Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters

J Physiol. 2007 Feb 1;578(Pt 3):633-40. doi: 10.1113/jphysiol.2006.124719. Epub 2006 Nov 16.


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.

Publication types

  • Lecture
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiporters / physiology
  • Chloride Channels / physiology*
  • Chlorides / metabolism*
  • Endosomes / physiology*
  • Humans
  • Kidney Calculi / etiology
  • Lysosomal Storage Diseases / etiology
  • Lysosomes / physiology*
  • Mice
  • Mice, Knockout
  • Neurodegenerative Diseases / etiology
  • Osteopetrosis / etiology
  • Proton-Translocating ATPases / physiology


  • Antiporters
  • Chloride Channels
  • Chlorides
  • Proton-Translocating ATPases