β-arrestins, their mechanisms of action and multiple roles in the biology of G protein-coupled receptors

Abstract

The stimulation of G protein-coupled receptors (GPCRs) induces biological responses to a wide range of extracellular cues. The heterotrimeric G proteins, which are recruited to the active conformation of GPCRs, lead to the generation of various diffusible second messengers. Only two other families of proteins exhibit the remarkable characteristic of recognizing and binding to the active conformation of most GPCRs: GPCR kinases (GRKs) and β-arrestins. These two families of proteins were initially identified as key players in the desensitization of G protein activation by GPCRs. Over the years, β-arrestins have been implicated in an increasing number of interactions with non-receptor proteins, expanding the range of cellular functions in which they are involved. It is now well established that β-arrestins, by scaffolding and recruiting protein complexes in an agonist-dependent manner, directly regulate the trafficking and signaling of GPCRs. Remarkable advances have been made in recent years which have made it possible i) to identify biased ligands capable, by stabilizing particular conformations of a growing number of GPCRs, of activating or blocking the action of β-arrestins independently of that of G proteins, some of these ligands holding great therapeutic interest; ii) to demonstrate β-arrestins' role in the compartmentalization of GPCR signaling within the cell, and iii) to understand the molecular details of their interaction with GPCRs and of their activation through structural and biophysical approaches.