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Activation of Adenosine Triphosphate-Sensitive Potassium Channels by Acyl Coenzyme A Esters Involves Multiple Phosphatidylinositol 4,5-Bisphosphate-Interacting Residues

Department of Pharmacology, University of Alberta (J.E.M.F., P.E.L.), Edmonton, Alberta, Canada T6G 2H7; and Department of Cell Biology and Physiology, Washington University School of Medicine (C.G.N.), St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. Jocelyn Manning Fox, 9-58 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. E-mail: jmanningfox{at}pmcol.ualberta.ca.

ATP-sensitive potassium (K_ATP) channels are crucial to pancreatic endocrine function and their activation by acyl coenzyme A esters (acyl CoAs) may disrupt hormone secretion, contributing to the pathophysiology of type 2 diabetes. The molecular mechanism of this activation is potentially important in our further understanding of this disease. We use excised patch-clamp techniques to assess the effects of N- and C-terminal Kir6.2 mutations on the activation of recombinant K_ATP channels by palmitoyl CoA. We demonstrate that several residues previously shown to be involved in channel activation by the structurally related lipid phosphatidylinositol 4,5-bisphosphate (PIP₂) also play a role in activation by acyl CoAs, including R54, R176, R192, and R301. Mutation of these residues caused decreased open probability in the absence of ATP and slower and greater relative activation by both PIP₂ and acyl CoAs. By contrast, K185Q, which probably alters ATP binding, had no effect on either PIP₂ or palmitoyl CoA activation. These findings suggest that activation by the two classes of lipids involves multiple common residues. We use the crystal structure of a related channel, KirBac1.1, as a template to locate the residues of interest in this study within a putative three-dimensional model of Kir6.2. We propose a model in which these residues mediate both direct electrostatic interactions and allosteric modulations of open state stability.

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