Modeling activation and desensitization of G-protein coupled receptors - Provides insight into ligand efficacy

Signaling through G-protein coupled receptors is one of the most prevalent and important methods of transmitting information to the inside of cells. M any mathematical models have been proposed to describe this type of signal transduction, and the ternary complex (ligand/receptor/G-protein) model and its derivatives are among the most widely accepted. Current versions of th ese equilibrium models include both active (i.e. signaling) and inactive co nformations of the receptor, but do not include the dynamics of G-protein a ctivation or receptor desensitization. Yet understanding how these dynamic events effect response behavior is crucial to determining ligand efficacy. We developed a mathematical model for G-protein coupled receptor signaling that includes G-protein activation and receptor desensitization, and used i t to predict how activation and desensitization would change if either the conformational selectivity (the effect of ligand binding on the distributio n of active and inactive receptor states) or the desensitization rate const ant was ligand-specific. In addition, the model was used to explore the imp lications of measuring responses far downstream from G-protein activation. By comparing the experimental data from the beta(2)-adrenergic, mu-opioid, D-1 dopamine, and neutrophil N-formyl peptide receptors with the prediction s of our model, we found that the conformational selectivity is the predomi nant factor in determining the amounts of activation and desensitization ca used by a particular ligand. (C) 1999 Academic Press.