A new pathway for glucose-dependent insulinotropic polypeptide (GIP) receptor signaling - Evidence for the involvement of phospholipase A, in GIP-stimulated insulin secretion

The hormone glucose-dependent insulinotropic polypeptide (GIP) is an import ant regulator of insulin secretion. GIP has been shown to increase adenylyl cyclase activity, elevate intracellular Ca2+ levels, and stimulate a mitog en-activated protein kinase pathway in the pancreatic beta -cell. In the cu rrent study we demon strate a role for arachidonic acid in GIP-mediated sig nal transduction. Static incubations revealed that both GIP (100 nM) and AT P (5 muM) significantly increased [H-3] arachidonic acid ([H-3]AA) efflux f rom transfected Chinese hamster ovary K1 cells expressing the GIP receptor (basal, 128 +/- 11 cpm/well; GIP, 212 +/- 32 cpm/well; ATP, 263 +/- 35 cpm/ well; n = 4; p < 0.05). In addition, GIP receptors were shown for the first time to be capable of functionally coupling to AA production through G bet a gamma dimers in Chinese hamster ovary K1 cells. In a beta -cell model (be ta TC-3), GIP was found to elicit [H-3]AA release, independent of glucose, in a concentration-dependent manner (EC50 value of 1.4 +/- 0.62 nM; n = 3). Although GIP did not potentiate insulin release under extracellular Ca2+-f ree conditions, it was still capable of elevating intracellular cAMP and st imulating [H-3]AA release. Our data suggest that cAMP is the proximal signa ling intermediate responsible for GIP-stimulated AA release. Finally, stimu lation of GIP-mediated AA production was shown to be mediated via a Ca2+-in dependent phospholipase A(2). Arachidonic acid is therefore a new component of GIP-mediated signal transduction in the beta -cell.