The chloride channel ClC-4 contributes to endosomal acidification and trafficking.
Mutations in the gene coding for the chloride channel ClC-5 cause Dent's disease, a disease associated with proteinuria and renal stones. Studies in ClC-5 knockout mice suggest that this phenotype is related to defective endocytosis of low molecular weight proteins and membrane proteins by the renal proximal tubule. In this study, confocal micrographs of proximal tubules and cultured epithelial cells revealed that the related protein ClC-4 is expressed in endosomal membranes suggesting that this channel may also contribute to the function of this organelle. In support of this hypothesis, specific disruption of endogenous ClC-4 expression by transfection of ClC-4 antisense cDNA acidified endosomal pH and altered transferrin trafficking in cultured epithelial cells to the same extent as the specific disruption of ClC-5. Both channels can be co-immunoprecipitated, arguing that they may partially contribute to endosomal function as a channel complex. These studies prompt future investigation of the role of ClC-4 in renal function in health and in Dent's disease. Future studies will assess whether the severity of Dent's disease relates not only to the impact of particular mutations on ClC-5 but also on the consequences of those mutations on the functional expression of ClC-4.
Mohammad-Panah
Raha
R
Programme in Structural Biology and Biochemistry, Research Institute, Hospital for Sick Children, Toronto, Ontario M5X 1G8, Canada.
Harrison
Rene
R
Dhani
Sonja
S
Ackerley
Cameron
C
Huan
Ling-Jun
LJ
Wang
Yanchun
Y
Bear
Christine E
CE
D000818:Animals; D016466:CHO Cells; D018938:Caco-2 Cells; D002478:Cells, Cultured; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006224:Cricetinae; D016373:DNA, Antisense / Q000235:genetics; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007163:Immunosorbent Techniques; D007669:Kidney Calculi / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009154:Mutation; D011507:Proteinuria / Q000235:genetics; D051381:Rats; D011990:Receptors, Transferrin / Q000378:metabolism; D014162:Transfection
C097503:CLC-5 chloride channel; D018118:Chloride Channels; D016373:DNA, Antisense; D011990:Receptors, Transferrin