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J. Biol. Chem. 278 (47): 46506-46515

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulators of G Protein Signaling and Transient Activation of Signaling

EXPERIMENTAL AND COMPUTATIONAL ANALYSIS REVEALS NEGATIVE AND POSITIVE FEEDBACK CONTROLS ON G PROTEIN ACTIVITY*

Nan Hao{ddagger}, Necmettin Yildirim§, Yuqi Wang{ddagger}, Timothy C. Elston§¶, , and Henrik G. Dohlman{ddagger}||

{ddagger}Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-0812 and the §Department of Mathematics, University of North Carolina, Chapel Hill, North Carolina 27599-3250

Abstract: 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.

Received for publication August 1, 2003.

* This work was supported by National Institutes of Health Grants GM55316 and GM59167 (to H. G. D.), by American Heart Association Fellowship 0225390U (to Y. W.), and by Defense Advanced Research Projects Agency Grant F30602-01-2-0579 (to T. C. E. and N. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: telston{at}amath.unc.edu. || To whom correspondence may be addressed. E-mail: hdohlman{at}med.unc.edu.

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