title: Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers.
abstract: Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto unrecognized cross-talk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant agomelatine. A suite of co-immunoprecipitation, bioluminescence resonance energy transfer, and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/phospholipase C response and triggered melatonin-induced unidirectional transactivation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling." These observations demonstrate the existence of functionally unique MT2/5-HT2C heteromers and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders.
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gbahou
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guillaume
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Avais M
authors.initials: AM
authors.lastname: Daulat
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Abla
authors.initials: A
authors.lastname: Benleulmi-Chaachoua
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Luka
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Patty
authors.initials: P
authors.lastname: Chen
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Dina
authors.initials: D
authors.lastname: Kalbasi Anaraki
authors.affiliation: INSERM, Jean-Pierre Aubert Research Center, U837, 59045 Lille, France, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Baroncini
authors.affiliation: Institut de Recherches Servier, 78290 Croissy/Seine, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.affiliation: Institut de Recherches Servier, 78290 Croissy/Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: INSERM, Jean-Pierre Aubert Research Center, U837, 59045 Lille, France, and.
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
authors.affiliation: Institut de Recherches Servier, 78290 Croissy/Seine, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.affiliation: From the INSERM, U1016, Institut Cochin, 75014 Paris, France, CNRS UMR 8104, 75014 Paris, France, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France, ralf.jockers@inserm.fr.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D010738:Type C Phospholipases / Q000378:metabolism; D000071557:beta-Arrestins; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D019390:Arrestins; D008550:Melatonin; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D044405:Receptor, Serotonin, 5-HT2C; D012701:Serotonin; D010738:Type C Phospholipases; D000071557:beta-Arrestins; C084711:agomelatine; D009281:Naphthalenes
keywords: Cell Signaling; Depression; G Protein-coupled Receptor (GPCR); GPCR; Heteromerization; Melatonin; Molecular Pharmacology; Serotonin