Biased GPCR Signaling: Possible Mechanisms and Therapeutic Applications

Biased signaling refers to the phenomenon where a ligand selectively activates specific downstream pathways of G protein-coupled receptors (GPCRs), such as the G protein-mediated pathway or the β-arrestin-mediated pathway. This mechanism can be influenced by receptor bias, ligand bias, system bias and spatial bias, all of which are shaped by the receptor’s conformational distinctions and kinetics. Since GPCRs are the largest class of drug targets, signaling bias garnered significant attention for its potential to enhance therapeutic efficacy while minimizing side effects. Despite intensive investigation, a major challenge lies in translating in vitro ligand efficacy into in vivo biological responses due to the dynamic and multifaceted nature of the in vivo environment. This review delves into the current understanding of GPCR-biased signaling, examining the role of structural bias at the molecular level, the impact of kinetic context on system and observational bias, and the challenges of applying these insights in drug development. It further explores future directions for advancing biased signaling applications, offering valuable perspectives on how to bridge the gap between in vitro studies and in vivo therapeutic design, ultimately accelerating the development of viable, biased therapeutics.