β-arrestins and G protein-coupled receptor trafficking

Abstract

Nonvisual arrestins (β-arrestin-1 and β-arrestin-2) are adaptor proteins that function to regulate G protein-coupled receptor (GPCR) signaling and trafficking. β-arrestins are ubiquitously expressed and function to inhibit GPCR/G protein coupling, a process called desensitization, and promote GPCR trafficking and arrestin-mediated signaling. β-arrestin-mediated endocytosis of GPCRs requires the coordinated interaction of β-arrestins with clathrin, adaptor protein 2 (AP2), and phosphoinositides. These interactions are facilitated by a conformational change in β-arrestin that is thought to occur upon binding to a phosphorylated activated GPCR. In this review, we provide an overview of the key interactions involved in β-arrestin-mediated trafficking of GPCRs.

Figure 1. Role of β-arrestins in GPCR trafficking

(1) Agonist binding to a GPCR results in heterotrimeric G protein activation leading to dissociation of Gα from Gβγ subunits. This promotes GRK association with the agonist-bound GPCR which mediates receptor phosphorylation and (2) promotes β-arrestin recruitment to the receptor. (3) β-arrestin association with the phosphorylated GPCR mediates conformational changes in arrestin that promote association of the GPCR-β-arrestin complex with the endocytic machinery and subsequent endocytosis (4). GPCRs then traffic to sorting endosomes (5) and ultimately either recycle back to the plasma membrane through recycling endosomes (6 and 7) or are sorted to lysosomes where they are degraded (8 and 9).

Figure 2. Secondary structure of β-arrestin-1L

Ribbon diagram of β-arrestin-1L (residues 6 to 399) indicating the N- and C-domains, the polar core and binding sites for the GPCR, phosphoinositides (high affinity site in C-domain and low affinity site in N-domain), clathrin (Lϕxϕ[D/E] and [L/I]₂GxL motifs) and β2-adaptin ([D/E]xxFxx[F/L]xxxR motif).