LIGAND-INDUCED OVEREXPRESSION OF A CONSTITUTIVELY ACTIVE BETA(2)-ADRENERGIC RECEPTOR - PHARMACOLOGICAL CREATION OF A PHENOTYPE IN TRANSGENIC MICE

Transgenic overexpression (40- to 100-fold) of the wild-type human bet a(2)-adrenergic receptor in the hearts of mice leads to a marked incre ase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the r eceptor. Here we report that transgenic mice expressing a mutated cons titutively active form of the receptor (CAM) show no such phenotype, o wing to its modest expression (3-fold above endogenous cardiac beta-ad renergic receptor levels), Surprisingly, treatment of the animals with a variety of beta-adrenergic receptor ligands leads to a 50-fold incr ease in CAM beta(2)-adrenergic receptor expression, by stabilizing the CAM beta(2)-adrenergic receptor protein, Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial ten sion determined in vitro, and indices of cardiac contractility determi ned in vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a cons titutively active but inherently unstable protein.