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J. Biol. Chem., Vol. 282, Issue 10, 7442-7449, March 9, 2007

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Modulation of the Pancreatic Islet -Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate^*

David A. Jacobson¹, Christopher R. Weber, Shunzhong Bao^¶, John Turk^¶, and Louis H. Philipson²

From the Department of Medicine, University of Chicago, Chicago, Illinois 60637, the Department of Pathology, University of Chicago, Chicago, Illinois 60637, and the ^¶Medicine Department Mass Spectrometry Facility and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110

Glucose stimulates both insulin secretion and hydrolysis of arachidonic acid (AA) esterified in membrane phospholipids of pancreatic islet -cells, and these processes are amplified by muscarinic agonists. Here we demonstrate that nonesterified AA regulates the biophysical activity of the pancreatic islet -cell-delayed rectifier channel, Kv2.1. Recordings of Kv2.1 currents from INS-1 insulinoma cells incubated with AA (5 µM) and subjected to graded degrees of depolarization exhibit a significantly shorter time-to-peak current interval than do control cells. AA causes a rapid decay and reduced peak conductance of delayed rectifier currents from INS-1 cells and from primary -cells isolated from mouse, rat, and human pancreatic islets. Stimulating mouse islets with AA results in a significant increase in the frequency of glucose-induced [Ca²⁺] oscillations, which is an expected effect of Kv2.1 channel blockade. Stimulation with concentrations of glucose and carbachol that accelerate hydrolysis of endogenous AA from islet phosphoplipids also results in accelerated Kv2.1 inactivation and a shorter time-to-peak current interval. Group VIA phospholipase A₂ (iPLA₂) hydrolyzes -cell membrane phospholipids to release nonesterified fatty acids, including AA, and inhibiting iPLA₂ prevents the muscarinic agonist-induced accelerated Kv2.1 inactivation. Furthermore, glucose and carbachol do not significantly affect Kv2.1 inactivation in -cells from iPLA₂^-/- mice. Stably transfected INS-1 cells that overexpress iPLA₂ hydrolyze phospholipids more rapidly than control INS-1 cells and also exhibit an increase in the inactivation rate of the delayed rectifier currents. These results suggest that Kv2.1 currents could be dynamically modulated in the pancreatic islet -cell by phospholipase-catalyzed hydrolysis of membrane phospholipids to yield non-esterified fatty acids, such as AA, that facilitate Ca²⁺ entry and insulin secretion.

Received for publication, August 16, 2006 , and in revised form, December 26, 2006.

^* This work was supported in part by National Institutes of Health Grants DK44840, DK48494, DK63493, and DK20595; United States Public Health Service Grants R37-DK34388, P60-DK20579, and P30-DK56341; the Diabetes Research and Training Center at the University of Chicago; and the Blum-Kovler Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported in part by an American Diabetes Association Mentor-based fellowship and the Cardiovascular Pathophysiology and Biochemistry Training Program from the National Institutes of Health (NHLBI/National Institutes of Health Grant 5T32 HL07237).

² To whom correspondence should be addressed. Tel.: 773-702-1661; Fax: 773-834-0851; E-mail: l-philipson{at}uchicago.edu.

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