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 | |
dc.contributor.author | Rockman, HA | |
dc.contributor.author | Milano, CA | |
dc.contributor.author | 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 | ||
dc.identifier.issn | 0027-8424 | |
dc.identifier.uri | ||
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 | |
dc.subject | Adrenergic beta-Antagonists | |
dc.subject | Animals | |
dc.subject | Atrial Function | |
dc.subject | Heart | |
dc.subject | Humans | |
dc.subject | Isometric Contraction | |
dc.subject | Isoproterenol | |
dc.subject | Ligands | |
dc.subject | Mice | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Mice, Transgenic | |
dc.subject | Mutation | |
dc.subject | Phenotype | |
dc.subject | Propanolamines | |
dc.subject | Receptors, Adrenergic, beta-2 | |
dc.subject | Up-Regulation | |
dc.subject | 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 | ||
pubs.begin-page | 137 | |
pubs.end-page | 141 | |
pubs.issue | 1 | |
pubs.organisational-group | Basic Science Departments | |
pubs.organisational-group | Biochemistry | |
pubs.organisational-group | Cell Biology | |
pubs.organisational-group | Chemistry | |
pubs.organisational-group | Clinical Science Departments | |
pubs.organisational-group | Duke | |
pubs.organisational-group | Duke Cancer Institute | |
pubs.organisational-group | Institutes and Centers | |
pubs.organisational-group | Medicine | |
pubs.organisational-group | Medicine, Cardiology | |
pubs.organisational-group | Molecular Genetics and Microbiology | |
pubs.organisational-group | Pathology | |
pubs.organisational-group | School of Medicine | |
pubs.organisational-group | Surgery | |
pubs.organisational-group | Surgery, Cardiovascular and Thoracic Surgery | |
pubs.organisational-group | Trinity College of Arts & Sciences | |
pubs.publication-status | Published | |
pubs.volume | 94 |
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