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Molecular Pharmacology

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Native Rat Hippocampal 5-HT1A Receptors Show Constitutive Activity

Jean-Claude Martel, Anne-Marie Ormière, Nathalie Leduc, Marie-Bernadette Assié, Didier Cussac and Adrian Newman-Tancredi
Molecular Pharmacology March 2007, 71 (3) 638-643; DOI: https://doi.org/10.1124/mol.106.029769
Jean-Claude Martel
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Anne-Marie Ormière
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Nathalie Leduc
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Marie-Bernadette Assié
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Didier Cussac
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Adrian Newman-Tancredi
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Abstract

Previous studies have shown that human 5-hydroxytryptamine (5-HT)1A receptors stably expressed in transfected cell lines show constitutive G-protein activity, as revealed by the inhibitory effect of inverse agonists, such as spiperone, on basal guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding. In the present study, we evaluated the constitutive activity of native rat 5-HT1A receptors in hippocampal membranes. Using anti-Gαo-antibody capture coupled to scintillation proximity assay under low sodium (30 mM) conditions, we observed high basal [35S]GTPγS binding to Gαo subunits (defined as 100%). Under these conditions, 5-HT and the prototypic selective 5-HT1A agonist (+)8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] both stimulated [35S]GTPγS binding to Gαo to a similar extent, raising binding to approximately 130% of basal with pEC50 values of 7.91 and 7.87, respectively. The 5-HT1A-selective neutral antagonist [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100,635) could block these effects in a competitive manner with pKb values (5-HT, 9.57; (+)-8-OH-DPAT, 9.52) that are consistent with its pKi value at r5-HT1A receptors (9.33). In this native receptor system, spiperone and methiothepin reduced basal [35S]GTPγS binding to Gαo in a concentration-dependent manner to 90% of basal with pIC50 values of 7.37 and 7.98, respectively. The inhibition of basal [35S]GTPγS binding induced by maximally effective concentrations of spiperone (10 μM) or methiothepin (1 μM) was antagonized by WAY100,635 in a concentration-dependent manner (pKb, 9.52 and 8.87, respectively), thus indicating that this inverse agonism was mediated by 5-HT1A receptors. These data provide the first demonstration that native rat serotonin 5-HT1A receptors can exhibit constitutive activity in vitro.

Footnotes

  • This work has been previously presented in abstract form: Martel JC, Ormiere AM, Assie MB, Cussac D, and Newman-Tancredi A (2005) Spiperone and methiothepin act as inverse agonists on native rat hippocampal 5-HT1A receptors coupled to Gαo-protein. Soc Neurosci Abstr31:373.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.029769.

  • ABBREVIATIONS: GPCR, G-protein-coupled receptor; WAY100,635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; [35S]GTPγS, guanosine-5′-O-(3-[35S]thio)-triphosphate; (+)8-OH-DPAT, (+)8-hydroxy-2-(di-n-propylamino)tetralin; SPA, scintillation proximity assay; 5-HT, 5-hydroxytryptamine; DTT, dithiothreitol.

    • Received August 10, 2006.
    • Accepted December 13, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Native Rat Hippocampal 5-HT1A Receptors Show Constitutive Activity

Jean-Claude Martel, Anne-Marie Ormière, Nathalie Leduc, Marie-Bernadette Assié, Didier Cussac and Adrian Newman-Tancredi
Molecular Pharmacology March 1, 2007, 71 (3) 638-643; DOI: https://doi.org/10.1124/mol.106.029769

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Native Rat Hippocampal 5-HT1A Receptors Show Constitutive Activity

Jean-Claude Martel, Anne-Marie Ormière, Nathalie Leduc, Marie-Bernadette Assié, Didier Cussac and Adrian Newman-Tancredi
Molecular Pharmacology March 1, 2007, 71 (3) 638-643; DOI: https://doi.org/10.1124/mol.106.029769
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