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

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Science  29 Apr 2010:
DOI: 10.1126/science.1188070


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 neutralization of proton pump currents. However, ClC-5 is a 2Cl/H+-exchanger rather than a Cl channel. We generated mice carrying the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl conductor. ATP-dependent acidification of renal endosomes was reduced in ClC-5 knockout mice, but normal in Clcn5unc mice. Surprisingly, 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.