Biosensors for translatable GPCR bias.

Abstract

Biased agonism at G protein-coupled receptors (GPCRs) is increasingly pursued to improve efficacy-safety relationships, but its translation remains limited by assay-dependent definitions of selectivity. Recent biosensors now resolve GPCR signaling across mechanistic layers that older endpoint assays often miss, including receptor conformational dynamics, heterotrimeric G protein coupling, Gα-GTP formation, β-arrestin and G protein-coupled receptor kinase engagement, activation trajectories, and signaling from intracellular compartments. Open and scalable platforms support comparative profiling, whereas more orthogonal unimolecular and endogenous-compatible systems improve mechanistic attribution and physiological relevance. Together with recent receptor-proximal studies, these advances indicate that bias should be treated as graded evidence rather than a binary label. In this opinion article, we discuss how biosensors convert assay-local signatures into translatable pharmacological evidence.