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Prince Henry’s Institute of Medical Research (D.D.F., M.H., N.T., D.J.K., C.C.), Clayton, Victoria 3168, Australia; Department of Physiology (D.D.F., Z.L.), XiangYa Medical School, Central-South University, Hunan 410018, China; and Department of Food Production Science (S.R.), Shinshu University, Nagano-ken 399-4598, Japan
Address all correspondence and requests for reprints to: Dr. Chen Chen, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: chen.chen{at}princehenrys.org.
Free fatty acids (FFAs), in addition to glucose, have been shown to stimulate insulin release through the G protein-coupled receptor (GPCR)40 receptor in pancreatic ß-cells. Intracellular free calcium concentration ([Ca2+]i) in ß-cells is elevated by FFAs, although the mechanism underlying the [Ca2+]i increase is still unknown. In this study, we investigated the action of linoleic acid on voltage-gated K+ currents. Nystatin-perforated recordings were performed on identified rat ß-cells. In the presence of nifedipine, tetrodotoxin, and tolbutamide, voltage-gated K+ currents were observed. The transient current represents less than 5%, whereas the delayed rectifier current comprises more than 95%, of the total K+ currents. A long-chain unsaturated FFA, linoleic acid (10 µM), reversibly decreased the amplitude of K+ currents (to less than 10%). This reduction was abolished by the cAMP/protein kinase A system inhibitors H89 (1 µM) and Rp-cAMP (10 µM) but was not affected by protein kinase C inhibitor. In addition, forskolin and 8'-bromo-cAMP induced a similar reduction in the K+ current as that evoked by linoleic acid. Insulin secretion and cAMP accumulation in ß-cells were also increased by linoleic acid. Methyl linoleate, which has a similar structure to linoleic acid but no binding affinity to GPR40, did not change K+ currents. Treatment of cultured cells with GPR40-specific small interfering RNA significantly reduced the decrease in K+ current induced by linoleic acid, whereas the cAMP-induced reduction of K+ current was not affected. We conclude that linoleic acid reduces the voltage-gated K+ current in rat ß-cells through GPR40 and the cAMP-protein kinase A system, leading to an increase in [Ca2+]i and insulin secretion.
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