Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization

Resensitization of G protein-coupled receptors (GPCRs) following agonist-me diated desensitization is a necessary step for maintaining physiological re sponsiveness. However, the molecular mechanisms governing the nature of GPC R resensitization are poorly understood. Here, we examine the role of beta- arrestin in the resensitization of the beta(2) adrenergic receptor (beta(2) AR), known to recycle and resensitize rapidly, and the vasopressin V2 recep tor (V2R), known to recycle and resensitize slowly. Upon agonist activation , both receptors recruit beta-arrestin to the plasma membrane and internali ze in a beta-arrestin- and clathrin-dependent manner. However, whereas beta -arrestin dissociates from the beta(2)AR at the plasma membrane, it interna lizes with the V2R into endosomes. The differential trafficking of beta-arr estin and the ability of these two receptors to dephosphorylate, recycle, a nd resensitize is completely reversed when the carboxyl-terminal tails of t hese two receptors are switched, Moreover, the ability of beta-arrestin to remain associated with desensitized GPCRs during clathrin-mediated endocyto sis is mediated by a specific cluster of phosphorylated serine residues in the receptor carboxyl-terminal tail. These results demonstrate that the int eraction of beta-arrestin with a specific motif in the GPCR carboxyl-termin al tail dictates the rate of receptor dephosphorylation, recycling, and res ensitization, and thus provide direct evidence for a novel mechanism by whi ch beta-arrestins regulate the reestablishment of GPCR responsiveness.