MOLECULAR REGULATION OF CARDIAC ADRENERGIC RECEPTORS

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Catecholamines such as norepinephrine and epinephrine are of vital importance in the hormonal control of the entire circulation. These compounds act via alpha- and beta-adrenergic receptors which are coupled through G proteins to enzymes such as adenylyl cyclase and phospholipase C as well as ion channels. Amongst a number of mechanisms which regulate receptor function, one of the most important is phosphorylation of the receptors by a novel family of G protein-coupled receptor kinases (GRKs) such as the beta-adrenergic receptor kinase (betaARK). This grant is requested to support a program in basic research directed at elucidating at a molecular and physiological level the mechanisms of regulation of adrenergic and other G protein-coupled receptors by these receptor kinases as well as by a recently identified unique phosphatase. These enzymes mediate, respectively, rapid agonist-promoted desensitization and resensitization of receptor signaling. Moreover, abnormal function of cardiac betaARK has recently been implicated as potentially contributing to the pathophysiology of heart failure. Accordingly, this research proposal has three closely linked goals, all of which involve a primary focus on the regulation of adrenergic receptor function by the G protein- coupled receptor kinases as an approach to gaining increased understanding of the normal and abnormal hormonal control of circulatory function. These goals are: 1) To determine the specificity of GRK action on adrenergic and other G protein-coupled receptors. 2) To define the physiological role of GRK's in vivo by "knocking out" their genes or by overexpressing the GRKs or specific inhibitors in transgenic animals. These experiments will allow us to assess the feasibility of altering cardiac function in vivo by manipulation of the betaARK system. 3) To determine the nature, properties and regulation of the phosphatases which reverse the action of GRKs. These studies will produce a comprehensive picture of the regulation of G protein-coupled receptors in which detailed information about molecular and cellular mechanisms provides the basis for understanding physiological consequences in the intact animal. Moreover, the results have the potential to point the way toward novel therapeutic strategies for cardiovascular diseases.