Document Detail

MedLine Citation:
PMID:  11259634     Owner:  NLM     Status:  MEDLINE    
I suggested in the accompanying article [Mol Pharmacol 2001;59:875-885] that muscarinic receptors catalyzed G protein activation. Acetylcholine or carbamylcholine recognition facilitated not only the GDP release from receptor-coupled inactive G proteins but also the release of G from the (unstable) HRG complex. The two effects facilitated [(35)S]GTP gamma S binding in the presence of GDP, but could be studied separately by comparing [(35)S]GTP gamma S binding in the absence and presence of GTP. Guanyl nucleotides affected the efficiency of receptor-G protein coupling. The relative efficacies of partial agonists in the absence and presence of GTP should remain nonlinearly correlated if all agonists stabilize (to different extents) the same active receptor conformation. The correlation between M(1) muscarinic agonists' efficacy in accelerating [(35)S]GTP gamma S binding in the absence of other nucleotides and their in vivo efficacy (inositol phosphate accumulation) was in fact very poor. This probably reflected the presence of GTP in intact cells: pertussis toxin pretreatment (which inactivates the G(i/o) proteins) did not affect the agonists' efficacy profile (evaluated in the absence of spare receptors), but the addition of GTP to the [(35)S]GTP gamma S binding medium did. These results did not support the allosteric "two states" model of receptor activation, but suggested that different agonists induced different receptor conformations ("induced fit").
M Waelbroeck
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular pharmacology     Volume:  59     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-03-22     Completed Date:  2001-04-19     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  886-93     Citation Subset:  IM    
Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
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MeSH Terms
Binding, Competitive / drug effects
CHO Cells
Cell Membrane / metabolism*
Dose-Response Relationship, Drug
GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
Guanosine 5'-O-(3-Thiotriphosphate) / metabolism*,  pharmacokinetics
Guanosine Diphosphate / metabolism
Guanosine Triphosphate / metabolism
Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors
Models, Biological*
Muscarinic Agonists / metabolism,  pharmacology
Pertussis Toxin
Receptor, Muscarinic M1
Receptors, Muscarinic / genetics,  metabolism*
Reproducibility of Results
Sulfur Radioisotopes
Virulence Factors, Bordetella / pharmacology
Reg. No./Substance:
0/Muscarinic Agonists; 0/Receptor, Muscarinic M1; 0/Receptors, Muscarinic; 0/Sulfur Radioisotopes; 0/Virulence Factors, Bordetella; 146-91-8/Guanosine Diphosphate; 37589-80-3/Guanosine 5'-O-(3-Thiotriphosphate); 86-01-1/Guanosine Triphosphate; EC Toxin; EC Protein alpha Subunits, Gi-Go; EC GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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