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J. Biol. Chem., Vol. 281, Issue 5, 3006-3012, February 3, 2006

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A Novel KCNJ11 Mutation Associated with Congenital Hyperinsulinism Reduces the Intrinsic Open Probability of -Cell ATP-sensitive Potassium Channels^*

Yu-Wen Lin, Courtney MacMullen, Arupa Ganguly, Charles A. Stanley¹, and Show-Ling Shyng²

From the Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97239 and Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

The -cell ATP-sensitive potassium (K_ATP) channel controls insulin secretion by linking glucose metabolism to membrane excitability. Loss of K_ATP channel function due to mutations in ABCC8 or KCNJ11, genes that encode the sulfonylurea receptor 1 or the inward rectifier Kir6.2 subunit of the channel, is a major cause of congenital hyperinsulinism. Here, we report identification of a novel KCNJ11 mutation associated with the disease that renders a missense mutation, F55L, in the Kir6.2 protein. Mutant channels reconstituted in COS cells exhibited a wild-type-like surface expression level and normal sensitivity to ATP, MgADP, and diazoxide. However, the intrinsic open probability of the mutant channel was greatly reduced, by 10-fold. This low open probability defect could be reversed by application of phosphatidylinositol 4,5-bisphosphates or oleoyl-CoA to the cytoplasmic face of the channel, indicating that reduced channel response to membrane phospholipids and/or long chain acyl-CoAs underlies the low intrinsic open probability in the mutant. Our findings reveal a novel molecular mechanism for loss of K_ATP channel function and congenital hyperinsulinism and support the importance of phospholipids and/or long chain acyl-CoAs in setting the physiological activity of -cell K_ATP channels. The F55L mutation is located in the slide helix of Kir6.2. Several permanent neonatal diabetes-associated mutations found in the same structure have the opposite effect of increasing intrinsic channel open probability. Our results also highlight the critical role of the Kir6.2 slide helix in determining the intrinsic open probability of K_ATP channels.

Received for publication, November 3, 2005 , and in revised form, December 5, 2005.

^* This work was supported by National Institutes of Health Grants R01DK57699 and DK66485 (to S.-L. S.) and R01DK56268 and 5-MO1-RR-000240 (to C. A. S.) and a predoctoral fellowship from the American Heart Association (to Y.-W. 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.

¹ To whom correspondence may be addressed: Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, 34th St. and Civic Center Boulevard, Philadelphia, PA 19104. Tel.: 215-590-3421; Fax: 215-590-3053; E-mail: stanleyc{at}email.chop.edu.

² To whom correspondence may be addressed: Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, 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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