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Linoleic acid induces an increase in intracellular calcium concentration and a membrane hyperpolarization of primary cultured rat pancreatic β-cells

Y.F. Zhao and C. Chen, Endocrine Cell Biology, Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.

Free fatty acids (FFAs) stimulate insulin secretion through activation of their receptor, GPR40. It is known that activation of GPR40 leads to an increase in intracellular free Ca2+ concentration ([Ca2+]i), which contributes to the secretion of insulin. Electrophysiological activities of β-cells are crucial in determining levels of [Ca2+]i and insulin secretion, but the action of FFAs on electrophysiological properties of β-cells is largely unknown. Moreover, the mechanism of increase in [Ca2+]i induced by FFAs is not fully understood. We used primary cultured rat pancreatic β-cells to test the effect of linoleic acid on [Ca2+]i and membrane potential. Linoleic acid (20 μM) induced an increase in [Ca2+]i under 3.5 mM glucose, which was eliminated by pretreatment of the cells with thapsigargin, but not blocked by removal of extracellular Ca2+. Simultaneously with the increase in [Ca2+]i, membrane potential was hyperpolarized by linoleic acids significantly (Mean±SD, -48±13.7 mV to -76±6.8 mV after linoleic acids, n=12, P<0.01). Only a very small component of calcium-activated potassium currents was involved, as apamin and charybdotoxin did not deter the hyperpolarization induced by linoleic acid. In contrast, the blockade of ATP-sensitive potassium channels (KATP channels) by tolbutamide totally abolished the hyperpolarization induced by linoleic acid. KATP current was then recorded by nystatin-perorated patch clamp. It was strongly increased by linoleic acid. We concluded that linoleic acid-induced increase in [Ca2+]i is due to calcium release from intracellular calcium stores of rat β-cells but not through voltage-dependent calcium channels. Electrophysiologically, linoleic acid induces hyperpolarization by activating KATP channels, but not calcium-activated potassium channels. This hyperpolarization may prevent insulin secretion induced by a high level of glucose.