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(Circulation Research. 2001;88:918.)
© 2001 American Heart Association, Inc.

Cellular Biology

Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to K_ATP Channels in the Heart

Gong Xin Liu, Peter J. Hanley, John Ray, ürgen Daut;

From the Institute of Physiology, Marburg University, Marburg, Germany.

Correspondence to Prof Jürgen Daut, Institute of Physiology, Marburg University, Deutschhausstrasse 2, 35037 Marburg, Germany. E-mail daut{at}mailer.uni-marburg.de

Abstract—ATP-sensitive K (K_ATP) channels are inhibited by cytosolic ATP, a defining property that implicitly links these channels to cellular metabolism. Here we report a direct link between fatty acid metabolism and K_ATP channels in cardiac muscle cells. Long-chain (LC) acyl–coenzyme A (CoA) esters are synthesized from fatty acids and serve as the principal metabolic substrates of the heart. We have studied the effects of LC acyl-CoA esters and LC fatty acids on K_ATP channels of isolated guinea pig ventricular myocytes and compared them with the effects of phosphatidylinositol 4,5-bisphosphate (PIP₂). Application of oleoyl-CoA (0.2 or 1 µmol/L), a naturally occurring acyl-CoA ester, to the cytosolic side of excised patches completely prevented rundown of K_ATP channels, but not of Kir2 channels. The open probability of K_ATP channels measured in the presence of oleoyl-CoA or PIP₂ was voltage dependent, increasing with depolarization. Oleoyl-CoA greatly reduced the ATP sensitivity of K_ATP channels. At a concentration of 2 µmol/L, oleoyl-CoA increased the half-maximal inhibitory concentration of ATP >200-fold. The time course of the decrease in ATP sensitivity was much faster during application of oleoyl-CoA than during application of PIP₂. The effects of PIP₂, but not of oleoyl-CoA, were inhibited by increasing Ca²⁺ to 1 mmol/L. Oleate (C18:1; 10 µmol/L), the precursor of oleoyl-CoA, inhibited K_ATP channels activated by oleoyl-CoA. Palmitoleoyl-CoA and palmitoleate (C16:1) exerted similar reciprocal effects. These findings indicate that LC fatty acids and their CoA-linked derivatives may be key physiological modulators of K_ATP channel activity in the heart.

Key Words: free fatty acids • acyl-CoA esters • PIP₂ • K_ATP channels

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