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J. Biol. Chem., Vol. 281, Issue 44, 33403-33413, November 3, 2006

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Sulfonylureas Correct Trafficking Defects of Disease-causing ATP-sensitive Potassium Channels by Binding to the Channel Complex^*

From the Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97239

ATP-sensitive potassium (K_ATP) channels mediate glucose-induced insulin secretion by coupling metabolic signals to -cell membrane potential and the secretory machinery. Reduced K_ATP channel expression caused by mutations in the channel proteins: sulfonylurea receptor 1 (SUR1) and Kir6.2, results in loss of channel function as seen in congenital hyperinsulinism. Previously, we reported that sulfonylureas, oral hypoglycemic drugs widely used to treat type II diabetes, correct the endoplasmic reticulum to the plasma membrane trafficking defect caused by two SUR1 mutations, A116P and V187D. In this study, we investigated the mechanism by which sulfonylureas rescue these mutants. We found that glinides, another class of SUR-binding hypoglycemic drugs, also markedly increased surface expression of the trafficking mutants. Attenuating or abolishing the ability of mutant SUR1 to bind sulfonylureas or glinides by the following mutations: Y230A, S1238Y, or both, accordingly diminished the rescuing effects of the drugs. Interestingly, rescue of the trafficking defects requires mutant SUR1 to be co-expressed with Kir6.2, suggesting that the channel complex, rather than SUR1 alone, is the drug target. Observations that sulfonylureas also reverse trafficking defects caused by neonatal diabetes-associated Kir6.2 mutations in a way that is dependent on intact sulfonylurea binding sites in SUR1 further support this notion. Our results provide insight into the mechanistic and structural basis on which sulfonylureas rescue K_ATP channel surface expression defects caused by channel mutations.

Received for publication, May 31, 2006 , and in revised form, August 31, 2006.

^* This work was supported by National Institutes of Health Grant DK57699 (to S.-L. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed: 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-2694; Fax: 503-494-3849; E-mail: shyngs{at}ohsu.edu.

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