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Gene Review

CLCN4  -  chloride channel, voltage-sensitive 4

Homo sapiens

Synonyms: CLC4, Chloride channel protein 4, Chloride transporter ClC-4, ClC-4, ClC-4A, ...
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Disease relevance of CLCN4


High impact information on CLCN4

  • The chloride channel gene, CLCN4, has been previously mapped to the X chromosome in humans [2].
  • Overexpression of ClC-4 doubled copper incorporation into ceruloplasmin (P = 0.011), whereas identical overexpression of ClC-3 had no effect [1].
  • Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin [1].
  • This gene, termed CICN4 (Chloride Channel 4), contains at least 10 exons spanning 60 to 80 kb on the X chromosome [3].
  • Electrophysiological recordings of the heterologously expressed channels in Xenopus oocytes showed that ClC-4 and ClC-4A have opposite sensitivity to pH and unique ion selectivity [4].

Biological context of CLCN4


Anatomical context of CLCN4

  • Here we report that ClC-4 and ClC-5 carry a substantial amount of protons across the plasma membrane when activated by positive voltages, as revealed by measurements of pH close to the cell surface [7].
  • When heterologously expressed in HEK293 cells and in skeletal muscle fibers, hClC-4 localizes to the endoplasmic/sarcoplasmic reticulum (ER/SR) membranes, in contrast to hClC-3, which localizes to vesicular structures [8].
  • This location was confirmed by identification of endogenous ClC-4 in membrane fractions from mouse brain homogenate enriched for the sarco-endoplasmic reticulum ATPase SERCA2, an ER/SR marker [8].
  • The human ClC-4 protein, a member of the CLC chloride channel/transporter family, is localized to the endoplasmic reticulum by its N-terminus [8].
  • We now show that ClC-4 also gives rise to strongly outwardly rectifying anion currents when expressed in oocytes [9].

Associations of CLCN4 with chemical compounds

  • Changing the extracellular (2 mM or nominal Ca(2+)-free) or intracellular Ca(2+) (25 or 250 nM) concentration did not alter hClC-4 currents [10].
  • Continuous activity of hClC-4 was sustained to different degrees by internal nucleotides: ATP approximately ATPgammaS >> AMP-PNP approximate GTP > ADP [10].
  • In all cells, the expression of hClC-4 generated strongly outward-rectifying Cl(-) currents with the conductance sequence: SCN(-) >> NO(3)(-) >> Cl(-) > Br(-) approximate I(-) >> aspartate [10].
  • X-ray crystallographic and electrophysiological studies have identified two glutamate residues required for gated Cl movement and proton permeation in bacterial and two mammalian (ClC-4, ClC-5) ClC transporters [11].

Co-localisations of CLCN4


Regulatory relationships of CLCN4


Other interactions of CLCN4

  • CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4 [13].
  • IHCEn cultivated on LAM showed stronger expression of VDAC3, CLCN4, and Na+/K+ ATPase mRNA than on plastic culture dish [14].
  • Hence, like CFTR, ClC-4 may cycle between the plasma membrane and endosomal compartment [12].

Analytical, diagnostic and therapeutic context of CLCN4


  1. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin. Wang, T., Weinman, S.A. Gastroenterology (2004) [Pubmed]
  2. A contravention of Ohno's law in mice. Palmer, S., Perry, J., Ashworth, A. Nat. Genet. (1995) [Pubmed]
  3. A gene from the Xp22.3 region shares homology with voltage-gated chloride channels. van Slegtenhorst, M.A., Bassi, M.T., Borsani, G., Wapenaar, M.C., Ferrero, G.B., de Conciliis, L., Rugarli, E.I., Grillo, A., Franco, B., Zoghbi, H.Y. Hum. Mol. Genet. (1994) [Pubmed]
  4. Identification and functional characterization of a voltage-gated chloride channel and its novel splice variant in taste bud cells. Huang, L., Cao, J., Wang, H., Vo, L.A., Brand, J.G. J. Biol. Chem. (2005) [Pubmed]
  5. Dent disease-like phenotype and the chloride channel ClC-4 (CLCN4) gene. Ludwig, M., Utsch, B. Am. J. Med. Genet. A (2004) [Pubmed]
  6. Channel or transporter? The CLC saga continues. Pusch, M., Zifarelli, G., Murgia, A.R., Picollo, A., Babini, E. Exp. Physiol. (2006) [Pubmed]
  7. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Picollo, A., Pusch, M. Nature (2005) [Pubmed]
  8. 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]
  9. Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents. Friedrich, T., Breiderhoff, T., Jentsch, T.J. J. Biol. Chem. (1999) [Pubmed]
  10. Functional characterization of recombinant human ClC-4 chloride channels in cultured mammalian cells. Vanoye, C.G., George, A.L. J. Physiol. (Lond.) (2002) [Pubmed]
  11. Molecular physiology of renal ClC chloride channels/transporters. Sile, S., Vanoye, C.G., George, A.L. Curr. Opin. Nephrol. Hypertens. (2006) [Pubmed]
  12. 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. Mohammad-Panah, R., Ackerley, C., Rommens, J., Choudhury, M., Wang, Y., Bear, C.E. J. Biol. Chem. (2002) [Pubmed]
  13. Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Fisher, S.E., van Bakel, I., Lloyd, S.E., Pearce, S.H., Thakker, R.V., Craig, I.W. Genomics (1995) [Pubmed]
  14. Characterization of immortalized human corneal endothelial cell line using HPV 16 E6/E7 on lyophilized human amniotic membrane. Kim, H.J., Ryu, Y.H., Ahn, J.I., Park, J.K., Kim, J.C. Korean journal of ophthalmology : KJO. (2006) [Pubmed]
  15. Anion permeation in human ClC-4 channels. Hebeisen, S., Heidtmann, H., Cosmelli, D., Gonzalez, C., Poser, B., Latorre, R., Alvarez, O., Fahlke, C. Biophys. J. (2003) [Pubmed]
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