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-mediated desensitization is a necessary step for maintaining physiological responsiveness. However, the molecular mechanisms governing the nature of GPCR 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 receptor (V2R), known to recycle and resensitize slowly. Upon agonist activation, both receptors recruit beta-arrestin to the plasma membrane and internalize in a beta-arrestin- and clathrin-dependent manner. However, whereas beta-arrestin dissociates from the beta(2)AR at the plasma membrane, it internalizes with the V2R into endosomes. The differential trafficking of beta-arrestin and the ability of these two receptors to dephosphorylate, recycle, and resensitize is completely reversed when the carboxyl-terminal tails of these two receptors are switched. Moreover, the ability of beta-arrestin to remain associated with desensitized GPCRs during clathrin-mediated endocytosis is mediated by a specific cluster of phosphorylated serine residues in the receptor carboxyl-terminal tail. These results demonstrate that the interaction of beta-arrestin with a specific motif in the GPCR carboxyl-terminal tail dictates the rate of receptor dephosphorylation, recycling, and resensitization, and thus provide direct evidence for a novel mechanism by which beta-arrestins regulate the reestablishment of GPCR responsiveness.
Oakley
R H
RH
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Laporte
S A
SA
Holt
J A
JA
Barak
L S
LS
Caron
M G
MG
D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000502:physiology*; D017483:Receptors, Vasopressin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D002966:Clathrin; D011956:Receptors, Cell Surface; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins