Insulin potentiates Ca2+ signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway

Endocrinology. 2007 Jul;148(7):3246-57. doi: 10.1210/en.2006-1711. Epub 2007 Mar 22.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / pharmacology
  • Blotting, Western
  • Bombesin / pharmacology
  • Bradykinin / pharmacology
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Hydrolysis / drug effects
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Insulin / pharmacology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism
  • Microscopy, Fluorescence
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Neurotensin / pharmacology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Vasopressins / pharmacology


  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, G-Protein-Coupled
  • Vasopressins
  • Angiotensin II
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Neurotensin
  • Inositol 1,4,5-Trisphosphate
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Bombesin
  • Bradykinin
  • Sirolimus