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 ISSN 0898-6568.
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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 GGTP 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, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) Faculty of Science, Engineering and Medicine > Research Centres > Molecular Organisation and Assembly in Cells (MOAC) Faculty of Science, Engineering and Medicine > 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 (Creative Commons open licence) |
| 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) |
| URI: | https://wrap.warwick.ac.uk/485/ |
Data sourced from Thomson Reuters' Web of Knowledge
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