansen-Rosseck, N., Amey, J.S., Carmena, D., Wiedenmann, B., Higgins, C.F., Sardini, A. Mol. Cancer Ther. (2007) [Pubmed]
  3. The ClC-3 Cl- channel in cell volume regulation, proliferation and apoptosis in vascular smooth muscle cells. Guan, Y.Y., Wang, G.L., Zhou, J.G. Trends Pharmacol. Sci. (2006) [Pubmed]
  4. Bcl-2-dependent modulation of swelling-activated Cl- current and ClC-3 expression in human prostate cancer epithelial cells. Lemonnier, L., Shuba, Y., Crepin, A., Roudbaraki, M., Slomianny, C., Mauroy, B., Nilius, B., Prevarskaya, N., Skryma, R. Cancer Res. (2004) [Pubmed]
  5. ClC-3: more than just a volume-sensitive Cl- channel. Remillard, C.V., Yuan, J.X. Br. J. Pharmacol. (2005) [Pubmed]
  6. CLC-3 Channels Modulate Excitatory Synaptic Transmission in Hippocampal Neurons. Wang, X.Q., Deriy, L.V., Foss, S., Huang, P., Lamb, F.S., Kaetzel, M.A., Bindokas, V., Marks, J.D., Nelson, D.J. Neuron (2006) [Pubmed]
  7. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin. Wang, T., Weinman, S.A. Gastroenterology (2004) [Pubmed]
  8. Differential expression of the human chloride channel genes in the trabecular meshwork under stress conditions. Comes, N., Gasull, X., Gual, A., Borrás, T. Exp. Eye Res. (2005) [Pubmed]
  9. Characterization of the canine CLCN3 gene and evaluation as candidate for late-onset NCL. Wohlke, A., Distl, O., Drogemuller, C. BMC Genet. (2006) [Pubmed]
  10. Expression of CLCN voltage-gated chloride channel genes in human blood vessels. Lamb, F.S., Clayton, G.H., Liu, B.X., Smith, R.L., Barna, T.J., Schutte, B.C. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  11. Chloride channels in physiological volume regulation of human spermatozoa. Yeung, C.H., Barfield, J.P., Cooper, T.G. Biol. Reprod. (2005) [Pubmed]
  12. Involvement of ion channels in human eosinophil respiratory burst. Schwingshackl, A., Moqbel, R., Duszyk, M. J. Allergy Clin. Immunol. (2000) [Pubmed]
  13. The human ClC-4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N-terminus. Okkenhaug, H., Weylandt, K.H., Carmena, D., Wells, D.J., Higgins, C.F., Sardini, A. FASEB J. (2006) [Pubmed]
  14. ClC-3 is a fundamental molecular component of volume-sensitive outwardly rectifying Cl- channels and volume regulation in HeLa cells and Xenopus laevis oocytes. Hermoso, M., Satterwhite, C.M., Andrade, Y.N., Hidalgo, J., Wilson, S.M., Horowitz, B., Hume, J.R. J. Biol. Chem. (2002) [Pubmed]
  15. Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein. Borsani, G., Rugarli, E.I., Taglialatela, M., Wong, C., Ballabio, A. Genomics (1995) [Pubmed]
  16. AP-3-dependent mechanisms control the targeting of a chloride channel (ClC-3) in neuronal and non-neuronal cells. Salazar, G., Love, R., Styers, M.L., Werner, E., Peden, A., Rodriguez, S., Gearing, M., Wainer, B.H., Faundez, V. J. Biol. Chem. (2004) [Pubmed]
  17. Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification. Barg, S., Huang, P., Eliasson, L., Nelson, D.J., Obermüller, S., Rorsman, P., Thévenod, F., Renström, E. J. Cell. Sci. (2001) [Pubmed]
  18. Human ClC-3 is not the swelling-activated chloride channel involved in cell volume regulation. Weylandt, K.H., Valverde, M.A., Nobles, M., Raguz, S., Amey, J.S., Diaz, M., Nastrucci, C., Higgins, C.F., Sardini, A. J. Biol. Chem. (2001) [Pubmed]
  19. Studies on the expression of mRNA for anion transport related proteins in corneal endothelial cells. Sun, X.C., McCutheon, C., Bertram, P., Xie, Q., Bonanno, J.A. Curr. Eye Res. (2001) [Pubmed]
  20. Cell volume regulation and swelling-activated chloride channels. Sardini, A., Amey, J.S., Weylandt, K.H., Nobles, M., Valverde, M.A., Higgins, C.F. Biochim. Biophys. Acta (2003) [Pubmed]
  21. Chloride channel expression in cultured human fetal RPE cells: response to oxidative stress. Wills, N.K., Weng, T., Mo, L., Hellmich, H.L., Yu, A., Wang, T., Buchheit, S., Godley, B.F. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  22. Intracellular localization of ClC chloride channels and their ability to form hetero-oligomers. Suzuki, T., Rai, T., Hayama, A., Sohara, E., Suda, S., Itoh, T., Sasaki, S., Uchida, S. J. Cell. Physiol. (2006) [Pubmed]
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