Biased Signaling in G Protein-Coupled Receptors: Understanding the Biological Relevance and Tools for Probing Functionally Selective Ligands

Abstract

Biased signaling has transformed pharmacology by revealing that receptors, particularly G protein-coupled receptors (GPCRs), can activate specific intracellular pathways selectively rather than uniformly. This discovery enables the development of targeted therapeutics that minimize side effects by precisely modulating receptor activity. Functionally selective ligands, which preferentially activate distinct signaling branches, have become essential tools for exploring receptor mechanisms and uncovering the complexities of GPCR signaling. These ligands help clarify receptor function in various physiological and pathological contexts, offering profound implications for therapeutic innovation. GPCRs, which mediate a wide range of cellular responses through coupling to G proteins and arrestins, are key pharmacological targets, with nearly a third of FDA-approved drugs acting on them. Recent advancements in biosensor development, multiplex assay platforms, and deep mutational scanning methods are improving our ability to define GPCR signaling, allowing for a better understanding of biased signaling pathways.