Insulin-like growth factor-I provokes functional antagonism and internalization of beta1-adrenergic receptors.
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 beta(1)-adrenergic receptor. Treating Chinese hamster ovary cells in culture with IGF-I is shown to functionally antagonize the ability of expressed beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to stimulation by the beta-adrenergic agonist Iso. The attenuation of beta(1)-adrenergic action was accompanied by internalization of beta(1)-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 beta(1)-adrenergic receptors. Mutation of one potential Akt substrate site Ser412Ala, but not another Ser312Ala, of the beta(1)-adrenergic receptor abolishes the ability of IGF-I to functionally antagonize and to sequester the beta(1)-adrenergic receptor. We also tested the ability of IGF-I to regulate beta(1)-adrenergic receptors and their signaling in adult canine cardiac myocytes. IGF-I attenuates the ability of beta(1)-adrenergic receptors to accumulate intracellular cAMP in response to Iso and promotes internalization of beta(1)-adrenergic receptors in these cardiac myocytes.
Gavi
Shai
S
Department of Pharmacology, Diabetes and Metabolic Diseases Research Center, School of Medicine-HSC, State University of New York at Stony Brook, Stony Brook, NY 11794, USA. sgavi@notes.cc.sunysb.edu
Yin
Dezhong
D
Shumay
Elena
E
Wang
Hsien-yu
HY
Malbon
Craig C
CC
D018674:Adrenergic Antagonists / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D018674:Adrenergic Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt