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Dual positive and negative regulation of GPCR signaling by GTP hydrolysis

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Smith, Benjamin, Hill, Claire, Godfrey, Emma L., Rand, D. A. (David A.), Berg, Hugo van den, 1968-, Thornton, Steve, Hodgkin, Matthew N., Davey, John and Ladds, Graham . (2009) Dual positive and negative regulation of GPCR signaling by GTP hydrolysis. Cellular Signalling, Vol.21 (No.7). pp. 1151-1160. ISSN 0898-6568

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Official URL: http://dx.doi.org/10.1016/j.cellsig.2009.03.004

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 increase the intrinsic GTPase activity of G-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 G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 G produces this unimodal relationship.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Science > Molecular Organisation and Assembly in Cells (MOAC) Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	G proteins, Computer simulation
Journal or Publication Title:	Cellular Signalling
Publisher:	Elsevier Inc.
ISSN:	0898-6568
Date:	July 2009
Volume:	Vol.21
Number:	No.7
Number of Pages:	10
Page Range:	pp. 1151-1160
Identification Number:	10.1016/j.cellsig.2009.03.004
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), University Hospitals Coventry and Warwickshire NHS Trust
Grant number:	BB/G01227X/1 (BBSRC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/485