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 microM) 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 microM), partially inhibited LA-induced opening of K(ATP) channels by 64%. The non-FFA G protein-coupled receptor (GPR) 40 agonist, GW9508 (40 microM), 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.
Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia.
Yu-Feng
YF
Zhao
Jianming
J
Pei
Chen
C
Chen
D000818:Animals; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D004594:Electrophysiology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019787:Linoleic Acid / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008744:Methylamines / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014044:Tolbutamide / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology
C473035:G-protein-coupled receptor 40, rat; C515630:GW9508; D054086:KATP Channels; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D014226:Triazenes; C034613:triacsin C; D014044:Tolbutamide; D019787:Linoleic Acid; D003066:Coenzyme A Ligases