[摘要]：Mutations in the CIC-7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated CIC-7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 beta-subunit are required for CIC-7 CI-/H+-exchange, whereas the Ostm1 transmembrane domain suffices for its CIC-7-dependent trafficking to lysosomes. CIC-7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2CI(-)/1H(+)-exchange stoichiometry. Several disease-causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine-beta-synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers. The EMBO Journal (2011) 30, 2140-2152. doi:10.1038/emboj.2011.137; Published online 28 April 2011
