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 β‐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.