Evolving concepts in G protein-coupled receptor endocytosis: The role in receptor desensitization and signaling

G protein-coupled receptors (GPCRs) are seven transmembrane proteins that f orm the largest single family of integral membrane receptors. GPCRs transdu ce information provided by extracellular stimuli into intracellular second messengers via their coupling to heterotrimeric G proteins and the subseque nt regulation of a diverse variety of effector systems. Agonist activation of GPCRs also initiates processes that are involved in the feedback desensi tization of GPCR responsiveness, the internalization of GPCRs, and the coup ling of GPCRs to heterotrimeric G protein-independent signal transduction p athways. GPCR desensitization occurs as a consequence of G protein uncoupli ng in response to phosphorylation by both second messenger-dependent protei n kinases and G protein-coupled receptor kinases (GRKs). GRK-mediated recep tor phosphorylation promotes the binding of beta -arrestins, which not only uncouple receptors from heterotrimeric G proteins but also target many GPC Rs for internalization in clathrin-coated vesicles. beta -Arrestin-dependen t endocytosis of GPCRs involves the direct interaction of the carboxyl-term inal tail domain of beta -arrestins with both beta -adaptin and clathrin. T he focus of this review is the current and evolving understanding of the co ntribution of GRKs, beta -arrestins, and endocytosis to GPCR-specific patte rns of desensitization and resensitization. In addition to their role as GP CR-specific endocytic adaptor proteins, beta -arrestins also serve as molec ular scaffolds that foster the formation of alternative, heterotrimeric G p rotein-independent signal transduction complexes. Similar to what is observ ed for GPCR desensitization and resensitization, beta -arrestin-dependent G PCR internalization is involved in the intracellular compartmentalization o f these protein complexes.