Role of GPR40 in fatty acid action on the β cell line INS-1E

GPR40 is a G protein-coupled receptor expressed preferentially in P cells, that has been implicated in mediating free fatty acidstimulated insulin release. GPR40 RNAi impaired the ability of palmitic acid (PA) to increase both insulin secretion and intracellular calcium ([Ca2+](i)). The PA-dependent [Ca2+](i) increase was attenuated by inhibitors of G alpha q, PLC, and SERCA. Thus GPR40 activates the G alpha q pathway, leading to release of Ca2+ from the ER. Yet the GPR40-dependent [Ca2+](i) rise was dependent on extracellular Ca2+ and elevated glucose, and was blocked by inhibition of L-type calcium channels (LTCC) or opening of the K-ATP channel; this suggests that GPR40 promotes Ca2+ influx through up-regulation of LTCC pre-activated by glucose and membrane depolarization. Taken together, the data indicate that GPR40 mediates the increase in [Ca2+](i) and insulin secretion through the Gotq-PLC pathway, resulting in release of Ca-2+ from the ER and leading to up-regulation of Ca2+ influx via LTCC. (c) 2005 Elsevier Inc. All rights reserved.