G protein-coupled receptors: what a difference a 'partner' makes

Abstract

G protein-coupled receptors (GPCRs) are important cell signaling mediators, involved in essential physiological processes. GPCRs respond to a wide variety of ligands from light to large macromolecules, including hormones and small peptides. Unfortunately, mutations and dysregulation of GPCRs that induce a loss of function or alter expression can lead to disorders that are sometimes lethal. Therefore, the expression, trafficking, signaling and desensitization of GPCRs must be tightly regulated by different cellular systems to prevent disease. Although there is substantial knowledge regarding the mechanisms that regulate the desensitization and down-regulation of GPCRs, less is known about the mechanisms that regulate the trafficking and cell-surface expression of newly synthesized GPCRs. More recently, there is accumulating evidence that suggests certain GPCRs are able to interact with specific proteins that can completely change their fate and function. These interactions add on another level of regulation and flexibility between different tissue/cell-types. Here, we review some of the main interacting proteins of GPCRs. A greater understanding of the mechanisms regulating their interactions may lead to the discovery of new drug targets for therapy.

Figure 1.

Schematic representation of the roles of GPCR interacting proteins in the localization of GPCRs at the cell-surface. (A) NinaA, RanBP2, RTPs, REEPs, ODR-4 and protein S100-A10 facilitate cell-surface localization by promoting correct folding and protein trafficking; (B) Receptor activity-modifying proteins (RAMPs) act as chaperones and traffic with GPCRs to the cell-surface and (C) promote glycosylation of the GPCR; (D) Melanocortin 2 receptor accessory proteins (MRAPs) and dopamine-receptor-interacting protein of 78 kDa (DRiP78) either promote or prevent cell-surface localization depending on the particular GPCR. represents glycosylation.

Figure 2.

Schematic representation of the roles of GPCR interacting proteins in the signaling and trafficking of GPCRs from the cell-surface. (A) DRiP78 coordinates the assembly of the G protein•GPCR complex to ensure proper GPCR signaling at the cell-surface; (B) Following activation of certain GPCRs, CaM regulates GPCR phosphorylation; (C) Calmodulin (CaM) and Na⁺/H⁺ exchanger regulatory factor (NHERF) both act to specify G protein coupling and enhance G protein-dependent signaling; (D) Receptor component protein (RCP) specifically interacts with CLR•RAMP complexes to enhance signaling; (E) At the cell-surface, RAMPs interact with GPCRs to confer agonist specificity; (F) GASPs and SNXs interact with activated GPCRs to promote efficient down-regulation and thereby permanently terminate signaling.