Long-chain acyl-coenzyme A esters and fatty acids directly link metabolism to KATP channels in the heart

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 mu mol/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 mu mol/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 mu mol/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.