Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits

Xiang-ming Zha; Runping Wang; Dan M Collier; Peter M Snyder; John A Wemmie; Michael J Welsh

doi:10.1073/pnas.0813402106

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Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits

Journal article

Open access

Peer reviewed

Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits

Xiang-ming Zha, Runping Wang, Dan M Collier, Peter M Snyder, John A Wemmie and Michael J Welsh

Proceedings of the National Academy of Sciences - PNAS, Vol.106(9), pp.3573-3578

03/03/2009

DOI: 10.1073/pnas.0813402106

PMCID: PMC2642663

PMID: 19218436

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Abstract

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.

Disulfides - metabolism

Cricetinae

Oxidants - pharmacology

Acid Sensing Ion Channels

Protein Multimerization

Xenopus laevis

Mutation - genetics

Protein Subunits - metabolism

Nerve Tissue Proteins - metabolism

Animals

Oxidation-Reduction - drug effects

Sodium Channels - metabolism

Female

Cell Membrane - metabolism

Details

Title: Subtitle: Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits
Creators: Xiang-ming Zha - 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
Runping Wang
Dan M Collier
Peter M Snyder
John A Wemmie
Michael J Welsh
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.106(9), pp.3573-3578
DOI: 10.1073/pnas.0813402106
PMID: 19218436
PMCID: PMC2642663
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: P01 HL051670 / NHLBI NIH HHS HL51670 / NHLBI NIH HHS Howard Hughes Medical Institute P30 DK054759 / NIDDK NIH HHS DK54759 / NIDDK NIH HHS R01 HL072256 / NHLBI NIH HHS
Language: English
Date published: 03/03/2009
Academic Unit: Neurology; Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute; Neurosurgery; Medicine Administration; Internal Medicine
Record Identifier: 9984003477502771

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