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dc.contributor.author Eckhart, AD
dc.contributor.author Duncan, SJ
dc.contributor.author Penn, RB
dc.contributor.author Benovic, JL
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Koch, WJ
dc.coverage.spatial United States
dc.date.accessioned 2012-10-24T20:55:59Z
dc.date.issued 2000-01-07
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/10625304
dc.identifier.citation Circ Res, 2000, 86 (1), pp. 43 - 50
dc.identifier.issn 0009-7330
dc.identifier.uri http://hdl.handle.net/10161/5938
dc.description.abstract G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including alpha(1B)-adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has been limited. Therefore, we generated hybrid transgenic mice with myocardium-targeted overexpression of 1 of 3 GRKs expressed in the heart (GRK2 [commonly known as the beta-AR kinase 1], GRK3, or GRK5) with concomitant cardiac expression of a constitutively activated mutant (CAM) or wild-type alpha(1B)AR. Transgenic mice with cardiac CAMalpha(1B)AR overexpression had enhanced myocardial alpha(1)AR signaling and elevated heart-to-body weight ratios with ventricular atrial natriuretic factor expression denoting myocardial hypertrophy. Transgenic mouse hearts overexpressing only GRK2, GRK3, or GRK5 had no hypertrophy. In hybrid transgenic mice, enhanced in vivo signaling through CAMalpha(1B)ARs, as measured by myocardial diacylglycerol content, was attenuated by concomitant overexpression of GRK3 but not GRK2 or GRK5. CAMalpha(1B)AR-induced hypertrophy and ventricular atrial natriuretic factor expression were significantly attenuated with either concurrent GRK3 or GRK5 overexpression. Similar GRK selectivity was seen in hybrid transgenic mice with wild-type alpha(1B)AR overexpression concurrently with a GRK. GRK2 overexpression was without effect on any in vivo CAM or wild-type alpha(1B)AR cardiac phenotype, which is in contrast to previously reported in vitro findings. Furthermore, endogenous myocardial alpha(1)AR mitogen-activated protein kinase signaling in single-GRK transgenic mice also exhibited selectivity, as GRK3 and GRK5 desensitized in vivo alpha(1)AR mitogen-activated protein kinase responses that were unaffected by GRK2 overexpression. Thus, these results demonstrate that GRKs differentially interact with alpha(1B)ARs in vivo such that GRK3 desensitizes all alpha(1B)AR signaling, whereas GRK5 has partial effects and, most interestingly, GRK2 has no effect on in vivo alpha(1B)AR signaling in the heart.
dc.format.extent 43 - 50
dc.language eng
dc.relation.ispartof Circ Res
dc.subject Animals
dc.subject Atrial Natriuretic Factor
dc.subject Cardiomegaly
dc.subject Cell Line
dc.subject Cyclic AMP-Dependent Protein Kinases
dc.subject Diglycerides
dc.subject G-Protein-Coupled Receptor Kinase 3
dc.subject G-Protein-Coupled Receptor Kinase 5
dc.subject Gene Expression
dc.subject Hybridization, Genetic
dc.subject JNK Mitogen-Activated Protein Kinases
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Mitogen-Activated Protein Kinases
dc.subject Mutation
dc.subject Myocardium
dc.subject Protein-Serine-Threonine Kinases
dc.subject RNA, Messenger
dc.subject Receptors, Adrenergic, alpha
dc.subject Transgenes
dc.subject beta-Adrenergic Receptor Kinases
dc.title Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart.
dc.type Journal Article
duke.description.endpage 50 en_US
duke.description.issue 1 en_US
duke.description.startpage 43 en_US
duke.description.volume 86 en_US
dc.relation.journal Circulation Research en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/10625304
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 86

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