Mechanisms of Location Bias in G Protein-Coupled Receptors

Abstract

GPCRs are known for their versatile signaling roles at the plasma membrane; however, recent studies have revealed that these receptors also function within various intracellular compartments, such as endosomes, the Golgi apparatus, and the endoplasmic reticulum. This spatially distinct signaling, termed location bias, allows GPCRs to initiate unique signaling cascades and influence cellular processes-including cAMP production, calcium mobilization, and protein phosphorylation-in a compartment-specific manner. By mapping the impact of GPCR signaling from these subcellular locations, this chapter emphasizes the mechanisms underlying signaling from intracellular receptor pools in diversifying receptor functionality. Such mechanistic insights into location-biased signaling open up novel therapeutic strategies aimed at targeting GPCRs within specific organelles, promising new levels of precision in therapeutic modulation and potential improvements in treatment efficacy and specificity.

Keywords: Endocytosis; G protein-coupled receptor; Location bias; Nanodomains; Subcellular locations; Trafficking.