Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.
Data(s) |
07/01/1997
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Formato |
137 - 141 |
Identificador |
http://www.ncbi.nlm.nih.gov/pubmed/8990174 Proc Natl Acad Sci U S A, 1997, 94 (1), pp. 137 - 141 0027-8424 |
Relação |
Proc Natl Acad Sci U S A 10.1073/pnas.94.1.137 |
Tipo |
Journal Article |
Cobertura |
United States |
Resumo |
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. |
Idioma(s) |
ENG |
Palavras-Chave | #Adrenergic beta-2 Receptor Antagonists #Adrenergic beta-Antagonists #Animals #Atrial Function #Heart #Humans #Isometric Contraction #Isoproterenol #Ligands #Mice #Mice, Inbred C57BL #Mice, Transgenic #Mutation #Phenotype #Propanolamines #Receptors, Adrenergic, beta-2 #Up-Regulation #Ventricular Function, Left |