title: Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway.
abstract: Multiple lines of evidence support the existence of crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling systems. However, the precise molecular mechanism(s) mediating this interaction is poorly understood. The results presented in this study show that exposure of ductal pancreatic adenocarcinoma BxPc-3, HPAF-II, and PANC-1 cells to insulin for as little as 1 min rapidly enhanced the magnitude and the rate of increase in intracellular Ca2+ concentration produced by the GPCR agonists bradykinin, angiotensin II, vasopressin, neurotensin, and bombesin. The potentiating effect of insulin was dose dependent, and it was produced in response to Gq protein-coupled, but not Gi protein-coupled, receptor agonists. Real-time imaging of single cells showed that treatment with insulin enhances the rate and magnitude of phosphatidylinositol 4,5-bisphosphate hydrolysis and generation of inositol 1,4,5-trisphosphate in response to GPCR stimulation. Short-term treatment with rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, completely abrogated the ability of insulin to increase the rate and magnitude of Ca2+ signaling and production of inositol 1,4,5-trisphosphate in response to bradykinin stimulation, indicating that insulin potentiates Gq protein-coupled receptor signaling through an mTOR-dependent pathway. We propose that the potentiation of GPCR signaling by insulin provides a mechanism by which insulin enhances cellular responsiveness to Gq protein-coupled receptor agonists, including GPCR-mediated autocrine and paracrine loops in cancer cells.
authors: Unit of Signal Transduction and Gastrointestinal Cancer, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles-Center for Ulcer Research and Education, Los Angeles, California 90095-1786, USA.
authors: Krisztina
authors: K
authors: Kisfalvi
authors: Osvaldo
authors: O
authors: Rey
authors: Steven H
authors: SH
authors: Young
authors: James
authors: J
authors: Sinnett-Smith
authors: Enrique
authors: E
authors: Rozengurt
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D001839:Bombesin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009496:Neurotensin / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D043562:Receptors, G-Protein-Coupled; D014667:Vasopressins; D000804:Angiotensin II; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009496:Neurotensin; D015544:Inositol 1,4,5-Trisphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001839:Bombesin; D001920:Bradykinin; D020123:Sirolimus