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Insulin-Like Growth Factor-I Provokes Functional Antagonism and Internalization of ß₁-Adrenergic Receptors

Departments of Pharmacology (S.G., D.Y., E.S., C.C.M.), Medicine (S.G.), and Physiology and Biophysics (H.-y.W.), Diabetes and Metabolic Diseases Research Center, School of Medicine-HSC, State University of New York at Stony Brook, Stony Brook, New York 11794

Address all correspondence and requests for reprints to: Dr. Shai Gavi, Department of Medicine, HSC, SUNY/Stony Brook, Stony Brook, New York 11794. E-mail: sgavi{at}notes.cc.sunysb.edu.

Hormones that activate receptor tyrosine kinases have been shown to regulate G protein-coupled receptors, and herein we investigate the ability of IGF-I to regulate the ß₁-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed ß₁-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the ß-adrenergic agonist Iso. The attenuation of ß₁-adrenergic action was accompanied by internalization of ß₁-adrenergic receptors in response to IGF-I. Inhibiting either phosphatidylinositol 3-kinase or the serine/threonine protein kinase Akt blocks the ability of IGF-I to antagonize and to internalize ß₁-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the ß₁-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the ß₁-adrenergic receptor. We also tested the ability of IGF-I to regulate ß₁-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of ß₁-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of ß₁-adrenergic receptors in these cardiac myocytes.