Pharmacological evidence for transactivation within melatonin MT <sub>2</sub> and serotonin 5‐HT <sub>2C</sub> receptor heteromers in mouse brain
Romain Gerbier, Delphine Ndiaye‐Lobry, Pablo B. Martínez de Morentin, Erika Cecon, Lora K. Heisler, Philippe Delagrange, Florence Gbahou, Ralf Jockers
Abstract
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.