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Cell Signal. 2009 Jul;21(7):1151-60. doi: 10.1016/j.cellsig.2009.03.004. Epub 2009 Mar 12.

Dual positive and negative regulation of GPCR signaling by GTP hydrolysis.

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1
Molecular Organization and Assembly of Cells Centre, University of Warwick, Coventry, UK.

Abstract

G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increases the intrinsic GTPase activity of Galpha-subunits and are widely regarded as negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where Galpha(GTP) enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the Galpha produces this unimodal relationship.

PMID:
19285552
DOI:
10.1016/j.cellsig.2009.03.004
[Indexed for MEDLINE]
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