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: 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)
• 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

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