Insulin inhibits cardiac contractility by inducing a Gi-biased β2-adrenergic signaling in hearts

Diabetes
Qin FuYang K Xiang

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 ...Continue Reading

References

Jul 19, 2000·American Journal of Physiology. Heart and Circulatory Physiology·Y Y ZhouR P Xiao
Dec 13, 2000·Journal of Molecular and Cellular Cardiology·A G Brittsan, E G Kranias
Jul 18, 2001·The Journal of Biological Chemistry·X SongH Wang
Jun 7, 2003·Science·Yang Xiang, Brian K Kobilka
Sep 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yang Xiang, Brian Kobilka
Mar 31, 2005·American Journal of Hypertension·Nicola FerraraFranco Rengo
Aug 3, 2005·The Journal of Clinical Investigation·Brian T O'Neill, E Dale Abel
Jan 18, 2006·British Journal of Pharmacology·Julia NevzorovaRoger J Summers
May 16, 2006·Trends in Pharmacological Sciences·Rui-Ping XiaoQide Han
Jul 15, 2006·Trends in Cardiovascular Medicine·Carmine MoriscoBruno Trimarco
Apr 7, 2007·Journal of Hypertension·Giuseppe ManciaPeter A Van Zwieten
May 9, 2007·American Journal of Hypertension·Maurizio GalderisiOreste de Divitiis
Jun 27, 2007·Circulation·Sihem Boudina, E Dale Abel
Sep 1, 2007·Current Opinion in Cardiology·Cinzia Perrino, Howard A Rockman
Jan 17, 2009·Cardiovascular Research·Jordan J WrightE Dale Abel
Oct 3, 2009·European Heart Journal·Stuart A CookPaolo G Camici
Apr 22, 2010·The Journal of Clinical Investigation·Ippei ShimizuIssei Komuro
Apr 12, 2012·Proceedings of the National Academy of Sciences of the United States of America·Shubai LiuYang K Xiang
Aug 17, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·E Dale AbelRavichandran Ramasamy
Nov 2, 2013·The Journal of Clinical Investigation·Christian RiehleE Dale Abel
Jan 31, 2014·Diabetologia·Heiko Bugger, E Dale Abel

❮ Previous
Next ❯

Citations

Dec 9, 2015·Archives of Physiology and Biochemistry·Elisa LucasRocio Vila-Bedmar
Nov 1, 2015·Diabetologia·Christopher M HaggertyBrandon K Fornwalt
Nov 9, 2015·Autonomic Neuroscience : Basic & Clinical·Ana Barbara Alves-WagnerUbiratan Fabres Machado
Feb 5, 2016·European Journal of Clinical Investigation·Aref NajafiJolanda van der Velden
Aug 25, 2015·Biochemical Pharmacology·Alejandra P OyarzúnSergio Lavandero
May 6, 2016·Frontiers in Physiology·Francisco WestermeierSergio Lavandero
Aug 28, 2015·Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance·Christopher M HaggertyBrandon K Fornwalt
Jul 23, 2015·Science Signaling·Rocio Vila-BedmarCristina Murga
Oct 21, 2014·Circulation Journal : Official Journal of the Japanese Circulation Society·Christian Riehle, E Dale Abel
Mar 5, 2015·Antioxidants & Redox Signaling·Anne D HafstadEllen Aasum
Mar 27, 2015·Antioxidants & Redox Signaling·Miranda M SungJason R B Dyck
Oct 28, 2016·European Journal of Clinical Investigation·Maria MizamtsidiAndromachi Vryonidou
Apr 12, 2016·Maturitas·Gaetano Santulli, Guido Iaccarino
Dec 31, 2016·Biomolecules & Therapeutics·Zuzana BolognaIl-Man Kim
Apr 2, 2016·Circulation Research·Christian Riehle, E Dale Abel
Mar 23, 2017·Journal of Cardiovascular Pharmacology·Qin FuYang K Xiang
Jul 18, 2019·Journal of the American Heart Association·Toni M WestYang K Xiang
Jan 22, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rui XuQin Fu
Dec 9, 2014·American Journal of Physiology. Heart and Circulatory Physiology·Niraj M BhattSonia Cortassa
May 22, 2020·Circulation Research·Rebecca H Ritchie, E Dale Abel
Jul 1, 2017·Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance·Linyuan JingBrandon K Fornwalt
Nov 18, 2018·Basic Research in Cardiology·Christian Riehle, Johann Bauersachs
Dec 13, 2018·Frontiers in Pharmacology·Li WuWei Wei
Nov 18, 2015·Current Opinion in Nephrology and Hypertension·Aleksandra Novikov, Volker Vallon
Apr 7, 2017·The Journal of Endocrinology·Cathy A Guo, Shaodong Guo
Aug 28, 2018·Frontiers in Pharmacology·Claudio de LuciaWalter J Koch
Mar 27, 2020·Frontiers in Physiology·Larissa VetterFelix T Kurz
Jan 20, 2021·The Journal of Clinical Investigation·E Dale Abel
Jan 21, 2021·Cells·Daniela SorrientoGuido Iaccarino
Jan 9, 2021·The FEBS Journal·Kirstie A De Jong, Viacheslav O Nikolaev
Oct 30, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Jinli PeiDayong Wang
May 14, 2021·Circulation Research·Gary D LopaschukE Dale Abel
Apr 15, 2021·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Jacqueline K LimbergJaume Padilla

❮ Previous
Next ❯

Methods Mentioned

BETA
biosensor
biosensors
immunoprecipitation assay
immunoprecipitation
FRET

Related Concepts

Related Feeds

Cardiovascular Disease Pathophysiology

Cardiovascular disease involves several different processes that contribute to the pathological mechanism, including hyperglycemia, inflammation, atherosclerosis, hypertension and more. Vasculature stability plays a critical role in the development of the disease. Discover the latest research on cardiovascular disease pathophysiology here.

Adrenergic Receptors: Trafficking

Adrenergic receptor trafficking is an active physiological process where adrenergic receptors are relocated from one region of the cell to another or from one type of cell to another. Discover the latest research on adrenergic receptor trafficking here.

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.