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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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 |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 290
Issue 18
Pg. 11537-46
(May 01 2015)
ISSN: 1083-351X [Electronic] United States |
PMID | 25770211
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. |
Chemical References |
- Acetamides
- Arrestins
- Receptor, Melatonin, MT1
- Receptor, Melatonin, MT2
- Receptor, Serotonin, 5-HT2C
- beta-Arrestins
- agomelatine
- Serotonin
- Type C Phospholipases
- Melatonin
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Topics |
- Acetamides
(pharmacology)
- Arrestins
(metabolism)
- Drug Synergism
- Gene Expression Regulation
(drug effects)
- HEK293 Cells
- HeLa Cells
- Humans
- Melatonin
(metabolism, pharmacology)
- Protein Multimerization
(drug effects)
- Protein Structure, Quaternary
- Protein Transport
(drug effects)
- Receptor, Melatonin, MT1
(metabolism)
- Receptor, Melatonin, MT2
(chemistry, genetics, metabolism)
- Receptor, Serotonin, 5-HT2C
(chemistry, genetics, metabolism)
- Serotonin
(metabolism, pharmacology)
- Signal Transduction
(drug effects)
- Transcriptional Activation
(drug effects, genetics)
- Type C Phospholipases
(metabolism)
- beta-Arrestins
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