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Molecular Pharmacology

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Research ArticleArticle

Chimeric Receptor Analysis of the Ketanserin Binding Site in the Human 5-Hydroxytryptamine1D Receptor: Importance of the Second Extracellular Loop and Fifth Transmembrane Domain in Antagonist Binding

Thierry Wurch, Francis C. Colpaert and Petrus J. Pauwels
Molecular Pharmacology December 1998, 54 (6) 1088-1096; DOI: https://doi.org/10.1124/mol.54.6.1088
Thierry Wurch
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 81106 Castres Cédex, France
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Francis C. Colpaert
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 81106 Castres Cédex, France
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Petrus J. Pauwels
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 81106 Castres Cédex, France
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Abstract

The 5-hydroxytryptamine (5-HT)1B/1D receptor subtypes are involved in the regulation of 5-HT release and have gained particular interest because of their apparent role in migraine. Although selective antagonists for both receptor subtypes recently have been developed, the receptor domains involved in the pharmacological specificity of these antagonists are defined poorly. This was investigated with a chimeric 5-HT1B/1D receptor analysis and using ketanserin as a selective antagonist of h5-HT1D(h5-HT1D)K i = 24–27 nm) as opposed to h5-HT1B(K i = 2193–2902 nm) receptors. A domain of the h5-HT1Dreceptor encompassing the second extracellular loop and the fifth transmembrane domain is necessary and sufficient to promote higher affinity binding (K i = 65–115 nm) for ketanserin to the h5-HT1Breceptor. The same domain of the h5-HT1B receptor, when exchanged in the h5-HT1D receptor, abolished high affinity binding of ketanserin (K i = 364-1265 nm). A similar observation was made with the antagonist ritanserin and seems specific because besides the unmodified binding affinities for 5-HT and zolmitriptan, only minor modifications (2–4-fold) were observed for the agonists L 694247 and sumatriptan and the antagonists GR 127935 and SB 224289. Generating point mutations of divergent amino acids compared with the h5-HT1B receptor did not demonstrate a smaller peptide region related to a significant modification of ketanserin binding. The antagonists ketanserin and ritanserin are likely to bind the h5-HT1D receptor by its second extracellular loop, near the exofacial surface of the fifth transmembrane domain, or both.

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Molecular Pharmacology: 54 (6)
Molecular Pharmacology
Vol. 54, Issue 6
1 Dec 1998
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Research ArticleArticle

Chimeric Receptor Analysis of the Ketanserin Binding Site in the Human 5-Hydroxytryptamine1D Receptor: Importance of the Second Extracellular Loop and Fifth Transmembrane Domain in Antagonist Binding

Thierry Wurch, Francis C. Colpaert and Petrus J. Pauwels
Molecular Pharmacology December 1, 1998, 54 (6) 1088-1096; DOI: https://doi.org/10.1124/mol.54.6.1088

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Research ArticleArticle

Chimeric Receptor Analysis of the Ketanserin Binding Site in the Human 5-Hydroxytryptamine1D Receptor: Importance of the Second Extracellular Loop and Fifth Transmembrane Domain in Antagonist Binding

Thierry Wurch, Francis C. Colpaert and Petrus J. Pauwels
Molecular Pharmacology December 1, 1998, 54 (6) 1088-1096; DOI: https://doi.org/10.1124/mol.54.6.1088
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