Smith, Benjamin, Hill, Claire, Godfrey, Emma L., Rand, D. A., Berg, Hugo van den, Thornton, Steven, 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. doi:10.1016/j.cellsig.2009.03.004

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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 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
Official Date:	July 2009
Dates:	Date Event July 2009 Published
Volume:	Vol.21
Number:	No.7
Number of Pages:	10
Page Range:	pp. 1151-1160
DOI:	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)

Data sourced from Thomson Reuters' Web of Knowledge

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