Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function.
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 articleSubject
AnimalsChimera
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
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Show full item recordScholars@Duke
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
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
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