Timing is everything the role of kinetics in G protein activation

The binding of a drug to a G-protein coupled receptor initiates a complex series of dynamic events that ultimately leads to a cellular response. In addition to the concentrations of receptor, drug and G-protein, important determinants of the cellular response are the rates at which these species interact. However, most models for G-protein coupled receptor signaling are equilibrium models that neglect the role of reaction kinetics. A kinetic ternary-complex model of signaling through G-protein coupled receptors is presented. We demonstrate that this kinetic model can make significantly different predictions than an equilibrium ternary complex model, which provides a different perspective on multiple aspects of the signal transduction cascade, such as agonist efficacy, the effect of precoupled receptors, and the role of RGS proteins. Incorporation of the reaction kinetics is critical for a complete understanding of signal transduction and will ultimately impact the fields of drug discovery and drug design.