Cell biology and physiology of CLC chloride channels and transporters.

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.