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

TLDR

β‑arrestins bind phosphorylated GPCRs and mediate desensitization by uncoupling signaling, while agonist‑mediated receptor sequestration is essential for GPCR resensitization. Overexpression of β‑arrestins restores sequestration of β2‑adrenergic receptor mutants and is enhanced by β‑adrenergic receptor kinase 1, whereas β‑arrestin mutants inhibit wild‑type β2‑AR sequestration, demonstrating β‑arrestins’ essential role in GPCR internalization and dual regulatory function.

Abstract

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.