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J. Biol. Chem., Vol. 280, Issue 35, 30760-30767, September 2, 2005

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Long Chain CoA Esters as Competitive Antagonists of Phosphatidylinositol 4,5-Bisphosphate Activation in Kir Channels^*

Markus Rapedius, Malle Soom, Ekaterina Shumilina, Dirk Schulze, Roland Schönherr¶, Cornelia Kirsch||, Florian Lang, Stephen J. Tucker**, and Thomas Baukrowitz

From the Institute of Physiology II, Friedrich Schiller University Jena, Teichgraben 8, 07743 Jena, Germany, the Department of Physiology I, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany, the ^¶Molecular and Cellular Biophysics, Friedrich Schiller University Jena, Drackendorfer Strasse 1, 07747 Germany, the ^||Institute for Biochemistry, Friedrich Schiller University Jena, Nonnenplan 2, 07743 Jena, Germany, and the ^**Oxford Centre for Gene Function, University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, United Kingdom

Long chain fatty acid esters of coenzyme A (LC-CoA) are potent activators of ATP-sensitive (K_ATP) channels, and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP₂), which activates all known inwardly rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterized. In this study, we show that in contrast to their stimulatory effect on K_ATP channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, while both its activatory and inhibitory effects critically depend on the presence of the 3'-ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP₂ and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2 and that PIP₂ binding can be competitively antagonized by LC-CoA, suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP₂. Furthermore, we demonstrate that in contrast to its stimulatory effect on K_ATP channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of Kir channel activity by LC-CoA and phosphoinositides and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity.

Received for publication, March 31, 2005 , and in revised form, June 10, 2005.

^* This work was supported in part by Deutsche Forschungsgemeinschaft Grant Ba 1793/4-1 (to T. B.). 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.

A Royal Society University Research Fellow.

To whom correspondence should be addressed: Inst. of Physiology II, Friedrich Schiller University Jena, Teichgraben 8, 07743 Jena, Germany. Tel.: 49-3641-938860; Fax: 49-3641-933202; E-mail: thbau{at}mti.uni-jena.de.

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