Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.
Eukaryotic members of the CLC gene family function as plasma membrane chloride channels, or may provide neutralizing anion currents for V-type H(+)-ATPases that acidify compartments of the endosomal/lysosomal pathway. Loss-of-function mutations in the endosomal protein ClC-5 impair renal endocytosis and lead to kidney stones, whereas loss of function of the endosomal/lysosomal protein ClC-7 entails osteopetrosis and lysosomal storage disease. Vesicular CLCs have been thought to be Cl- channels, in particular because ClC-4 and ClC-5 mediate plasma membrane Cl- currents upon heterologous expression. Here we show that these two mainly endosomal CLC proteins instead function as electrogenic Cl-/H+ exchangers (also called antiporters), resembling the transport activity of the bacterial protein ClC-e1, the crystal structure of which has already been determined. Neutralization of a critical glutamate residue not only abolished the steep voltage-dependence of transport, but also eliminated the coupling of anion flux to proton counter-transport. ClC-4 and ClC-5 may still compensate the charge accumulation by endosomal proton pumps, but are expected to couple directly vesicular pH gradients to Cl- gradients.
Scheel
Olaf
O
Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20246 Hamburg, Germany.
Zdebik
Anselm A
AA
Lourdel
Stéphane
S
Jentsch
Thomas J
TJ
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D004553:Electric Conductivity; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D017136:Ion Transport; D008564:Membrane Potentials; D020125:Mutation, Missense / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011522:Protons; D014101:Torpedo; D014981:Xenopus
D017920:Antiporters; D001426:Bacterial Proteins; C097503:CLC-5 chloride channel; D018118:Chloride Channels; D002712:Chlorides; D011522:Protons