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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Landry, Y. Chahdi, A. Daeffler, L. Gies, J. P. |
| Description | Author Affiliation: Daeffler L ( Laboratoire de Neuroimmunopharmacologie, INSERM U 425, Faculté de Pharmacie, Université Strasbourg I, Illkirch, France.) |
| Abstract | 1. The effects of spermine and methoctramine, a selective M2 muscarinic receptor antagonist, were studied on the high-affinity GTPase activity of G proteins, and on ligand binding to M2 muscarinic receptors in pig heart sarcolemma. 2. The spontaneous GTP hydrolysis by pig heart sarcolemma and its stimulation by mastoparan or carbachol were prevented by pertussis toxin and inhibited by methoctramine (IC50s: 21, 13 and 0.005 microM, respectively), and spermine (IC50s: 967, 278 and 11 microM). Spermine and methoctramine also inhibited spontaneous GTP hydrolysis by rat peritoneal mast cell membranes which do not respond to carbachol. 3. The neutral muscarinic antagonists, AF-DX 116 and atropine, did not modify the inhibitory effect of high concentrations of methoctramine, indicating that this effect was not related to the antagonist binding site of muscarinic receptors. We suggest that methoctramine behaves as a receptor antagonist at nanomolar concentrations and interacts with G proteins at micromolar concentrations. 4. Spermine did not modify the binding of the tritiated muscarinic antagonist [3H]-NMS, but decreased the binding of the agonist [3H]-Oxo-M. Spermine elicited a rightward shift of the carbachol/[3H]-NMS binding isotherm with a decrease in the proportion of sites with high-affinity for carbachol, suggesting that polyamines uncouple Gi proteins from receptors. 5. The inhibition of GTPase activity by polyamines, preventing the re-association of alpha and betagamma subunits of Gi proteins, might sustain the regulatory effect of Gi subunits on downstream effectors. The level of intracellular polyamines might be important for the control of the transduction of extracellular signals through Gi protein-coupled receptors. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 127 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 1999-06-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Diamines Pharmacology GTP Phosphohydrolases Antagonists & Inhibitors GTP-Binding Protein Alpha Subunits, Gi-Go Muscarinic Agonists Metabolism Muscarinic Antagonists Receptors, Muscarinic Spermine Animals N-Methylscopolamine Organ Specificity Oxotremorine Analogs & Derivatives Receptor, Muscarinic M2 Swine |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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