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Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance Is Crucial for Renal Endocytosis

Science  11 Jun 2010:
Vol. 328, Issue 5984, pp. 1398-1401
DOI: 10.1126/science.1188070

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Abstract

Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent’s disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl–)/proton (/H+) exchanger rather than a Cl channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl conductor. Adenosine triphosphate (ATP)–dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5unc mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis.

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