Cell biology and physiology of CLC chloride channels and transporters.

Abstract

Proteins of the CLC gene family assemble to homo- or sometimes heterodimers and either function as Cl(-) channels or as Cl(-)/H(+)-exchangers. CLC proteins are present in all phyla. Detailed structural information is available from crystal structures of bacterial and algal CLCs. Mammals express nine CLC genes, four of which encode Cl(-) channels and five 2Cl(-)/H(+)-exchangers. Two accessory β-subunits are known: (1) barttin and (2) Ostm1. ClC-Ka and ClC-Kb Cl(-) channels need barttin, whereas Ostm1 is required for the function of the lysosomal ClC-7 2Cl(-)/H(+)-exchanger. ClC-1, -2, -Ka and -Kb Cl(-) channels reside in the plasma membrane and function in the control of electrical excitability of muscles or neurons, in extra- and intracellular ion homeostasis, and in transepithelial transport. The mainly endosomal/lysosomal Cl(-)/H(+)-exchangers ClC-3 to ClC-7 may facilitate vesicular acidification by shunting currents of proton pumps and increase vesicular Cl(-) concentration. ClC-3 is also present on synaptic vesicles, whereas ClC-4 and -5 can reach the plasma membrane to some extent. ClC-7/Ostm1 is coinserted with the vesicular H(+)-ATPase into the acid-secreting ruffled border membrane of osteoclasts. Mice or humans lacking ClC-7 or Ostm1 display osteopetrosis and lysosomal storage disease. Disruption of the endosomal ClC-5 Cl(-)/H(+)-exchanger leads to proteinuria and Dent's disease. Mouse models in which ClC-5 or ClC-7 is converted to uncoupled Cl(-) conductors suggest an important role of vesicular Cl(-) accumulation in these pathologies. The important functions of CLC Cl(-) channels were also revealed by human diseases and mouse models, with phenotypes including myotonia, renal loss of salt and water, deafness, blindness, leukodystrophy, and male infertility.

• Authors: Tobias Stauber, Stefanie Weinert, Thomas J Jentsch
• Journal: Comprehensive Physiology (Compr Physiol) Vol. 2 Issue 3 Pg. 1701-44 (Jul 2012) ISSN: 2040-4603 [Electronic] United States
• PMID: 23723021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2012 American Physiological Society. Compr Physiol 2:1745-1766, 2012.

Chemical References

• Chloride Channels
• Chlorides
• Ion Pumps

Topics

• Animals
• Cell Membrane (metabolism)
• Channelopathies (genetics)
• Chloride Channels (genetics, metabolism, physiology)
• Chlorides (metabolism)
• Humans
• Ion Pumps (genetics, metabolism, physiology)
• Mice