Ligand-specific Biphasic Modulation In G Protein Coupled Receptor And Its Mechanism

G protein-coupled receptors are seven transmembrane-domain proteins.Representing the largest family of cell-surface receptors,it plays an important role in physiological and pathological processes.In 1980,De Lean and Lefkowitz proposed the ternary complex model which revealed the mechanism for G protein coupling to the receptors and established the theoretical basis of different ligand-receptor interactions.Our research focuses on two types of G protein-coupled receptors:Formyl peptide receptor 2 and chemokine-like receptor 1.We have detected different ligand-receptor interactions on these two receptors and their effects on downstream signaling pathways.We used a common ligand for the two receptors:Aβ₄₂ that can modulate the effect produced by orthosteric agonists.This modulation dose not fit the classic hyperbolic kinetics but shows biphasic dose-response curves.In further research,we discovered that Aβ₄₂ can modulate the affinity and efficacy of agonists,suggesting that it can act as an allosteric modulator.In addition to these observations,we found that another ligand of formyl-peptide receptor 2,AC2-26,can have diverse allosteric effects compared with Aβ₄₂.This ligand-specific allosteric modulation also influences the activation of phosphorylation pathways.By applying quantitive models to experimental results,we proposed that these interactions fit a two-allosteric-site model.