Journal article
Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts
Diabetes (New York, N.Y.), Vol.63(8), pp.2676-2689
08/2014
DOI: 10.2337/db13-1763
PMCID: PMC4113065
PMID: 24677713
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 β
2
-adrenergic receptor (β
2
AR) in the heart. The IR/β
2
AR 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 β
2
AR, which promotes β
2
AR coupling to the inhibitory G-protein, G
i
. The insulin-induced phosphorylation of β
2
AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β
2
AR-G
i
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 β
2
AR-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.
Details
- Title: Subtitle
- Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts
- Creators
- Qin Fu - Department of Pharmacology, University of California, Davis, Davis, CABing Xu - Department of Pharmacology, University of California, Davis, Davis, CAYongming Liu - Department of Pharmacology, University of California, Davis, Davis, CADippal Parikh - Department of Pharmacology, University of California, Davis, Davis, CAJing Li - Temple UniversityYing Li - Temple UniversityYuan Zhang - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTChristian Riehle - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTYi Zhu - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTTenley Rawlings - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTQian Shi - Department of Pharmacology, University of California, Davis, Davis, CARichard B Clark - Department of Integrative Biology and Pharmacology, University of Texas Houston Medical Center, Houston, TXXiongwen Chen - Department of Physiology and Cardiovascular Research Center, Temple University Medical Center, Philadelphia, PAE. Dale Abel - Division of Endocrinology, Metabolism, and Diabetes, Program in Molecular Medicine, University of Utah, Salt Lake City, UTYang K Xiang - Department of Pharmacology, University of California, Davis, Davis, CA
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.63(8), pp.2676-2689
- Publisher
- American Diabetes Association
- DOI
- 10.2337/db13-1763
- PMID
- 24677713
- PMCID
- PMC4113065
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 08/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Biostatistics; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024540302771
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