| Title: | Dual positive and negative regulation of GPCR signaling by GTP hydrolysis |
| Author(s): | Smith B; Hill C; Godfrey EL; Rand D; van den Berg H; Thornton S; Hodgkin M; Davey J; Ladds G; |
| Address: | "Molecular Organization and Assembly of Cells Centre, University of Warwick, Coventry, UK" |
| DOI: | 10.1016/j.cellsig.2009.03.004 |
| ISSN/ISBN: | 1873-3913 (Electronic) 0898-6568 (Linking) |
| 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" |
| Keywords: | "GTP-Binding Protein alpha Subunits/metabolism Gene Deletion Guanosine Triphosphate/*metabolism Hydrolysis Models, Biological Pheromones/metabolism RGS Proteins/metabolism Receptors, G-Protein-Coupled/*metabolism Schizosaccharomyces/*metabolism Schizosacch;" |
| Notes: | "MedlineSmith, Benjamin Hill, Claire Godfrey, Emma L Rand, David van den Berg, Hugo Thornton, Steven Hodgkin, Matthew Davey, John Ladds, Graham eng BB/G01227X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom Research Support, Non-U.S. Gov't England 2009/03/17 Cell Signal. 2009 Jul; 21(7):1151-60. doi: 10.1016/j.cellsig.2009.03.004. Epub 2009 Mar 12" |
