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Gene Review

CLCN2  -  chloride channel, voltage-sensitive 2

Homo sapiens

Synonyms: CIC-2, CLC2, Chloride channel protein 2, ClC-2, ECA2, ...
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Disease relevance of CLCN2


Psychiatry related information on CLCN2


High impact information on CLCN2

  • New molecular candidates responsible for I(Cl.vol), I(Cl.Ca), and I( (ClC-3, CLCA1, and ClC-2, respectively) have recently been identified and are presently being evaluated [6].
  • M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition [1].
  • In this issue of Neuron, Jentsch, Pusch, and colleagues use the structure of a bacterial ClC homolog to guide a mutagenic analysis of inhibitor binding to ClC-0, ClC-1, and ClC-2 [7].
  • Consistent with this hypothesis, we show that heterologously expressed rat ClC-2 is also activated by serine/threonine dephosphorylation, suggesting that the two channels have common regulatory mechanisms [8].
  • Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells [9].

Chemical compound and disease context of CLCN2


Biological context of CLCN2


Anatomical context of CLCN2


Associations of CLCN2 with chemical compounds


Regulatory relationships of CLCN2

  • Hypotonic conditions consistently up regulated CLCN2 and slightly up regulated CLCN3 [12].
  • CIC-2 is a voltage- and volume-regulated chloride channel expressed in many tissues [21].
  • These data suggest that IFN-gamma activates ClC-2 channel activity in lung epithelial cells via mRNA stabilization [22].
  • TGF-alpha (0.17 nM) irreversibly inhibited ClC-2 current in nystatin-perforated whole cell patch-clamp experiments, whereas a superimposed reversible activation of the current was observed at 8.3 nM TGF-alpha [23].

Other interactions of CLCN2

  • We determined the ontogeny of expression of the CLCN family of voltage-dependent Cl channel genes (CLCN2 through 6, K(a) and K(b)) in the human lung to identify potential pathways for pulmonary liquid secretion [14].
  • DEX treatment markedly down regulated CLCN3 and little, if any, reduced ClC-2 [12].
  • The properties of the vesicles' Cl- conductance resemble those of the intermediate conductance outwardly rectifying Cl- channel and tentatively exclude contributions of CFTR, pICln and ClC-2 [24].
  • CLCN2 and idiopathic generalized epilepsy [25].
  • Activation of chloride currents was also observed after introducing homologous mutations in ClC-Ka and ClC-K1, but not in ClC-2 and ClC-5 chloride channels [26].

