Mechanistic model of G-protein signal transduction. Determinants of efficacy and effect of precoupled receptors.

Tissue-specific characteristics (e.g. receptor number) and agonist-specific characteristics (e.g. agonist binding kinetics) play roles in determining cellular response. The roles that these characteristics play are quantified by models of signal transduction. We examined signal transduction through G-protein-linked receptors, using a model based on the collision coupling model but including interconverting receptor states and the precoupling of receptors with G-proteins prior to the addition of agonist. Reaction and diffusion of molecules within the plasma membrane were simulated using Monte Carlo techniques. The G-protein activation produced by our model was compared with that produced by the collision coupling model. We quantitatively examined how the parameters characteristic of the tissue and agonist determine the midpoint and maximal response of the dose-response curve. Activation through agonist binding to precoupled receptors can produce significantly higher activation rates than does collision coupling. Tissue and agonist characteristics have qualitatively similar effects but quantitatively distinct effects on activation for the two models. Using standard experimental techniques, it may be possible to exploit these differences to determine the mechanism of G-protein activation in a specific cell system. A quantitative comparison of model predictions with published data on the beta-adrenergic receptor system (Stickle D and Barber R, Mole Pharmacol 40: 276-288, 1991) also is presented.