Emerging Functional Divergence of β-Arrestin Isoforms in GPCR Function

G protein-coupled receptors (GPCRs) are tightly regulated by multifunctional protein β-arrestins. Two isoforms of β-arrestin sharing more than 70% sequence identity and overall very similar 3D structures, β-arrestins 1 and 2, were originally expected to be functionally redundant. However, in recent years multiple lines of emerging evidence suggest they have distinct roles in various aspects of GPCR regulation and signaling. We summarize selected examples of GPCRs where β-arrestin isoforms are discovered to display non-overlapping and sometimes even antagonistic functions. We also discuss potential mechanistic basis for their functional divergence and highlight new frontiers that are likely to form the focal points of research in this area in coming years.

TrendsGPCR functions are crucially regulated by multifunctional scaffold protein β-arrestins.Emerging evidence suggests that, for many different GPCRs, the two isoforms of β-arrestin (β-arrestins 1 and 2) play distinct roles in downstream functional outcomes.Despite highly conserved primary sequence and overall very similar 3D structure, there are conformational differences in β-arrestin isoforms that potentially underlie their functional divergence.Distinct functional outcomes of β-arrestin isoforms add a new dimension to the functional selectivity of GPCRs and offer novel therapeutic possibilities.