Convergence of Melatonin and Serotonin (5-HT) Signaling at MT2/5-HT2C Receptor Heteromers |
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Authors: | Maud Kamal Florence Gbahou Jean-Luc Guillaume Avais M. Daulat Abla Benleulmi-Chaachoua Marine Luka Patty Chen Dina Kalbasi Anaraki Marc Baroncini Clotilde Mannoury la Cour Mark J. Millan Vincent Prevot Philippe Delagrange Ralf Jockers |
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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.;‖INSERM, Jean-Pierre Aubert Research Center, U837, 59045 Lille, France, and ;**Institut de Recherches Servier, 78290 Croissy/Seine, France |
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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. |
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Keywords: | Cell Signaling Depression G Protein-coupled Receptor (GPCR) Molecular Pharmacology Serotonin GPCR Heteromerization Melatonin |
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