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CLC chloride channels and transporters: a biophysical and physiological perspective

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Reviews of Physiology, Biochemistry and Pharmacology

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 158))

Abstract

Chloride-transporting proteins play fundamental roles in many tissues in the plasma membrane as well as in intracellular membranes. They have received increasing attention in the last years because crucial, and often unexpected and novel, physiological functions have been disclosed with gene-targeting approaches, X-ray crystallography, and biophysical analysis. CLC proteins form a gene family that comprises nine members in mammals, at least four of which are involved in human genetic diseases. The X-ray structure of the bacterial CLC homolog, ClC-ec1, revealed a complex fold and confirmed the anticipated homodimeric double-barreled architecture of CLC-proteins with two separate Cl− ion transport pathways, one in each subunit. Four of the mammalian CLC proteins, ClC-1, ClC-2, ClC-Ka, and ClC-Kb, are chloride ion channels that fulfill their functional roles—stabilization of the membrane potential, transepithelial salt transport, and ion homeostasis—in the plasma membrane. The other five CLC proteins are predominantly expressed in intracellular organelles like endosomes and lysosomes, where they are probably important for a proper luminal acidification, in concert with the V-type H+-ATPase. Surprisingly, ClC-4, ClC-5, and probably also ClC-3, are not Cl− ion channels but exhibit significant Cl−/H+ antiporter activity, as does the bacterial homolog ClC-ec1 and the plant homolog AtCLCa. The physiological significance of the Cl−/H+ antiport activity remains to be established.

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Acknowledgements

We thank Elena Babini for critical review of the manuscript. The financial support by Telethon Italy (grant GGP04018) is gratefully acknowledged.

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    G. Zifarelli & M. Pusch

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    S.G. Amara

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Zifarelli, G., Pusch, M. (2007). CLC chloride channels and transporters: a biophysical and physiological perspective. In: Amara, S. (eds) Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 158. Springer, Berlin, Heidelberg. https://doi.org/10.1007/112_2006_0605

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