Mathematical modeling of RGS and G-protein regulation in yeast.

G-protein-activated signaling pathways are capable of adapting to a persistent external stimulus. Desensitization is thought to occur at the receptor level as well as through negative feedback by a family of proteins called regulators of G-protein signaling (RGS). The pheromone response pathway in yeast is a typical example of such a system, and the relative simplicity of this pathway makes it an attractive system in investigating the regulatory role of RGS proteins. Two studies have used computational modeling to gain insight into how this pathway is regulated (Hao et al., 2003; Yi et al., 2003). This article provides an introduction to computational analysis of signaling pathways by developing a mathematical model of the pheromone response pathway that synthesizes the results of these two investigations. Our model qualitatively captures many features of the pathway and suggests an additional mechanism for pathway inactivation. It also illustrates that a complete understanding of signaling pathways requires an investigation of their time-dependent behavior.