A new pathway for glucose-dependent insulinotropic polypeptide (GIP) receptor signaling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion.
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.
Ehses
J A
JA
Department of Physiology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Lee
S S
SS
Pederson
R A
RA
McIntosh
C H
CH
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction; D013449:Sulfonamides; D014162:Transfection
D004791:Enzyme Inhibitors; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007328:Insulin; D007546:Isoquinolines; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D011994:Recombinant Proteins; D013449:Sulfonamides; D016718:Arachidonic Acid; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C114043:BARKct protein, recombinant; D010741:Phospholipases A; D054467:Phospholipases A2; D020962:Heterotrimeric GTP-Binding Proteins; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium