Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins

Item Type:	Article
Title:	Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins
Creators Name:	Scheel, O. and Zdebik, A.A. and Lourdel, S. and Jentsch, T.J.
Abstract:	Eukaryotic members of the CLC gene family function as plasma membrane chloride channels, or may provide neutralizing anion currents for V-type H(+)-ATPases that acidify compartments of the endosomal/lysosomal pathway. Loss-of-function mutations in the endosomal protein ClC-5 impair renal endocytosis and lead to kidney stones, whereas loss of function of the endosomal/lysosomal protein ClC-7 entails osteopetrosis and lysosomal storage disease. Vesicular CLCs have been thought to be Cl- channels, in particular because ClC-4 and ClC-5 mediate plasma membrane Cl- currents upon heterologous expression. Here we show that these two mainly endosomal CLC proteins instead function as electrogenic Cl-/H+ exchangers (also called antiporters), resembling the transport activity of the bacterial protein ClC-e1, the crystal structure of which has already been determined. Neutralization of a critical glutamate residue not only abolished the steep voltage-dependence of transport, but also eliminated the coupling of anion flux to proton counter-transport. ClC-4 and ClC-5 may still compensate the charge accumulation by endosomal proton pumps, but are expected to couple directly vesicular pH gradients to Cl- gradients.
Keywords:	Antiporters, Bacterial Proteins, Cell Line, Chloride Channels, Chlorides, Electric Conductivity, Endosomes, Hydrogen-Ion Concentration, Ion Channel Gating, Ion Transport, Membrane Potentials, Missense Mutation, Oocytes, Patch-Clamp Techniques, Protons, Torpedo, Animals, Xenopus
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	436
Number:	7049
Page Range:	424-427
Date:	21 July 2005
Official Publication:	https://doi.org/10.1038/nature03860
PubMed:	View item in PubMed

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