title: Insulin induces IRS2-dependent and GRK2-mediated β2AR internalization to attenuate βAR signaling in cardiomyocytes.
abstract: The counter-regulatory effects of insulin and catecholamines on carbohydrate and lipid metabolism are well studied, whereas the details of insulin regulation of β adrenergic receptor (βAR) signaling pathway in heart remain unknown. Here, we characterize a novel signaling pathway of insulin receptor (IR) to G protein-coupled receptor kinase 2 (GRK2) in the heart. Insulin stimulates recruitment of GRK2 to β2AR, which induces β2AR phosphorylation at the GRK sites of serine 355/356 and subsequently β2AR internalization. Insulin thereby suppresses βAR-induced cAMP-PKA activities and contractile response in neonatal and adult mouse cardiomyocytes. Deletion of insulin receptor substrate 2 (IRS2) disrupts the complex of IR and GRK2, which attenuates insulin-mediated β2AR phosphorylation at the GRK sites and β2AR internalization, and the counter-regulation effects of insulin on βAR signaling. These data indicate the requirements of IRS2 and GRK2 for insulin to stimulate counter-regulation of βAR via β2AR phosphorylation and internalization in cardiomyocytes.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology, University of California at Davis, CA 95616, United States. Electronic address: fu_qin@aliyun.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, University of California at Davis, CA 95616, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of California at Davis, CA 95616, United States.
authors.forename: Dippal
authors.initials: D
authors.lastname: Parikh
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL 61801, United States.
authors.forename: David
authors.initials: D
authors.lastname: Cervantes
authors.affiliation: Department of Pharmacology, University of California at Davis, CA 95616, United States.
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
mesh_terms: D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: Adrenergic receptor; Cardiac contractility; GRK2; Insulin receptor; Internalization; cAMP