Fine-tuning of GPCR activity by receptor-interacting proteins

Abstract

G protein-coupled receptors (GPCRs) are a large family of seven-transmembrane proteins that can be activated by a diverse array of ligands, including hormones, neurotransmitters and sensory stimuli. Following activation, GPCRs associate with heterotrimeric G proteins to stimulate G protein-mediated signalling. GPCR activity can be regulated by receptor interactions with kinases, arrestins and other receptors. In addition to GPCR associations with G proteins, kinases, arrestins and other receptors, GPCRs can interact in a more receptor-selective manner with various other cytoplasmic or transmembrane proteins. These receptor-selective partners can mediate GPCR signalling, organize receptor signalling through G proteins, direct GPCR trafficking, anchor GPCRs in particular subcellular areas and/or influence GPCR ligand binding properties. GPCR interactors that modulate GPCR signalling can either enhance G protein-mediated signalling, by tethering downstream effectors in the vicinity of activated receptors, or impair G protein-mediated signalling, by hindering the ability of the receptors to interact with G proteins and/or by recruiting negative regulators of G protein signalling to the receptor complex. Some GPCR interactors are required for efficient biosynthetic trafficking of their associated GPCRs. Other GPCR interactors primarily regulate the post-endocytic trafficking of GPCRs, determining whether their associated receptors are recycled back to the plasma membrane or targeted to lysosomes for degradation. GPCR interactors can exert multiple effects on their associated GPCRs. For example, the receptor activity-modifying proteins influence the biosynthetic trafficking and the ligand binding properties of their associated receptors. Many GPCRs are important drug targets, and therefore advances in understanding the fine-tuning of GPCR activity by receptor-interacting proteins can provide novel therapeutic insights.