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

Nature volume 436, pages 424–427 (2005)Cite this article

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 pathway1. Loss-of-function mutations in the endosomal protein ClC-5 impair renal endocytosis2 and lead to kidney stones3, whereas loss of function of the endosomal/lysosomal protein ClC-7 entails osteopetrosis4 and lysosomal storage disease5. Vesicular CLCs have been thought to be Cl- channels, in particular because ClC-4 and ClC-5 mediate plasma membrane Cl- currents upon heterologous expression6,7. 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 determined9. Neutralization of a critical glutamate residue not only abolished the steep voltage-dependence of transport7, 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.

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Figure 1: Depolarization alkalinizes cells expressing ClC-4 or ClC-5, but not those expressing ClC-0.
Figure 2: The E211A mutation abolishes flux coupling to H+.
Figure 3: H + transport depends on chloride and voltage.

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Acknowledgements

We thank M. Lazdunski for the gift of the FaNaC-CD8 expression vector, and M. Petersen and P. Breiden for technical assistance. This work was supported in part by the Prix Louis-Jeantet de Médecine.

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  1. Olaf Scheel and Anselm A. Zdebik: *These authors contributed equally to this work

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  1. Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20246, Hamburg, Germany

    Olaf Scheel, Anselm A. Zdebik, Stéphane Lourdel & Thomas J. Jentsch

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  1. Olaf Scheel
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Correspondence to Thomas J. Jentsch.

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Scheel, O., Zdebik, A., Lourdel, S. et al. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436, 424–427 (2005). https://doi.org/10.1038/nature03860

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