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    Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.

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    Date
    2007-09
    Authors
    Barki-Harrington, L
    Chen, J
    Le Corvoisier, P
    Lefkowitz, Robert J
    Lemaire, A
    Naga Prasad, SV
    Noma, T
    Rockman, Howard A
    Tilley, DG
    Violin, JD
    Wei, H
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    Abstract
    Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (betaARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby beta-arrestins mediate beta1AR signaling to the EGFR. This beta-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via beta-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.
    Type
    Journal article
    Subject
    Animals
    Arrestins
    Cell Line
    Heart
    Humans
    Mice
    Mice, Transgenic
    Mutation
    Myocardium
    Phosphorylation
    Protein Binding
    Protein-Serine-Threonine Kinases
    Receptor, Epidermal Growth Factor
    Receptors, Adrenergic, beta-1
    Signal Transduction
    Transcriptional Activation
    beta-Arrestins
    Permalink
    http://hdl.handle.net/10161/5925
    Published Version (Please cite this version)
    10.1172/JCI31901
    Publication Info
    Barki-Harrington, L; Chen, J; Le Corvoisier, P; Lefkowitz, Robert J; Lemaire, A; Naga Prasad, SV; ... Wei, H (2007). Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest, 117(9). pp. 2445-2458. 10.1172/JCI31901. Retrieved from http://hdl.handle.net/10161/5925.
    This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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    Scholars@Duke

    Lefkowitz

    Robert J. Lefkowitz

    James B. Duke Professor of Medicine
    The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Stud
    Rockman

    Howard Allan Rockman

    Edward S. Orgain Professor of Cardiology, in the School of Medicine
    Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively
    Alphabetical list of authors with Scholars@Duke profiles.
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