A new pathway for glucose-dependent insulinotropic polypeptide (GIP) receptor signaling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion

• Published in: The Journal of biological chemistry Vol. 276; no. 26; p. 23667
• Main Authors: Ehses, J A, Lee, S S, Pederson, R A, McIntosh, C H
• Format: Journal Article
• Language: English
• Published: United States 29-06-2001
• Subjects: Animals; Arachidonic Acid - metabolism; Arachidonic Acid - pharmacology; Calcium - metabolism; Cell Line; CHO Cells; Cricetinae; Cyclic AMP - biosynthesis; Cyclic AMP-Dependent Protein Kinases - genetics; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Gastric Inhibitory Polypeptide - pharmacology; Glucose - pharmacology; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; Heterotrimeric GTP-Binding Proteins - antagonists & inhibitors; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Isoquinolines - pharmacology; Peptide Fragments - genetics; Phospholipases A - physiology; Phospholipases A2; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Recombinant Proteins; Signal Transduction; Sulfonamides; Transfection
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M103023200

The hormone glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of insulin secretion. GIP has been shown to increase adenylyl cyclase activity, elevate intracellular Ca(2+) levels, and stimulate a mitogen-activated protein kinase pathway in the pancreatic beta-cell. In the current study we demonstrate a role for arachidonic acid in GIP-mediated signal transduction. Static incubations revealed that both GIP (100 nm) and ATP (5 microm) significantly increased [(3)H]arachidonic acid ([(3)H]AA) efflux from 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 Gbetagamma dimers in Chinese hamster ovary K1 cells. In a beta-cell model (betaTC-3), GIP was found to elicit [(3)H]AA release, independent of glucose, in a concentration-dependent manner (EC(50) value of 1.4 +/- 0.62 nm; n = 3). Although GIP did not potentiate insulin release under extracellular Ca(2+)-free conditions, it was still capable of elevating intracellular cAMP and stimulating [(3)H]AA release. Our data suggest that cAMP is the proximal signaling intermediate responsible for GIP-stimulated AA release. Finally, stimulation of GIP-mediated AA production was shown to be mediated via a Ca(2+)-independent phospholipase A(2). Arachidonic acid is therefore a new component of GIP-mediated signal transduction in the beta-cell.