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 s eries of dynamic events that ultimately leads to a cellular response. In ad dition to the concentrations of receptor, drug and G-protein, important det erminants of the cellular response are the rates at which these species int eract. However, most models for G-protein coupled receptor signaling are eq uilibrium models that neglect the role of reaction kinetics. A kinetic tern ary-complex model of signaling through G-protein coupled receptors is prese nted. We demonstrate that this kinetic model can make significantly differe nt predictions than an equilibrium ternary complex model, which provides a different perspective on multiple aspects of the signal transduction cascad e, such as agonist efficacy, the effect of precoupled receptors, and the ro le 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. (C) 2000 Elsevier Science Inc . All rights reserved.