Regulators of G protein signaling and transient activation of signaling: experimental and computational analysis reveals negative and positive feedback controls on G protein activity.
Cellular responses to hormones and neurotransmitters are necessarily transient. The mating pheromone signal in yeast is typical. Signal initiation requires cell surface receptors, a G protein heterotrimer, and down-stream effectors. Signal inactivation requires Sst2, a regulator of G protein signaling (RGS) protein that accelerates GTPase activity. We conducted a quantitative analysis of RGS and G protein expression and devised computational models that describe their activity in vivo. These results indicated that pheromone-dependent transcriptional induction of the RGS protein constitutes a negative feedback loop that leads to desensitization. Modeling also suggested the presence of a positive feedback loop leading to resensitization of the pathway. In confirmation of the model, we found that the RGS protein is ubiquitinated and degraded in response to pheromone stimulation. We identified and quantitated these positive and negative feedback loops, which account for the transient response to external signals observed in vivo.
Hao
Nan
N
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-0812, USA.
Yildirim
Necmettin
N
Wang
Yuqi
Y
Elston
Timothy C
TC
Dohlman
Henrik G
HG
D003198:Computer Simulation; D025461:Feedback, Physiological; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D010675:Pheromones; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D020710:RGS Proteins
D020690:GTPase-Activating Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D010675:Pheromones; D029701:Saccharomyces cerevisiae Proteins; C094301:SST2 protein, S cerevisiae; D020710:RGS Proteins