Insulin-Like Growth Factor-I Provokes Functional Antagonism and Internalization of β1-Adrenergic Receptors

Abstract

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 β1-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed β1-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the β-adrenergic agonist Iso. The attenuation of β1-adrenergic action was accompanied by internalization of β1-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 β1-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the β1-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the β1-adrenergic receptor. We also tested the ability of IGF-I to regulate β1-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of β1-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of β1-adrenergic receptors in these cardiac myocytes.