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J. Biol. Chem., Vol. 279, Issue 45, 47125-47131, November 5, 2004

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Syntaxin-1A Inhibits Cardiac K_ATP Channels by Its Actions on Nucleotide Binding Folds 1 and 2 of Sulfonylurea Receptor 2A^*

Youhou Kang, Yuk-Man Leung¶, Jocelyn E. Manning-Fox||, Fuzhen Xia, Huanli Xie, Laura Sheu, Robert G. Tsushima**, Peter E. Light, and Herbert Y. Gaisano¶¶||

From the Departments of Medicine and Physiology, University of Toronto, Toronto M5S 1A8, Canada and the Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

ATP-sensitive potassium (K_ATP) channels couple the metabolic status of the cell to its membrane potential to regulate a number of cell actions, including secretion (neurons and neuroendocrine cells) and muscle contractility (skeletal, cardiac, and vascular smooth muscle). K_ATP channels consist of regulatory sulfonylurea receptors (SUR) and pore-forming (Kir6.X) subunits. We recently reported (Pasyk, E. A., Kang, Y., Huang, X., Cui, N., Sheu, L., and Gaisano, H. Y. (2004) J. Biol. Chem. 279, 4234–4240) that syntaxin-1A (Syn-1A), known to mediate exocytotic fusion, was capable of binding the nucleotide binding folds (NBF1 and C-terminal NBF2) of SUR1 to inhibit the K_ATP channels in insulin-secreting pancreatic islet beta cells. This prompted us to examine whether Syn-1A might modulate cardiac SUR2A/K_ATP channels. Here, we show that Syn-1A is present in the plasma membrane of rat cardiac myocytes and binds the SUR2A protein (of rat brain, heart, and human embryonic kidney 293 cells expressing SUR2A/Kir6. 2) at its NBF1 and NBF2 domains to decrease K_ATP channel activation. Unlike islet beta cells, in which Syn-1A inhibition of the channel activity was apparently mediated only via NBF1 and not NBF2 of SUR1, both exogenous recombinant NBF1 and NBF2 of SUR2A were found to abolish the inhibitory actions of Syn-1A on K_ATP channels in rat cardiac myocytes and HEK293 cells expressing SUR2A/Kir6.2. Together with our recent report, this study suggests that Syn-1A binds both NBFs of SUR1 and SUR2A but appears to exhibit distinct interactions with NBF2 of these SUR proteins in modulating the K_ATP channels in islet beta cells and cardiac myocytes.

Received for publication, May 4, 2004 , and in revised form, August 20, 2004.

^* This work was supported by grants from the Juvenile Diabetes Research Foundation Grant 1-2001-521 (to H. Y. G.), Canadian Institutes for Health Research (CIHR) Grants MOP-69083 and PPP-52103 (to H. Y. G.), Canadian Association of Gastroenterology Gastroenterology/Abbott Laboratories/CIHR Grant DOP-68570 (to H. Y. G.), and the Canadian Diabetes Association (to P. E. L.). 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.

These authors contributed equally to this work.

^¶ Supported by a fellowship from the Canadian Diabetes Association.

^|| Supported by a fellowship from the Alberta Heritage Foundation for Medical Research (AHFMR).

^** Supported by a New Investigator Award from the Heart and Stroke Foundation of Canada.

AHFMR scholar and CIHR new investigator.

^¶¶ To whom correspondence should be addressed: Rm. 7226, Medical Science Bldg., University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-1526; Fax: 416-978-8765; E-mail: Herbert.gaisano{at}utoronto.ca.

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