PMID- 19285552
OWN - NLM
STAT- MEDLINE
DCOM- 20090603
LR  - 20211028
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 21
IP  - 7
DP  - 2009 Jul
TI  - Dual positive and negative regulation of GPCR signaling by GTP hydrolysis.
PG  - 1151-60
LID - 10.1016/j.cellsig.2009.03.004 [doi]
AB  - 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.
FAU - Smith, Benjamin
AU  - Smith B
AD  - Molecular Organization and Assembly of Cells Centre, University of Warwick, 
      Coventry, UK.
FAU - Hill, Claire
AU  - Hill C
FAU - Godfrey, Emma L
AU  - Godfrey EL
FAU - Rand, David
AU  - Rand D
FAU - van den Berg, Hugo
AU  - van den Berg H
FAU - Thornton, Steven
AU  - Thornton S
FAU - Hodgkin, Matthew
AU  - Hodgkin M
FAU - Davey, John
AU  - Davey J
FAU - Ladds, Graham
AU  - Ladds G
LA  - eng
GR  - BB/G01227X/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090312
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (GTP-Binding Protein alpha Subunits)
RN  - 0 (Pheromones)
RN  - 0 (RGS Proteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Rgs1 protein, S pombe)
RN  - 0 (Schizosaccharomyces pombe Proteins)
RN  - 86-01-1 (Guanosine Triphosphate)
SB  - IM
MH  - GTP-Binding Protein alpha Subunits/metabolism
MH  - Gene Deletion
MH  - Guanosine Triphosphate/*metabolism
MH  - Hydrolysis
MH  - Models, Biological
MH  - Pheromones/metabolism
MH  - RGS Proteins/metabolism
MH  - Receptors, G-Protein-Coupled/*metabolism
MH  - Schizosaccharomyces/*metabolism
MH  - Schizosaccharomyces pombe Proteins/metabolism
MH  - *Signal Transduction
MH  - Time Factors
EDAT- 2009/03/17 09:00
MHDA- 2009/06/06 09:00
CRDT- 2009/03/17 09:00
PHST- 2009/01/19 00:00 [received]
PHST- 2009/03/04 00:00 [accepted]
PHST- 2009/03/17 09:00 [entrez]
PHST- 2009/03/17 09:00 [pubmed]
PHST- 2009/06/06 09:00 [medline]
AID - S0898-6568(09)00106-5 [pii]
AID - 10.1016/j.cellsig.2009.03.004 [doi]
PST - ppublish
SO  - Cell Signal. 2009 Jul;21(7):1151-60. doi: 10.1016/j.cellsig.2009.03.004. Epub 
      2009 Mar 12.