Molecular and genetic basis of beta2-adrenergic receptor function.

The beta(2 )-adrenergic receptor has been cloned, mutated, and recombinantly expressed such that many structural features involved in receptor function have been defined. Agonists bind in a pocket formed by transmembrane spanning domains 3, 5, and 6, where key contact points initiate receptor activation. An interaction with the beta-hydroxyl group of beta-agonists and Asn293 of the latter transmembrane domain is the basis of the stereoselectivity of R- vs S-isomers of catecholamine-like agonists. Sites within the receptor that serve to dampen the signal with continuous agonist exposure have also been identified and include sites for phosphorylation by protein kinase A and G-protein-coupled receptor kinases and structural features that direct the receptor toward degradation (downregulation). Several regions of the beta(2 )-adrenergic receptor show genetic diversity within the human population, such that expression, coupling, and agonist regulation may be different in individuals with these polymorphisms.