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

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Abstract
—ATP-sensitive K (KATP) 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 KATP 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 KATP 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 KATP channels, but not of Kir2 channels. The open probability of KATP channels measured in the presence of oleoyl-CoA or PIP2 was voltage dependent, increasing with depolarization. Oleoyl-CoA greatly reduced the ATP sensitivity of KATP 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 KATP 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 KATP channel activity in the heart.