The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling

Abstract

The visual/-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein-coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure-function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit.

Arrestin mutations: Some cause diseases, others promise cure

“…30 Arrestins were implicated in the activation ofc-Src 31 and all three major MAP kinase classes, JNK, 32 ERK, 33 and p38, 34 shown to bind cAMP phosphodiesterase, 35 calmodulin, 36 microtubules, 37,38 ubiquitin ligases Mdm2, 39 AIP4, 40 parkin, 41 and many other signaling proteins (reviewed in refs. 11,42,43). Thus, it appears that arrestins are at the crossroads of numerous vital signaling pathways in the cell.…”

GPCR signaling: conformational activation of arrestins

“…While initially discovered in the context of receptor desensitization, it was subsequently discovered that β-arrestins also serve as multifunctional adapters mediating receptor interaction with several components of the clathrincoated pit endocytic machinery, thus mediating receptor internalization and trafficking. 1,3,6 They also bind to a long list of signaling proteins thus enabling β-arrestins to serve as signaling intermediates in their own right, acting either independently of or in concert with G-proteins to modulate cellular activities. 6 The remarkable diversity of functions carried out by arrestins after their interaction with the receptors has engendered much interest in the mechanisms of GPCR-β-arrestin interactions and how these are translated into specific cellular consequences.…”

“…1,3,6 They also bind to a long list of signaling proteins thus enabling β-arrestins to serve as signaling intermediates in their own right, acting either independently of or in concert with G-proteins to modulate cellular activities. 6 The remarkable diversity of functions carried out by arrestins after their interaction with the receptors has engendered much interest in the mechanisms of GPCR-β-arrestin interactions and how these are translated into specific cellular consequences. Confirming decades-long ideas, recent structural studies of both visual arrestin interaction with rhodopsin and β-arrestin interaction with other GPCRs, have revealed two types of interactions within receptor-arrestin complexes: one involving the phosphorylated cytoplasmic tail of the GPCR (R P -tail), referred to as the 'tail' interaction, and one involving the transmembrane core of the GPCR, referred to as the 'core' interaction.…”

Decoding the chemotactic signal

“…In the context of mammalian cell chemotaxis, β‐arrestins not only modulate receptor G protein signaling and surface expression, but to also contribute to the spatial regulation of actin assembly proteins . Mammals express 2 nonvisual arrestins (β‐arrestin1 and β‐arrestin2), both of which play important roles in mammalian cell chemotaxis . β‐arrestin1 and β‐arrestin2 are required for chemotaxis in some mammalian cell systems, though their precise role is undefined in many contexts .…”