GPCR signaling from endosome: mechanistic insights and therapeutic potentials

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors in the human body, playing key roles in numerous physiological and pathological processes. Notably, over 30 % of clinically approved drugs target GPCRs. The canonical paradigm suggests that GPCRs are activated at the plasma membrane, where ligand binding evokes the conformational changes that initiate downstream signaling cascades via G proteins and β-arrestin. Emerging evidence has revealed that GPCRs can be internalized into endosome, where they form GPCR-G protein-β-arrestin complex to trigger sustained signal transduction including cAMP, ERK1/2, mTOR and PKC signaling from endosome. Importantly, endosomal signaling by GPCR is crucial in various physiological functions and disease progression, such as pain, itch, cancer and inflammatory diseases. Targeting endosomal signaling becomes a promising direction in GPCR pharmacology, however, the modulatory effects on GPCR endosomal signaling and disease-related functions remain insufficiently explored. This review provides an updated overview of the structure, activation, signaling, and function of endosomal GPCRs, assisting better understanding of their roles in the endosome and providing a potential target or therapeutical strategy for diseases linked to endosomal signaling.