title: Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis.
abstract: Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent's disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl-)/proton (H+) exchanger rather than a Cl- channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl- conductor. Adenosine triphosphate (ATP)-dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5(unc) mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H+-ATPase, may play a role in endocytosis.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13125 Berlin, Germany.
authors.forename: Gaia
authors.initials: G
authors.lastname: Novarino
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weinert
authors.forename: Gesa
authors.initials: G
authors.lastname: Rickheit
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007674:Kidney Diseases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011522:Protons
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D002712:Chlorides; D050505:Mutant Proteins; D011522:Protons; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases