Gx. Liu et al., Long-chain acyl-coenzyme A esters and fatty acids directly link metabolismto K-ATP channels in the heart, CIRCUL RES, 88(9), 2001, pp. 918-924
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 i
n cardiac muscle cells. Long-chain (LC) acyl-coenzyme A (CoA) esters are sy
nthesized 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 fatt
y acids on K-ATP channels of isolated guinea pig ventricular myocytes and c
ompared them with the effects of phosphatidylinositol 4,5-bisphosphate (PIP
2). Application of oleoyl-CoA (0.2 or 1 mu mol/L), a naturally occurring ac
yl-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 voltag
e dependent, increasing with depolarization. Oleoyl-CoA greatly reduced the
ATP sensitivity of K-ATP channels. At a concentration of 2 mu mol/L, oleoy
l-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.