Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits.
The acid-sensing ion channel-1a (ASIC1a) is composed of 3 subunits and is activated by a decrease 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 inter-subunit disulfide bonds and the oxidant H(2)O(2) increased this link between subunits. Cys-495 in the ASIC1a C terminus was particularly important for inter-subunit disulfide bond formation, although other C-terminal cysteines contributed. Inter-subunit disulfide bonds also produced some ASIC1a complexes larger than trimers. Inter-subunit disulfide bond formation reduced the proportion of ASIC1a located on the cell surface and contributed to the H(2)O(2)-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.
Zha
Xiang-ming
XM
Howard Hughes Medical Institute and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Wang
Runping
R
Collier
Dan M
DM
Snyder
Peter M
PM
Wemmie
John A
JA
Welsh
Michael J
MJ
D062565:Acid Sensing Ion Channels; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004220:Disulfides / Q000378:metabolism*; D005260:Female; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D055503:Protein Multimerization; D021122:Protein Subunits / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D014982:Xenopus laevis
D062565:Acid Sensing Ion Channels; D004220:Disulfides; D009419:Nerve Tissue Proteins; D016877:Oxidants; D021122:Protein Subunits; D015222:Sodium Channels