Analytical, diagnostic and therapeutic context of CLCN2


  1. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Haug, K., Warnstedt, M., Alekov, A.K., Sander, T., Ramírez, A., Poser, B., Maljevic, S., Hebeisen, S., Kubisch, C., Rebstock, J., Horvath, S., Hallmann, K., Dullinger, J.S., Rau, B., Haverkamp, F., Beyenburg, S., Schulz, H., Janz, D., Giese, B., Müller-Newen, G., Propping, P., Elger, C.E., Fahlke, C., Lerche, H., Heils, A. Nat. Genet. (2003) [Pubmed]
  2. 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]
  3. CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity. Blaisdell, C.J., Howard, T.D., Stern, A., Bamford, P., Bleecker, E.R., Stine, O.C. BMC Med. Genet. (2004) [Pubmed]
  4. Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes. Stogmann, E., Lichtner, P., Baumgartner, C., Schmied, M., Hotzy, C., Asmus, F., Leutmezer, F., Bonelli, S., Assem-Hilger, E., Vass, K., Hatala, K., Strom, T.M., Meitinger, T., Zimprich, F., Zimprich, A. Neurogenetics (2006) [Pubmed]
  5. Evidence for a functional interaction between the ClC-2 chloride channel and the retrograde motor dynein complex. Dhani, S.U., Mohammad-Panah, R., Ahmed, N., Ackerley, C., Ramjeesingh, M., Bear, C.E. J. Biol. Chem. (2003) [Pubmed]
  6. Anion transport in heart. Hume, J.R., Duan, D., Collier, M.L., Yamazaki, J., Horowitz, B. Physiol. Rev. (2000) [Pubmed]
  7. The poststructural festivities begin. Maduke, M., Mindell, J.A. Neuron (2003) [Pubmed]
  8. Cell cycle- and swelling-induced activation of a Caenorhabditis elegans ClC channel is mediated by CeGLC-7alpha/beta phosphatases. Rutledge, E., Denton, J., Strange, K. J. Cell Biol. (2002) [Pubmed]
  9. Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. Schwiebert, E.M., Cid-Soto, L.P., Stafford, D., Carter, M., Blaisdell, C.J., Zeitlin, P.L., Guggino, W.B., Cutting, G.R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  10. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Camilleri, M., Bharucha, A.E., Ueno, R., Burton, D., Thomforde, G.M., Baxter, K., McKinzie, S., Zinsmeister, A.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  11. Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies. Niemeyer, M.I., Yusef, Y.R., Cornejo, I., Flores, C.A., Sepúlveda, F.V., Cid, L.P. Physiol. Genomics (2004) [Pubmed]
  12. 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]
  13. Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues. Cid, L.P., Montrose-Rafizadeh, C., Smith, D.I., Guggino, W.B., Cutting, G.R. Hum. Mol. Genet. (1995) [Pubmed]
  14. Ontogeny of CLCN3 chloride channel gene expression in human pulmonary epithelium. Lamb, F.S., Graeff, R.W., Clayton, G.H., Smith, R.L., Schutte, B.C., McCray, P.B. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  15. 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]
  16. Tumorigenicity of human breast cancer is associated with loss of the Ca2+-activated chloride channel CLCA2. Gruber, A.D., Pauli, B.U. Cancer Res. (1999) [Pubmed]
  17. Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte. Huber, S.M., Duranton, C., Henke, G., Van De Sand, C., Heussler, V., Shumilina, E., Sandu, C.D., Tanneur, V., Brand, V., Kasinathan, R.S., Lang, K.S., Kremsner, P.G., Hübner, C.A., Rust, M.B., Dedek, K., Jentsch, T.J., Lang, F. J. Biol. Chem. (2004) [Pubmed]
  18. Sites of protein kinase A activation of the human ClC-2 Cl(-) channel. Cuppoletti, J., Tewari, K.P., Sherry, A.M., Ferrante, C.J., Malinowska, D.H. J. Biol. Chem. (2004) [Pubmed]
  19. Is the ClC-2 chloride channel involved in the Cl- secretory mechanism of gastric parietal cells? Hori, K., Takahashi, Y., Horikawa, N., Furukawa, T., Tsukada, K., Takeguchi, N., Sakai, H. FEBS Lett. (2004) [Pubmed]
  20. Distribution of ClC-2 chloride channel in rat and human epithelial tissues. Lipecka, J., Bali, M., Thomas, A., Fanen, P., Edelman, A., Fritsch, J. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  21. A short CIC-2 mRNA transcript is produced by exon skipping. Chu, S., Murray, C.B., Liu, M.M., Zeitlin, P.L. Nucleic Acids Res. (1996) [Pubmed]
  22. Interferon-gamma regulates ClC-2 chloride channel in lung epithelial cells. Chu, S., Blaisdell, C.J., Bamford, P., Ferro, T.J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  23. Regulation of ClC-2 chloride channels in T84 cells by TGF-alpha. Bali, M., Lipecka, J., Edelman, A., Fritsch, J. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  24. Chloride conductance in HT29 cells: investigations with apical membrane vesicles and RT-PCR. Hagos, Y., Krick, W., Burckhardt, G. Pflugers Arch. (1999) [Pubmed]
  25. CLCN2 and idiopathic generalized epilepsy. Heils, A. Advances in neurology. (2005) [Pubmed]
  26. A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Jeck, N., Waldegger, P., Doroszewicz, J., Seyberth, H., Waldegger, S. Kidney Int. (2004) [Pubmed]
  27. Expression of swelling- and/or pH-regulated chloride channels (ClC-2, 3, 4 and 5) in human leukemic and normal immune cells. Jiang, B., Hattori, N., Liu, B., Kitagawa, K., Inagaki, C. Life Sci. (2002) [Pubmed]
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