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    Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.

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    Date
    1996-11-12
    Authors
    Bond, RA
    Caron, MG
    Giros, B
    Jaber, M
    Koch, Walter J
    Lefkowitz, Robert J
    Rockman, Howard A
    Ross, J
    Smith, Bradley
    Sulik, KK
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    Abstract
    The beta-adrenergic receptor kinase 1 (beta ARK1) is a member of the G protein-coupled receptor kinase (GRK) family that mediates the agonist-dependent phosphorylation and desensitization of G protein-coupled receptors. We have cloned and disrupted the beta ARK1 gene in mice by homologous recombination. No homozygote beta ARK1-/- embryos survive beyond gestational day 15.5. Prior to gestational day 15.5, beta ARK1-/- embryos display pronounced hypoplasia of the ventricular myocardium essentially identical to the "thin myocardium syndrome" observed upon gene inactivation of several transcription factors (RXR alpha, N-myc, TEF-1, WT-1). Lethality in beta ARK1-/- embryos is likely due to heart failure as they exhibit a > 70% decrease in cardiac ejection fraction determined by direct in utero intravital microscopy. These results along with the virtual absence of endogenous GRK activity in beta ARK1-/- embryos demonstrate that beta ARK1 appears to be the predominant GRK in early embryogenesis and that it plays a fundamental role in cardiac development.
    Type
    Journal article
    Subject
    Animals
    Chimera
    Cyclic AMP-Dependent Protein Kinases
    DNA Primers
    Embryonic and Fetal Development
    Exons
    Female
    Fetal Death
    Fetal Heart
    Heart Defects, Congenital
    Homozygote
    Mice
    Mice, Transgenic
    Myocardium
    Polymerase Chain Reaction
    Pregnancy
    Recombination, Genetic
    beta-Adrenergic Receptor Kinases
    Permalink
    http://hdl.handle.net/10161/7833
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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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