Linked Life Data

12446706

Source:http://linkedlifedata.com/resource/pubmed/id/12446706

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2003-2-24
pubmed:abstractText
Regulators of G protein signaling (RGS) are GTPase-accelerating proteins (GAPs), which can inhibit heterotrimeric G protein pathways. In this study, we provide experimental and theoretical evidence that high concentrations of receptors (as at a synapse) can lead to saturation of GDP-GTP exchange making GTP hydrolysis rate-limiting. This results in local depletion of inactive heterotrimeric G-GDP, which is reversed by RGS GAP activity. Thus, RGS enhances receptor-mediated G protein activation even as it deactivates the G protein. Evidence supporting this model includes a GTP-dependent enhancement of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding to G(i) by RGS. The RGS domain of RGS4 is sufficient for this, not requiring the NH(2)- or COOH-terminal extensions. Furthermore, a kinetic model including only the GAP activity of RGS replicates the GTP-dependent enhancement of GTPgammaS binding observed experimentally. Finally in a Monte Carlo model, this mechanism results in a dramatic "spatial focusing" of active G protein. Near the receptor, G protein activity is maintained even with RGS due to the ability of RGS to reduce depletion of local Galpha-GDP levels permitting rapid recoupling to receptor and maintained G protein activation near the receptor. In contrast, distant signals are suppressed by the RGS, since Galpha-GDP is not depleted there. Thus, a novel RGS-mediated "kinetic scaffolding" mechanism is proposed which narrows the spatial range of active G protein around a cluster of receptors limiting the spill-over of G protein signals to more distant effector molecules, thus enhancing the specificity of G(i) protein signals.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7278-84
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12446706-Animals, pubmed-meshheading:12446706-CHO Cells, pubmed-meshheading:12446706-Cricetinae, pubmed-meshheading:12446706-Dose-Response Relationship, Drug, pubmed-meshheading:12446706-GTP Phosphohydrolases, pubmed-meshheading:12446706-Glutathione Transferase, pubmed-meshheading:12446706-Guanosine 5'-O-(3-Thiotriphosphate), pubmed-meshheading:12446706-Guanosine Diphosphate, pubmed-meshheading:12446706-Guanosine Triphosphate, pubmed-meshheading:12446706-Hydrolysis, pubmed-meshheading:12446706-Kinetics, pubmed-meshheading:12446706-Monte Carlo Method, pubmed-meshheading:12446706-Protein Binding, pubmed-meshheading:12446706-Protein Structure, Tertiary, pubmed-meshheading:12446706-RGS Proteins, pubmed-meshheading:12446706-Recombinant Fusion Proteins, pubmed-meshheading:12446706-Signal Transduction, pubmed-meshheading:12446706-Time Factors
pubmed:year
2003
pubmed:articleTitle
A spatial focusing model for G protein signals. Regulator of G protein signaling (RGS) protien-mediated kinetic scaffolding.
pubmed:affiliation
Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109-0632, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.