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

Abstract.

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 guinea-pig ventricular myocytes. L-PC (1 µM) 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 µM]. In contrast, PIP₂ attenuated the ATP sensitivity (IC₅₀ 343.6±54.4 µM) 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 µM 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 µM). Thus, interaction between L-PC and PIP₂ in the plasma membrane appears to regulate K_ATP channels.