Specific interaction of 5-HT-moduline with human 5-HT1b as well as 5-HT1d receptors expressed in transfected cultured cells |
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Authors: | Jean-Claude Rousselle Mathieu Plantefol Marie-Paule Fillion Olivier Massot Petrus J Pauwels G Fillion |
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Institution: | (1) Unité de Pharmacologie Neuro-Immuno-Endocrinienne, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris Cedex 15, France, FR;(2) Centre de Recherche Pierre Fabre, Department of Cellular and Molecular Neurobiology, 17, avenue Jean Moulin, F-81106 Castres Cedex, France, FR |
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Abstract: | 5-HT1B receptors are the predominant auto- and heteroreceptors located on serotonergic and non-serotonergic terminals where they
regulate the neuronal release of neurotransmitters. 5-HT-moduline (Leu-Ser-Ala-Leu) has been shown to specifically interact
with a very high apparent affinity and in a non-competitive manner with 5-HT1B receptors (Massot et al. 1996; Rousselle et al. 1996). Using transfected cells expressing either 5-HT1B or 5-HT1D receptors, it was shown that 5-HT-moduline prevents the binding of 3H]5-HT to 5-HT1B as well as to 5-HT1D receptors with similar biochemical characteristics: the IC50 of the peptide was 1.2×10–12 M for 5-HT1B and 9×10–13 M for 5-HT1D receptors. The observed effect corresponds to a marked decrease of the maximal binding for 3H]5-HT on 5-HT1B (–51.2±1%) as well as 5-HT1D binding (–47.2±7.7% of the control binding) whereas the affinity of 5-HT is increased by a factor close to 3. No effect is
observed using the “scrambled” peptide (Ala-Leu-Leu-Ser). Parallel assays using transfected cells expressing 5-HT1A or 5-ht6 receptors did not show any significant change induced by the peptide under similar assay conditions. The interaction of the
peptide was also studied on the functional activity related to the stimulation of the receptors as measured by the increase
in 35S]GTPγS binding reflecting the coupling of the receptor to the G-protein. 5-HT-moduline yields an antagonistic effect on the
5-HT induced coupling with a corresponding IC50=1.2±0.7×10–12 M for 5-HT1B and 9.8±4.0×10–12 M for 5-HT1D receptors, respectively. The present results demonstrate that 5-HT-moduline interacts with 5-HT1D as well as 5-HT1B receptors and possesses a non-competitive antagonistic activity, likely corresponding to its role of endogenous allosteric
modulator, specific for both 5-HT1B and 5-HT1D receptors.
Received: 26 March 1998 / Accepted: 22 May 1998 |
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Keywords: | 5-HT moduline 5-HT1B receptors 5-HT1D receptors Allosteric modulator Endogenous peptide |
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