Beta-adrenergic receptors (betaAR) are cell surface proteins that are receptors for the endogenous catecholamines epinephrine and norepinephrine, as well as synthetic agonists arid antagonists in clinical use. These receptors densely populate the pulmonary and cardiovascular systems and are important in modulating bronchial smooth muscle tone, epithelial mucus secretion, cardiac inotropy and chronotropy, and vascular tone. Recent data from several groups, including our own, have clearly shown that significant functional differences exist between betaAR subtypes, and in particular between the beta1AR and beta2AR. However, most of our current understanding of beta1AR-mediated signal transduction has been extrapolated from studies of the beta2AR. Using site-directed mutagenesis, recombinant expression, and biochemical characterization, this proposal intends to directly elucidate the unique molecular pharmacology of the beta1AR. In particular, this proposal aims to delineate the molecular determinants of five specific aspects of beta1AR function which have particular physiologic and clinical relevance: l) ligand binding domains; 2) Gs coupling motifs; 3) the structural basis of active and inactive conformations of the receptor; 4) recognition sites for short-term desensitization by the receptor kinases PKA and betaARK; and 5) determinants of agonist-promoted receptor sequestration.
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