title: Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters.
abstract: Several members of the CLC family of Cl- channels and transporters are expressed in vesicles of the endocytotic-lysosomal pathway, all of which are acidified by V-type proton pumps. These CLC proteins are thought to facilitate vesicular acidification by neutralizing the electric current of the H+-ATPase. Indeed, the disruption of ClC-5 impaired the acidification of endosomes, and the knock-out (KO) of ClC-3 that of endosomes and synaptic vesicles. KO mice are available for all vesicular CLCs (ClC-3 to ClC-7), and ClC-5 and ClC-7, as well as its beta-subunit Ostm1, are mutated in human disease. The associated mouse and human pathologies, ranging from impaired endocytosis and nephrolithiasis (ClC-5) to neurodegeneration (ClC-3), lysosomal storage disease (ClC-6, ClC-7/Ostm1) and osteopetrosis (ClC-7/Ostm1), were crucial in identifying the physiological roles of vesicular CLCs. Whereas the intracellular localization of ClC-6 and ClC-7/Ostm1 precluded biophysical studies, the partial expression of ClC-4 and -5 at the cell surface allowed the detection of strongly outwardly rectifying currents that depended on anions and pH. Surprisingly, ClC-4 and ClC-5 (and probably ClC-3) do not function as Cl- channels, but rather as electrogenic Cl--H+ exchangers. This hints at an important role for luminal chloride in the endosomal-lysosomal system.
authors.affiliation: FMP/MDC, Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Zentrum für Molekulare Medizin, Robert-Rössle Strasse 10, D-13125 Berlin, FRG. jentsch@fmp-berlin.de
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D017920:Antiporters / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D011992:Endosomes / Q000502:physiology*; D006801:Humans; D007669:Kidney Calculi / Q000209:etiology; D016464:Lysosomal Storage Diseases / Q000209:etiology; D008247:Lysosomes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000209:etiology; D010022:Osteopetrosis / Q000209:etiology; D006180:Proton-Translocating ATPases / Q000502:physiology
chemical_list: D017920:Antiporters; D018118:Chloride Channels; D002712:Chlorides; D006180:Proton-Translocating ATPases