Whereas in mammals the serum concentration of Cl − is universally high (~120 mM) and intracellular chloride concentration ( i) much lower, different cell types display a wide range of i (from ~5–10 mM in most mature neurons up to ~40 mM in epithelial cells). The direction of Cl − transport through channels is entirely determined by the transmembrane gradient of the electrochemical potential, which is given by the difference in Cl − concentration and the transmembrane voltage according to the Nernst equation. These exchangers also generate currents (are ‟electrogenicˮ), but, as discussed below, coupling of Cl − to H + transport has additional important implications for their biological roles.
Cl − channels might also influence the voltage of intracellular organelles, but most likely the main Cl − transporters of endosomes and lysosomes are 2Cl −/H + exchangers of the CLC gene family, which encompasses both these exchangers and Cl − channels.
Cl − channels can therefore change the voltage across the plasma membrane and thereby influence the electrical excitability of neurons, muscle, and endocrine cells ( 310, 423, 477, 572, 702). Chloride transport across cellular membranes generates electrical currents if its transport is not strictly coupled to that of other ions, such as in ‟electroneutralˮ K +-Cl − or Na +-K +-2Cl − cotransporters or Cl −/HCO 3 − exchangers. Examples are given by the lysosomal enzyme cathepsin C, the activity of which is modulated by the binding of chloride to the protein ( 138) and WNK protein kinases ( 616, 646, 830), but many other proteins are known to be chloride sensitive ( 207). Chloride may also have ‟chemicalˮ roles by binding to proteins and thereby modifying their function. Owed to its high concentration, it serves, together with positively charged counterions, as important osmolyte to drive water across cellular membranes in cell volume regulation and transepithelial secretion or absorption of water. As a counterion for Na + and K +, chloride ensures electroneutrality both under steady state and during transport across cellular membranes, as exemplified by transepithelial transport and acidification of intracellular vesicles. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.Ĭhloride is the most abundant anion and serves many different biological roles. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. CLC Cl − channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl − channels, whereas ClC-3 through ClC-7 are 2Cl −/H +-exchangers in endolysosomal membranes.
Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. Structures of these two CLC protein classes are surprisingly similar. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC anion transporters are found in all phyla and form a gene family of eight members in mammals.
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