Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

dc.contributor.author

Samama, P

dc.contributor.author

Bond, RA

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Rockman, HA

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Milano, CA

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Lefkowitz, RJ

dc.coverage.spatial

United States

dc.date.accessioned

2013-09-10T14:35:27Z

dc.date.issued

1997-01-07

dc.description.abstract

Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the receptor. Here we report that transgenic mice expressing a mutated constitutively active form of the receptor (CAM) show no such phenotype, owing to its modest expression (3-fold above endogenous cardiac beta-adrenergic receptor levels). Surprisingly, treatment of the animals with a variety of beta-adrenergic receptor ligands leads to a 50-fold increase in CAM beta2-adrenergic receptor expression, by stabilizing the CAM beta2-adrenergic receptor protein. Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial tension determined in vitro, and indices of cardiac contractility determined in vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a constitutively active but inherently unstable protein.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/8990174

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0027-8424

dc.identifier.uri

https://hdl.handle.net/10161/7830

dc.language

eng

dc.publisher

Proceedings of the National Academy of Sciences

dc.relation.ispartof

Proc Natl Acad Sci U S A

dc.subject

Adrenergic beta-2 Receptor Antagonists

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Adrenergic beta-Antagonists

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Animals

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Atrial Function

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Heart

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Humans

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Isometric Contraction

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Isoproterenol

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Ligands

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Mice

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Mice, Inbred C57BL

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Mice, Transgenic

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Mutation

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Phenotype

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Propanolamines

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Receptors, Adrenergic, beta-2

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Up-Regulation

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Ventricular Function, Left

dc.title

Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

dc.type

Journal article

duke.contributor.orcid

Rockman, HA|0000-0003-2921-1584

duke.contributor.orcid

Lefkowitz, RJ|0000-0003-1472-7545

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/8990174

pubs.begin-page

137

pubs.end-page

141

pubs.issue

1

pubs.organisational-group

Basic Science Departments

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Biochemistry

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Cell Biology

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Chemistry

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

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Medicine

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Medicine, Cardiology

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Molecular Genetics and Microbiology

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Pathology

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School of Medicine

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Surgery

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Surgery, Cardiovascular and Thoracic Surgery

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Trinity College of Arts & Sciences

pubs.publication-status

Published

pubs.volume

94

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