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J. Biol. Chem., Vol. 283, Issue 14, 9146-9156, April 4, 2008

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Destabilization of ATP-sensitive Potassium Channel Activity by Novel KCNJ11 Mutations Identified in Congenital Hyperinsulinism^*

Yu-Wen Lin, Jeremy D. Bushman, Fei-Fei Yan, Sara Haidar, Courtney MacMullen, Arupa Ganguly^¶, Charles A. Stanley, and Show-Ling Shyng¹

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

The inwardly rectifying potassium channel Kir6.2 is the pore-forming subunit of the ATP-sensitive potassium (K_ATP) channel, which controls insulin secretion by coupling glucose metabolism to membrane potential in β-cells. Loss of channel function because of mutations in Kir6.2 or its associated regulatory subunit, sulfonylurea receptor 1, causes congenital hyperinsulinism (CHI), a neonatal disease characterized by persistent insulin secretion despite severe hypoglycemia. Here, we report a novel K_ATP channel gating defect caused by CHI-associated Kir6.2 mutations at arginine 301 (to cysteine, glycine, histidine, or proline). These mutations in addition to reducing channel expression at the cell surface also cause rapid, spontaneous current decay, a gating defect we refer to as inactivation. Based on the crystal structures of Kir3.1 and KirBac1.1, Arg-301 interacts with several residues in the neighboring Kir6.2 subunit. Mutation of a subset of these residues also induces channel inactivation, suggesting that the disease mutations may cause inactivation by disrupting subunit-subunit interactions. To evaluate the effect of channel inactivation on β-cell function, we expressed an alternative inactivation mutant R301A, which has equivalent surface expression efficiency as wild type channels, in the insulin-secreting cell line INS-1. Mutant expression resulted in more depolarized membrane potential and elevated insulin secretion at basal glucose concentration (3 mM) compared with cells expressing wild type channels, demonstrating that the inactivation gating defect itself is sufficient to cause loss of channel function and hyperinsulinism. Our studies suggest the importance of Kir6.2 subunit-subunit interactions in K_ATP channel gating and function and reveal a novel gating defect underlying CHI.

Received for publication, October 24, 2007 , and in revised form, January 24, 2008.

^* This work was supported by National Institutes of Health Grants R01DK66485 (to S.-L. S.) and 2R01DK56268-07, UL1 RR024134, and 2R01DK53012-09 (to C. A. 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.

¹ To whom correspondence should 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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