Pharmacological evidence for transactivation within melatonin MT ₂ and serotonin 5‐HT _2C receptor heteromers in mouse brain

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.

Therapeutic potential of melatonin and melatonergic drugs on K18‐hACE2 mice infected with SARS‐CoV‐2

“…F(DFn, DFd) and p-value of the F ratio are: IL1β (F(5,35)=1.610; p=0.187); IL6 (F(5,32)=1.340; p=0.2730); TNFα (F(5,34)=2.801; p=0.0319); CXCL2 (F(5,34)=1.047; p=0.4063); CXCL9 (F(5,34)=1.385; p=0.2543); IP10/CXCL10 (F(5,34)=2.091; p=0.0906); IL10 (F(5,35)=1.163; p=0.0267); MCP1/CCL2 (F(5,34)=1.269; p=0.3000); RANTES/CCL5 (F(5,34)=1.987; p=0.1058); IL18 (F(5,35)=3.886; p=0.0066) 5-HT 2C receptors and melatonin receptors have been described as an additional target of AgoMLT. 42,43 The fact that AgoMLT has no distinctive effect compared to the other treatments argues against a significant participation of 5-HT 2C receptors in the observed effects. However, a participation of the 5-HT 2C receptors component in the effect of AgoMLT cannot be fully excluded at this point, in particular as our analysis was performed at the final…”

“… 41 The serotonin 5‐HT 2C receptors and heterodimers between 5‐HT 2C receptors and melatonin receptors have been described as an additional target of AgoMLT. 42 , 43 The fact that AgoMLT has no distinctive effect compared to the other treatments argues against a significant participation of 5‐HT 2C receptors in the observed effects. However, a participation of the 5‐HT 2C receptors component in the effect of AgoMLT cannot be fully excluded at this point, in particular as our analysis was performed at the final disease stage and did not monitor the effects at the different disease stages.…”

Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action

“…First, at the cellular level, by analogy to 5-HT 2C receptor-Oxytocin receptor heterodimers ( vide supra ), a physical interaction between 5-HT 2C and MT 2 receptors has been demonstrated both in cellular expression systems, as well as the hippocampus and cortex of rats. 144 , 145 5-HT 2C -MT 2 functional heterodimers possess ligand recognition and coupling properties that differ from the constituent monomers and dimers. Since agomelatine potently recognizes these heterodimers, it has been speculated that they may be involved in the clinical actions of agomelatine in depression.…”

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

“…These receptors modulate many hormones like oxytocin, prolactin, vasopressin, cortisol, and corticotropin. Serotonin receptors were also responsible for aggression, anxiety, memory, learning, nausea, mood, and sleep [ 71 , 72 ]. Among such antagonists, tropisetron, a fused pyrrole, an indole analog blocks the action of serotonin at 5HT3 receptors, resulting in control of nausea and vomiting induced by chemotherapy and radiotherapy [ 73 , 74 ].…”