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

• Published in: The FASEB journal Vol. 35; no. 1; p. e21161
• Main Authors: Gerbier, Romain, Ndiaye-Lobry, Delphine, Martinez de Morentin, Pablo B, Cecon, Erika, Heisler, Lora K, Delagrange, Philippe, Gbahou, Florence, Jockers, Ralf
• Format: Journal Article
• Language: English
• Published: United States Federation of American Society of Experimental Biology 01-01-2021
• Subjects: Acetamides - pharmacology; Animals; Brain - metabolism; Gene Expression Regulation, Enzymologic; Indoles - pharmacology; Life Sciences; Male; Mice; Mice, Knockout; Pharmaceutical sciences; Pharmacology; Protein Multimerization; Pyridines - pharmacology; Receptor, Melatonin, MT2 - genetics; Receptor, Melatonin, MT2 - metabolism; Receptor, Serotonin, 5-HT2C - genetics; Receptor, Serotonin, 5-HT2C - metabolism; Transcriptional Activation; Type C Phospholipases - biosynthesis; Type C Phospholipases - genetics; 5-HT2C; receptor transactivation; melatonin receptors; GPCR heteromerization; cerebellum; hypothalamus
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202000305R

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