The 5-HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT4(c) receptor |
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| Authors: | Olivier Blondel Monique Gastineau Michel Langlois Rodolphe Fischmeister |
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| Affiliation: | 1.Institut de Signalisation et Innovation Thérapeutique (IFR-ISIT), France;2.Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, France;3.Laboratoire de Reconnaissance Moléculaire et Cellulaire, BIOCIS CNRS URA 1843, Université de Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France |
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| Abstract: | Transient expression in COS-7 cells of the recombinant human 5-hydroxytryptamine (5-HT) h5-HT4(c) receptor isoform led to constitutive activity of the receptor. The 5-HT4 receptor antagonist 2-(cis-3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate (ML10375) at 1 μM completely abolished the 5-HT (1 μM)-mediated increase in adenylyl cyclase activity in COS-7 cells expressing the h5-HT4(c) receptor. Moreover, ML10375 also reduced basal cAMP levels in cells over-expressing the receptor, even in the absence of agonist. The inhibitory effect of ML10375 on basal adenylyl cyclase activity was not modified by pre-treatment of the cells with pertussis toxin, indicating that ML10375 acts through inactivation of spontaneously active h5-HT4(c) receptors rather than through a Gi/Go regulatory pathway. We conclude that ML10375 acts as an inverse agonist on the h5-HT4(c) receptor. |
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| Keywords: | Human serotonin 5-HT4 receptors inverse agonist ML10375 |
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