期刊
FASEB JOURNAL
卷 35, 期 1, 页码 -出版社
WILEY
DOI: 10.1096/fj.202000305R
关键词
cerebellum; GPCR heteromerization; hypothalamus; melatonin receptors; receptor transactivation; 5‐ HT2C
资金
- Fondation Recherche Medicale (Equipe FRM2013) [DEQ 20130326503]
- Fondation Recherche Medicale (Equipe FRM 2019) [EQU201903008055]
- French National Research Agency (ANR) [ANR-19-CE16-0025-01]
- Recherches Partenariales et Innovation Biomedicale 2012 MED-HET-REC-2
- INSERM
- CNRS
- Who am I? laboratory of excellence - French Government through its Investments for the Future program [ANR-11-LABX- 0071, ANR-11-IDEX-0005-01]
- La Ligue Contre le Cancer [RS19/75-127]
- Biotechnology and Biological Sciences Research Council [BB/R01857X/1, BB/N017838/1]
Functional fingerprint of heteromers composed of G(i)-coupled melatonin MT2 receptors and G(q)-coupled serotonin 5-HT2C receptors was identified in mouse brain, with melatonin activating G(q) proteins and PLC in a concentration-dependent manner in the hypothalamus and cerebellum. These effects were absent in cortex, inhibited by the 5-HT2C receptor-specific inverse agonist SB-243213, and were fully recapitulated in MT2 and 5-HT2C knockout mice. Furthermore, antidepressant agomelatine had similar effects to melatonin but blocked melatonin-promoted G(q) activation due to its 5-HT2C antagonistic component, providing strong functional evidence for the existence of MT2/5-HT2C heteromeric complexes.
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 MT2 receptors and G(q)-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. G(q) protein activation was probed by [S-35]GTP gamma S 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-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 G(q) 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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