Kinetic Model of Partial Agonism Reveals Cellular Basis of Ligand Efficacy

Titrating G protein-coupled receptor (GPCR) signaling to achieve desired physiological outcomes without overdose can be accomplished through partial agonism rather than drug dosage.In this study, we use FRET-based biosensors in combination with ordinary differential equation modelling to identify two key kinetic features that determine agonist efficacy: the concentration-dependent association rate of the G protein to the agonist-bound receptor, and the catalytic rate of G protein activation by the receptor.While both rate constants scale proportionally with reported molecular efficacy metrics, we find the concentrationdependent association rate to be the governing parameter across multiple distinct GPCR-ligand pairings.Our model explains discrepancies in signaling outcomes observed between physiological observations and cellular model systems that rely on receptor overexpression.