Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice.
Abstract
Transgenic mice were generated with cardiac-specific overexpression of the G protein-coupled
receptor kinase-5 (GRK5), a serine/threonine kinase most abundantly expressed in the
heart compared with other tissues. Animals overexpressing GRK5 showed marked beta-adrenergic
receptor desensitization in both the anesthetized and conscious state compared with
nontransgenic control mice, while the contractile response to angiotensin II receptor
stimulation was unchanged. In contrast, the angiotensin II-induced rise in contractility
was significantly attenuated in transgenic mice overexpressing the beta-adrenergic
receptor kinase-1, another member of the GRK family. These data suggest that myocardial
overexpression of GRK5 results in selective uncoupling of G protein-coupled receptors
and demonstrate that receptor specificity of the GRKs may be important in determining
the physiological phenotype.
Type
Journal articleSubject
AnimalsCyclic AMP-Dependent Protein Kinases
G-Protein-Coupled Receptor Kinase 5
GTP-Binding Proteins
Mice
Mice, Transgenic
Myocardial Contraction
Myocardium
Phenotype
Protein-Serine-Threonine Kinases
RNA, Messenger
Receptor Protein-Tyrosine Kinases
Receptors, Adrenergic, beta
Receptors, Angiotensin
beta-Adrenergic Receptor Kinases
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https://hdl.handle.net/10161/7834Collections
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Show full item recordScholars@Duke
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the
Howard Allan Rockman
Edward S. Orgain Distinguished 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 overexp
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