Abstract
The acid‐sensing ion channel‐1a (ASIC1a) is composed of three subunits and is activated by a fall in extracellular pH. It plays an important role in diseases associated with a reduced pH and production of oxidants. Previous work showed that oxidants reduce ASIC1a currents. However, the effects on channel structure and composition are unknown. We found that ASIC1a formed intersubunit disulfide bonds and the oxidant H2O2 increased this link between subunits. Cys495 in the ASIC1a C‐terminus was particularly important for intersubunit disulfide bond formation, although other C‐terminal cysteines contributed. Intersubunit disulfide bonds produced some ASIC1a complexes larger than trimers. Intersubunit disulfide bond formation also reduced the proportion of ASIC1a located on the cell surface and contributed to the H2O2‐induced decrease in H+‐gated current. These results indicate that channel function is controlled by disulfide bond formation between intracellular residues on distinct ASIC1a subunits. They also suggest a mechanism by which the redox state can dynamically regulate membrane protein activity by forming intracellular bridges.
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