Role of β-Arrestin in Mediating Agonist-Promoted G Protein-Coupled Receptor Internalization

β-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the desensitization of GPCRs by uncoupling the signal transduction process. Resensitization of GPCR responsiveness involves agonist-mediated receptor sequestration. Overexpression of β-arrestins in human embryonic kidney cells rescued the sequestration of β 2 -adrenergic receptor (β 2 AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpression of β-adrenergic receptor kinase 1. Wild-type β 2 AR sequestration was inhibited by the overexpression of two β-arrestin mutants. These findings suggest that β-arrestins play an integral role in GPCR internalization and thus serve a dual role in the regulation of GPCR function.