ATP-sensitive potassium channelopathies: focus on insulin secretion
Frances M. Ashcroft
Frances M. Ashcroft
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2047-2058. https://doi.org/10.1172/JCI25495.
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ATP-sensitive potassium channelopathies: focus on insulin secretion

Abstract

ATP-sensitive potassium (KATP) channels, so named because they are inhibited by intracellular ATP, play key physiological roles in many tissues. In pancreatic β cells, these channels regulate glucose-dependent insulin secretion and serve as the target for sulfonylurea drugs used to treat type 2 diabetes. This review focuses on insulin secretory disorders, such as congenital hyperinsulinemia and neonatal diabetes, that result from mutations in KATP channel genes. It also considers the extent to which defective regulation of KATP channel activity contributes to the etiology of type 2 diabetes.

Authors

Frances M. Ashcroft

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Figure 3

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Location of disease-causing mutations in Kir6.2. (A) Structural model of...
Location of disease-causing mutations in Kir6.2. (A) Structural model of Kir6.2 (116) viewed from the side. For clarity, only 2 transmembrane domains, and 2 separate cytosolic domains, are shown. Residues mutated in neonatal diabetes are shown in red, and those that cause hyperinsulinism of infancy in blue. ATP (green) is docked into its binding site. Of the residues implicated in neonatal diabetes, R50, R201, Y330C, and F333I lie close to the ATP-binding site; F35, C42, and E332K at the interface between Kir6.2 subunits; Q52 and G53 in a region postulated to interface with SUR1; and V59, C166, and I296L within regions of the channel involved in gating. (B) Close-up of the putative ATP-binding site with residues lying within 3.5 Å of ATP indicated. Residues mutated in neonatal diabetes are shown in red. Part B is adapted with permission from The EMBO Journal (116).