Overexpression of myocardial Gsα prevents full expression of catecholamine desensitization despite increased β-adrenergic receptor kinase

Abstract

Inotropic and chronotropic responses to catecholamines in young adult transgenic mice overexpressing myocardial Gsα are enhanced. One might predict that over the life of the animal, this chronically enhanced β- adrenergic receptor stimulation would result in homologous catecholamine desensitization. To test this hypothesis, old transgenic Gsα mice and age- matched controls were studied physiologically in terms of responsiveness of left ventricular function (ejection fraction) to isoproterenol in vivo and in vitro in terms of β-adrenergic receptor signaling. Old transgenic mice still responded to isoproterenol with augmented (P < 0.05) left ventricular ejection fraction (+44±3%) compared with age-matched controls (+24±1%). Although total β-adrenergic receptor density was reduced in the old transgenic mice, and G protein receptor kinase 2 (β-adrenergic receptor kinase) levels were increased, the fraction of receptors binding agonist with high affinity as well as isoproterenol- and G protein-stimulated adenylyl cyclase activities were enhanced. Thus, classical catecholamine desensitization is not effective in attenuation of persistently enhanced responses to sympathetic stimulation in mice overexpressing myocardial Gsα. To support this conclusion further, experiments were performed with chronic isoproterenol, which elicited effective desensitization in wild-type controls, but failed to elicit desensitization in overexpressed Gsα mice. The results of this study suggest that the lack of protective desensitization mechanisms may be responsible in part for the dilated cardiomyopathy which develops with chronic sympathetic stress over the life of these animals.