CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl À concentration. Disruption of endosomal ClC-3 causes severe neurodegeneration. To assess the importance of ClC-3 Cl À /H + exchange, we now generate Clcn3 unc/unc mice in which ClC-3 is converted into a Cl À channel. Unlike Clcn3 À/À mice, Clcn3 unc/unc mice appear normal owing to compensation by ClC-4 with which ClC-3 forms heteromers. ClC-4 protein levels are strongly reduced in Clcn3 À/À , but not in Clcn3 unc/unc mice because ClC-3 unc binds and stabilizes ClC-4 like wild-type ClC-3. Although mice lacking ClC-4 appear healthy, its absence in Clcn3 unc/unc /Clcn4 À/À mice entails even stronger neurodegeneration than observed in Clcn3 À/À mice. A fraction of ClC-3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3 unc/unc or Clcn3 À/À mice before neurodegeneration sets in. Both, Cl À /H + -exchange activity and the stabilizing effect on ClC-4, are central to the biological function of ClC-3.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.