Alteration of the membrane lipid environment by L-palmitoylcarnitine modulates KATP channels in guinea-pig ventricular myocytes

Sarcolemmal adenosine 5'-triphosphate-sensitive K+ channels (K-ATP) are dramatically up-regulated by a membrane phospholipid, phosphatidyl-inositol-4,5-bisphosphate (PIP2). During ischaemia, L-palmitoylcarnitine (L-PC), a fatty acid metabolite, accumulates in the sarcolemma and deranges the membrane lipid environment. We therefore investigated whether alteration of the membrane lipid environment by L-PC modulates the K-ATP channel activity in inside-out patches from guineapig ventricular myocytes. L-PC (1 muM) inhibited K-ATP channel activity, without affecting the single channel conductance, through interaction with Kir6.2. L-PC simultaneously enhanced the ATP sensitivity of the channel [concentration for half-maximal inhibition (IC50) fell from 62.0+/-2.7 to 30.3+/-5.5 muM]. In contrast, PIP2 attenuated the ATP sensitivity (IC50 343.6+/-54.3 muM) and restored Ca2+-induced inactivation of K-ATP channels (94.1+/-13.7% of the control current immediately before the Ca2+-induced inactivation). Pretreatment of the patch membrane with 1 muM L-PC, however, reduced the magnitude of the PIP2-induced recovery to 22.7+/-6.3% of the control (P<0.01 vs. 94.1+/-13.7% in the absence of L-PC). Conversely, after the PIP2-induced recovery, L-PC's inhibitory action was attenuated, but L-PC partly reversed the PIP2-mediated decrease in the ATP sensitivity (IC50 fell from 310+/-19.2 to 93.1+/-9.8 <mu>M). Thus, interaction between L-PC and PIP2 in the plasma membrane appears to regulate K-ATP channels.