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This version published online on December 23, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0431
A more recent version of this article appeared on March 1, 2004
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Submitted on November 5, 2003
Accepted on December 16, 2003

Activation of ATP-sensitive potassium channels by acyl CoAs involves multiple PIP2-interacting residues

Jocelyn E. Manning Fox1*, Colin G. Nichols1, and Peter E. Light1

1 Department of Pharmacology, University of Alberta, Edmonton T6G 2H7, Canada; and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

* To whom correspondence should be addressed. E-mail: jmanningfox{at}pmcol.ualberta.ca.

ATP-sensitive potassium (KATP) channels are crucial to pancreatic endocrine function and their activation by 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-terminus Kir6.2 mutations on the activation of recombinant KATP channels by palmitoyl CoA. We demonstrate that several residues previously shown to be involved in channel activation by the structurally related lipid 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 likely alters ATP binding, had no effect on either PIP2 or palmitoyl CoA activation. These findings suggest 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 3D model of Kir6.2. We propose a model in which these residues mediate both direct electrostatic interactions and allosteric modulations of open state stability.
Key words: KATP channel • acyl CoA • PIP2 • diabetes • {beta}-cell • metabolism




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