Convergence of Melatonin and 5-HT Signaling at MT2/5-HT2C Receptor Heteromers [Signal Transduction]

March 13th, 2015 by Kamal, M., Gbahou, F., Guillaume, J.-L., Daulat, A. M., Benleulmi-Chaachoua, A., Luka, M., Chen, P., Kalbasi Anaraki, D., Baroncini, M., Mannoury la Cour, C., Millan, M. J., Prevot, V., Delagrange, P., Jockers, R.

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 crosstalk 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, BRET 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/PLC response and triggered melatonin-induced unidirectional trans-activation 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.