Activation of ATP-sensitive potassium channels in rat pancreatic beta-cells by linoleic acid through both intracellular metabolites and membrane receptor signalling pathway

ATP-sensitive potassium channels (K-ATP channels) determine the excitability of pancreatic beta-cells and importantly regulate glucose-stimulated insulin secretion (GSIS). Long-chain free fatty acids (FFAs) decrease GSIS after long-term exposure to beta-cells, but the effects of exogenous FFAs on K-ATP channels are not yet well clarified. In this study, the effects of linoleic acid (LA) on membrane potential (MP) and K-ATP channels were observed in primary cultured rat pancreatic beta-cells. LA (20 mu M) induced hyperpolarization of MP and opening of K-ATP channels, which was totally reversed and inhibited by tolbutamide, a K-ATP channel blocker. Inhibition of LA metabolism by acyl-CoA synthetase inhibitor, triacsin C (10 mu M), partially inhibited LA-induced opening of K-ATP channels by 64%, The non-FFA G protein-coupled receptor (GPR) 40 agonist, GW9508 (40 mu M), induced an opening of K-ATP channels, which was similar to that induced by LA under triacsin C treatment. Blockade of protein kinases A and C did not influence the opening of K-ATP channels induced by LA and GW9508, indicating that these two protein kinase pathways are not involved in the action of LA on K-ATP channels. The present study demonstrates that LA induces hyperpolarization of MP by activating K-ATP channels via both intracellular metabolites and activation of GPR40. It indicates that not only intracellular metabolites of FFAs but also GPR40-mediated pathways take part in the inhibition of GSIS and beta-cell dysfunction induced by FFAs.