Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5‐HT 2C receptor heteromers in mouse brain - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue FASEB Journal Année : 2021

Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5‐HT 2C receptor heteromers in mouse brain

Romain Gerbier
Erika Cecon
Florence Gbahou
  • Fonction : Auteur
Ralf Jockers

Résumé

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 Gi-coupled melatonin MT2 receptors and Gq-coupled serotonin 5-HT2C receptors, in which melatonin transactivates phospholipase C (PLC) through 5-HT2C. Here, we identified this functional fingerprint in the mouse brain. Gq protein activation was probed by [35S]GTPγS incorporation followed by Gq immunoprecipitation, and PLC activation by determining the inositol phosphate levels in brain lysates of animals previously treated with melatonin. Melatonin concentration-dependently activated Gq proteins and PLC in the hypothalamus and cerebellum but not in cortex. These effects were inhibited by the 5-HT2C receptor-specific inverse agonist SB-243213, and were absent in MT2 and 5-HT2C knockout mice, fully recapitulating previous in vitro data and indicating the involvement of MT2/5-HT2C heteromers. The antidepressant agomelatine had a similar effect than melatonin when applied alone but blocked the melatonin-promoted Gq activation due to its 5-HT2C antagonistic component. Collectively, we provide strong functional evidence for the existence of MT2/5-HT2C heteromeric complexes in mouse brain. These heteromers might participate in the in vivo effects of agomelatine.
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Dates et versions

hal-03560716 , version 1 (07-02-2022)

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Romain Gerbier, Delphine Ndiaye‐lobry, Pablo Martinez de Morentin, Erika Cecon, Lora Heisler, et al.. Pharmacological evidence for transactivation within melatonin MT 2 and serotonin 5‐HT 2C receptor heteromers in mouse brain. FASEB Journal, 2021, 35 (1), ⟨10.1096/fj.202000305r⟩. ⟨hal-03560716⟩
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