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Insulin Potentiates Ca²⁺ Signaling and Phosphatidylinositol 4,5-Bisphosphate Hydrolysis Induced by G_q Protein-Coupled Receptor Agonists through an mTOR-Dependent Pathway

Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, University of California at Los Angeles-Center for Ulcer Research and Education, Digestive Diseases Research Center and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Enrique Rozengurt, Department of Medicine, David Geffen School of Medicine, 900 Veteran Avenue, Warren Hall Room 11-124, University of California at Los Angeles, Los Angeles, California 90095-1786. E-mail: erozengurt{at}mednet.ucla.edu.

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 G_q protein-coupled, but not G_i 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 G_q 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 G_q protein-coupled receptor agonists, including GPCR-mediated autocrine and paracrine loops in cancer cells.