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Receptor/ß-Arrestin Complex Formation and the Differential Trafficking and Resensitization of ß₂-Adrenergic and Angiotensin II Type 1A Receptors

The John P. Robarts Research Institute and Departments of Physiology (J.L.S., S.S.G.F.) and Pharmacology and Toxicology (L.B.D., S.S.G.F.) University of Western Ontario London, Ontario, Canada N6A 5K8

ß-Arrestins target G protein-coupled receptors (GPCRs) for endocytosis via clathrin-coated vesicles. ß-Arrestins also become detectable on endocytic vesicles in response to angiotensin II type 1A receptor (AT_1AR), but not ß₂-adrenergic receptor (ß₂AR), activation. The carboxyl-terminal tails of these receptors contribute directly to this phenotype, since a ß₂AR bearing the AT_1AR tail acquired the capacity to stimulate ß-arrestin redistribution to endosomes, whereas this property was lost for an AT_1AR bearing the ß₂AR tail. Using ß₂AR/AT_1AR chimeras, we tested whether the ß₂AR and AT_1AR carboxyl-terminal tails, in part via their association with ß-arrestins, might regulate differences in the intracellular trafficking and resensitization patterns of these receptors. In the present study, we find that ß-arrestin formed a stable complex with the AT_1AR tail in endocytic vesicles and that the internalization of this complex was dynamin dependent. Internalization of the ß₂AR chimera bearing the AT_1AR tail was observed in the absence of agonist and was inhibited by a dominant-negative ß-arrestin1 mutant. Agonist-independent AT_1AR internalization was also observed after ß-arrestin2 overexpression. After internalization, the ß₂AR, but not the AT_1AR, was dephosphorylated and recycled back to the cell surface. However, the AT_1AR tail prevented ß₂AR dephosphorylation and recycling. In contrast, although the ß₂AR-tail promoted AT_1AR recycling, the chimeric receptor remained both phosphorylated and desensitized, suggesting that receptor dephosphorylation is not a property common to all receptors. In summary, we show that the carboxyl-terminal tails of GPCRs not only contribute to regulating the patterns of receptor desensitization, but also modulate receptor intracellular trafficking and resensitization patterns.

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