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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., 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. 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 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:

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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