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

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 a...

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Bibliographic Details
Published in:Nature 2005-07, Vol.436 (7049), p.424-427
Main Authors: Zdebik, Anselm A, Scheel, Olaf, Lourdel, Stéphane, Jentsch, Thomas J
Format: Article
Language:English
Subjects:
Animals
Antiporters - genetics
Antiporters - metabolism
Bacterial proteins
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Biological and medical sciences
Cell Line
Cellular Biology
Chloride Channels - genetics
Chloride Channels - metabolism
Chlorides - metabolism
Diseases of the osteoarticular system
Electric Conductivity
Endosomes - metabolism
Eukaryotes
Gene expression
Humans
Hydrogen-Ion Concentration
Ion Channel Gating
Ion Transport
Kidney stones
Life Sciences
Malformations and congenital and or hereditary diseases involving bones. Joint deformations
Medical sciences
Membrane Potentials
Mutation
Mutation, Missense - genetics
Nephrology. Urinary tract diseases
Oocytes - metabolism
Patch-Clamp Techniques
Protons
Torpedo
Urinary lithiasis
Xenopus
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Summary: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 (ref. 8), 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature03860