ROLE OF G-PROTEIN-COUPLED RECEPTOR KINASE-2 AND ARRESTINS IN BETA-ADRENERGIC-RECEPTOR INTERNALIZATION

G protein-coupled receptors (GPCRs) mediate the action of messengers t hat are key modulators of the function, growth, and differentiation of cardiac and vascular cells. A general feature of GPCRs is the existen ce of complex regulatory mechanisms that modulate receptor responsiven ess and underlie important physiologic phenomena such as signal integr ation and desensitization. The molecular mechanisms of desensitization have been investigated with the beta(2)-adrenergic receptor (beta(2)A R) used as the main model system. Rapid regulation of beta AR and othe r GPCRs appears to involve agonist-promoted receptor phosphorylation b y G protein-coupled receptor kinases (GRKs). This is followed by bindi ng of uncoupling proteins termed arrestins and transient receptor inte rnalization, which plays a key role in resensitizing GPCR by allowing its dephosphorylation and recycling. Recent data indicate that, beside s the uncoupling function, GRK2 and beta-arrestin also directly partic ipate in beta(2)AR sequestration, thus providing the trigger for its r esensitization. A detailed knowledge of role of GRKs and arrestins in beta AR internalization would make their physiologic role in the modul ation of cellular responses to messenger better understood. (C) 1998, Elsevier Science Inc.