title: Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts.
abstract: Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CADepartment of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CAShuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA.
authors.forename: Dippal
authors.initials: D
authors.lastname: Parikh
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Temple University Medical Center, Philadelphia, PA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Temple University Medical Center, Philadelphia, PA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTFraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTFraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Tenley
authors.initials: T
authors.lastname: Rawlings
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CADepartment of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Houston Medical Center, Houston, TX.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Clark
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Temple University Medical Center, Philadelphia, PA.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTFraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CADepartment of Molecular and Integrative Physiology, University of Illinois at Urbana, Urbana, IL ykxiang@ucdavis.edu.
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D017868:Cyclic AMP-Dependent Protein Kinases; D054769:G-Protein-Coupled Receptor Kinase 2