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Gene Review

Clcn5  -  chloride channel 5

Mus musculus

Synonyms: 5430408K11Rik, Chloride channel protein 5, Chloride transporter ClC-5, ClC-5, Clc5, ...
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Disease relevance of Clcn5


High impact information on Clcn5


Chemical compound and disease context of Clcn5


Biological context of Clcn5


Anatomical context of Clcn5

  • We found that ClC-5 is highly expressed in wild-type mouse thyroid ( approximately 40% of mRNA kidney level) [2].
  • In Percoll gradients, ClC-5 overlapped with plasma membrane and early endosome markers, but best codistributed with the late endosomal marker, Rab7 [2].
  • Impaired endosomal acidification in proximal tubule caused by reduced chloride conductance is a proposed mechanism; however, functional analysis of ClC-5 in oocytes predicts low ClC-5 chloride conductance in endosomes because of their acid interior pH and positive potential [8].
  • ClC-5 is expressed in part in cells lining the proximal tubule (PT) of the kidney, where it colocalizes with albumin-containing endocytic vesicles belonging to the receptor-mediated endocytic pathway that ensures efficient reabsorption of ultrafiltrated LMW proteins [4].
  • These observations allowed us to conclude that defective protein endocytosis linked to ClC-5 inactivation is due at least in part to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells [4].

Associations of Clcn5 with chemical compounds

  • METHODS: We studied the effect of zero and high citrate diet on renal function of ClC-5 knockout mice and wild-type mice [3].
  • When comparing ClC-5 KO with wild-type mice, thyroid 125I uptake after 1 h was doubled, incorporation into Tg was decreased by approximately 2-fold, so that trichloroacetic acid-soluble 125I increased approximately 4-fold [2].
  • Our results provide direct evidence for ClC-5 involvement in acidification of early endosomes in proximal tubule by a chloride shunt mechanism [8].
  • The defective endocytosis in ClC-5 KO mice entails an increased luminal concentration of PTH, subsequent stimulation of apical PTH receptors which causes an increased endocytosis of the phosphate transporter NaPi and phosphaturia [11].
  • In spite of reduced serum levels of 1,25(OH)(2)-vitamin D(3) in ClC-5 KO mice, 1,25(OH)(2)-vitamin D(3) is increased in later nephron segments as a consequence of impaired proximal tubular endocytosis [10].

Physical interactions of Clcn5


Regulatory relationships of Clcn5

  • ClC-5 is expressed in apical endosomes of proximal tubular cells where it co-localizes with endocytosed proteins and the proton ATPase [11].

Other interactions of Clcn5

  • Transforming growth factor-beta1 (TGF-beta1) was significantly increased in 9-month-old ClC-5 knockout mice on zero citrate diet compared to 9-month-old wild-type mice on the same diet [3].
  • Initial pH in transferrin-labeled endosomes was approximately 7.2, decreasing at 15 min to 6.0 vs. 6.5 in wildtype vs. ClC-5 deficient cells, respectively; corresponding endosomal chloride concentration increased from approximately 16 mM to 47 vs. 36 mM [8].
  • Thus, the endocytosis of ClC-5, which itself is crucial for the endocytosis of other proteins, depends on the interaction of a carboxyl-terminal internalization signal with ubiquitin-protein ligases containing WW domains [7].
  • Stimulating endocytosis by expressing rab5 or its GTPase-deficient Q79L mutant decreased WT ClC-5 currents but did not affect channels with mutated motifs [7].
  • The reduction in proximal tubular endocytosis resulting from a lack of ClC-5 raises the luminal concentration of filtered proteins and peptides like parathyroid hormone (PTH) [10].

Analytical, diagnostic and therapeutic context of Clcn5


  1. ClC-5: role in endocytosis in the proximal tubule. Wang, Y., Cai, H., Cebotaru, L., Hryciw, D.H., Weinman, E.J., Donowitz, M., Guggino, S.E., Guggino, W.B. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  2. The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland. van den Hove, M.F., Croizet-Berger, K., Jouret, F., Guggino, S.E., Guggino, W.B., Devuyst, O., Courtoy, P.J. Endocrinology (2006) [Pubmed]
  3. High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Cebotaru, V., Kaul, S., Devuyst, O., Cai, H., Racusen, L., Guggino, W.B., Guggino, S.E. Kidney Int. (2005) [Pubmed]
  4. Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice. Devuyst, O., Jouret, F., Auzanneau, C., Courtoy, P.J. Nephron. Physiology [electronic resource]. (2005) [Pubmed]
  5. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease. Piwon, N., Günther, W., Schwake, M., Bösl, M.R., Jentsch, T.J. Nature (2000) [Pubmed]
  6. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Christensen, E.I., Devuyst, O., Dom, G., Nielsen, R., Van der Smissen, P., Verroust, P., Leruth, M., Guggino, W.B., Courtoy, P.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease. Schwake, M., Friedrich, T., Jentsch, T.J. J. Biol. Chem. (2001) [Pubmed]
  8. Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Hara-Chikuma, M., Wang, Y., Guggino, S.E., Guggino, W.B., Verkman, A.S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  9. Characterization of novel promoter and enhancer elements of the mouse homologue of the Dent disease gene, CLCN5, implicated in X-linked hereditary nephrolithiasis. Tanaka, K., Fisher, S.E., Craig, I.W. Genomics (1999) [Pubmed]
  10. Kidney-specific upregulation of vitamin D3 target genes in ClC-5 KO mice. Maritzen, T., Rickheit, G., Schmitt, A., Jentsch, T.J. Kidney Int. (2006) [Pubmed]
  11. The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease. Günther, W., Piwon, N., Jentsch, T.J. Pflugers Arch. (2003) [Pubmed]
  12. ClC-5 Does Not Affect Megalin Expression and Function in the Thyroid. Maritzen, T., Lisi, S., Botta, R., Pinchera, A., Fanelli, G., Viacava, P., Marcocci, C., Marinò, M. Thyroid (2006) [Pubmed]
  13. The voltage-dependent Cl(-) channel ClC-5 and plasma membrane Cl(-) conductances of mouse renal collecting duct cells (mIMCD-3). Sayer, J.A., Stewart, G.S., Boese, S.H., Gray, M.A., Pearce, S.H., Goodship, T.H., Simmons, N.L. J. Physiol. (Lond.) (2001) [Pubmed]
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