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Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5‐HT 2C receptor heteromers in mouse brain
Author(s) -
Gerbier Romain,
NdiayeLobry Delphine,
Martinez de Morentin Pablo B.,
Cecon Erika,
Heisler Lora K.,
Delagrange Philippe,
Gbahou Florence,
Jockers Ralf
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000305r
Subject(s) - melatonin , melatonin receptor , serotonin , agomelatine , receptor , 5 ht2c receptor , agonist , g protein coupled receptor , 5 ht receptor , chemistry , knockout mouse , in vivo , pharmacology , medicine , microbiology and biotechnology , endocrinology , neuroscience , biology , biochemistry , antidepressant , hippocampus
Abstract Association of G protein‐coupled receptors into heterodimeric complexes has been reported for over 50 receptor pairs in vitro but functional in vivo validation remains a challenge. Our recent in vitro studies defined the functional fingerprint of heteromers composed of G i ‐coupled melatonin MT 2 receptors and G q ‐coupled serotonin 5‐HT 2C receptors, in which melatonin transactivates phospholipase C (PLC) through 5‐HT 2C . Here, we identified this functional fingerprint in the mouse brain. G q protein activation was probed by [ 35 S]GTPγS incorporation followed by G q immunoprecipitation, and PLC activation by determining the inositol phosphate levels in brain lysates of animals previously treated with melatonin. Melatonin concentration‐dependently activated G q proteins and PLC in the hypothalamus and cerebellum but not in cortex. These effects were inhibited by the 5‐HT 2C receptor‐specific inverse agonist SB‐243213, and were absent in MT 2 and 5‐HT 2C knockout mice, fully recapitulating previous in vitro data and indicating the involvement of MT 2 /5‐HT 2C heteromers. The antidepressant agomelatine had a similar effect than melatonin when applied alone but blocked the melatonin‐promoted G q activation due to its 5‐HT 2C antagonistic component. Collectively, we provide strong functional evidence for the existence of MT 2 /5‐HT 2C heteromeric complexes in mouse brain. These heteromers might participate in the in vivo effects of agomelatine.

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