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Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers.

Authors
  • Kamal, Maud
  • Gbahou, Florence
  • Guillaume, Jean-Luc
  • Daulat, Avais M
  • Benleulmi-Chaachoua, Abla
  • Luka, Marine
  • Chen, Patty
  • Kalbasi Anaraki, Dina
  • Baroncini, Marc
  • Mannoury la Cour, Clotilde
  • Millan, Mark J
  • Prevot, Vincent
  • Delagrange, Philippe
  • Ralf Jockers
Type
Published Article
Journal
Brain Behavior and Immunity
Publisher
Elsevier
Publication Date
Apr 30, 2015
Volume
290
Issue
18
Pages
11537–11546
Identifiers
DOI: 10.1074/jbc.M114.559542
PMID: 25770211
Source
USPC - SET - SVS
Keywords
License
Unknown

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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