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J. Biol. Chem., Vol. 280, Issue 10, 8793-8799, March 11, 2005

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Two SUR1-specific Histidine Residues Mandatory for Zinc-induced Activation of the Rat K_ATP Channel^*

Victor Bancila, Thierry Cens, Dominique Monnier, Frédéric Chanson, Cécile Faure¶, Yves Dunant, and Alain Bloc||

From the Neurosciences Fondamentales, CMU, 1 rue Michel Servet, 1211 Genève 04, Switzerland, the CRBM, CNRS FRE 2593, 34293 Montpellier Cedex 05, France, and the ^¶Synthélabo Recherche, 10 rue des Carrières, B.P. 248, 92504 Rueil Malmaison Cedex, France

Zinc at micromolar concentrations hyperpolarizes rat pancreatic -cells and brain nerve terminals by activating ATP-sensitive potassium channels (K_ATP). The molecular determinants of this effect were analyzed using insulinoma cell lines and cells transfected with either wild type or mutated K_ATP subunits. Zinc activated K_ATP in cells co-expressing rat Kir6.2 and SUR1 subunits, as in insulinoma cell lines. In contrast, zinc exerted an inhibitory action on SUR2A-containing cells. Therefore, SUR1 expression is required for the activating action of zinc, which also depended on extracellular pH and was blocked by diethyl pyrocarbonate, suggesting histidine involvement. The five SUR1-specific extracellular histidine residues were submitted to site-directed mutagenesis. Of them, two histidines (His-326 and His-332) were found to be critical for the activation of K_ATP by zinc, as confirmed by the double mutation H326A/H332A. In conclusion, zinc activates K_ATP by binding itself to extracellular His-326 and His-332 of the SUR1 subunit. Thereby zinc could exert a negative control on cell excitability and secretion process of pancreatic -and -cells. In fact, we have recently shown that such a mechanism occurs in hippocampal mossy fibers, a brain region characterized, like the pancreas, by an important accumulation of zinc and a high density of SUR1-containing K_ATP.

Received for publication, November 29, 2004 , and in revised form, December 14, 2004.

^* This work was supported by Swiss Fonds National pour la Recherche Scientifique (FNRS) Grants 31-057135.99 (to Y. D. and A. B.) and the European Union project Lipidiet (QLK1-CT-2002-00172). 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: DBCM, Université de Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland. Tel.: 41-21-692-5284; Fax: 41-21-692-5105; E-mail: Alain.Bloc{at}unil.ch.

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