title: The 5-HT4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT4(c) receptor.
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 microM completely abolished the 5-HT (1 microM)-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.
authors.affiliation: Institut de Signalisation et Innovation Thérapeutique (IFR-ISIT), Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université de Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: O
authors.initials: O
authors.lastname: Blondel
authors.forename: M
authors.initials: M
authors.lastname: Gastineau
authors.forename: M
authors.initials: M
authors.lastname: Langlois
authors.forename: R
authors.initials: R
authors.lastname: Fischmeister
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D037342:Pertussis Toxin; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D062366:para-Aminobenzoates
chemical_list: C117877:2-(3,5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate; D037361:Adenylate Cyclase Toxin; D062365:Aminobenzoates; D010880:Piperidines; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D010566:Virulence Factors, Bordetella; D062366:para-Aminobenzoates; D012701:Serotonin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases