ClC-7 is a lysosomal 2 Cl−/1 H+ antiporter of the CLC protein family, which comprises Cl− channels and other Cl−/H+ antiporters. Mutations in ClC-7 and its associated β subunit Ostm1 lead to osteopetrosis and lysosomal storage disease in humans and mice. Previous studies on other mammalian CLC transporters showed that mutations of a conserved, intracellularly located glutamate residue, the so-called proton glutamate, abolish steady-state transport activity but increase transient capacitive currents associated with partial reactions of the transport cycle. In contrast, we observed large, transient capacitive currents for the wild-type ClC-7, which depend on external pH and internal, but not external, Cl−. Very similar transient currents were observed for the E312A mutant of the proton glutamate. Interestingly, and unlike in other mammalian CLC transporters investigated so far, the E312A mutation strongly reduces, but does not abolish, stationary transport currents, potentially explaining the intermediate phenotype observed in the E312A mouse line.
Large transient capacitive currents in wild-type lysosomal Cl−/H+ antiporter ClC-7 and residual transport activity in the proton glutamate mutant E312A
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Michael Pusch, Giovanni Zifarelli; Large transient capacitive currents in wild-type lysosomal Cl−/H+ antiporter ClC-7 and residual transport activity in the proton glutamate mutant E312A. J Gen Physiol 4 January 2021; 153 (1): e202012583. doi: https://doi.org/10.1085/jgp.202012583
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