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Originally published In Press as doi:10.1074/jbc.M407708200 on October 7, 2004

J. Biol. Chem., Vol. 279, Issue 51, 53886-53891, December 17, 2004
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Stomatin Modulates Gating of Acid-sensing Ion Channels*

Margaret P. Price{ddagger}, Robert J. Thompson{ddagger}§, Jayasheel O. Eshcol{ddagger}, John A. Wemmie§, and Christopher J. Benson{ddagger}||

From the Departments of {ddagger}Internal Medicine and Psychiatry and the §Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52242

Acid-sensing ion channels (ASICs) are H+-gated members of the degenerin/epithelial Na+ channel (DEG/ENaC) family in vertebrate neurons. Several ASICs are expressed in sensory neurons, where they play a role in responses to nociceptive, taste, and mechanical stimuli; others are expressed in central neurons, where they participate in synaptic plasticity and some forms of learning. Stomatin is an integral membrane protein found in lipid/protein-rich microdomains, and it is believed to regulate the function of ion channels and transporters. In Caenorhabditis elegans, stomatin homologs interact with DEG/ENaC channels, which together are necessary for normal mechanosensation in the worm. Therefore, we asked whether stomatin interacts with and modulates the function of ASICs. We found that stomatin co-immunoprecipitated and co-localized with ASIC proteins in heterologous cells. Moreover, stomatin altered the function of ASIC channels. Stomatin potently reduced acid-evoked currents generated by ASIC3 without changing steady state protein levels or the amount of ASIC3 expressed at the cell surface. In contrast, stomatin accelerated the desensitization rate of ASIC2 and heteromeric ASICs, whereas current amplitude was unaffected. These data suggest that stomatin binds to and alters the gating of ASICs. Our findings indicate that modulation of DEG/ENaC channels by stomatin-like proteins is evolutionarily conserved and may have important implications for mammalian nociception and mechanosensation.


Received for publication, July 9, 2004 , and in revised form, September 20, 2004.

* This work was supported by NHLBI, National Institutes of Health Grant HL04349 (to C. J. B.) and by a Veterans Affairs Research Career Development Award and the Howard Hughes Medical Institute Biomedical Research Support Program (to J. A. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Internal Medicine, 200 Hawkins Dr., E314-1 GH, Iowa City, IA 52242-1009. Tel.: 319-356-7031; Fax: 319-353-6343; E-mail: chris-benson{at}uiowa.edu.


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