Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex
Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex
复制标题
DOI：
10.1016/j.neuropharm.2020.108394
复制
发表时间：
2021-02-01
影响因子：
4.7
通讯作者：
Schellekens, Harriet
中科院分区：
文献类型：
--
作者：
Chruscicka, Barbara;Cowan, Caitlin S. M.;Schellekens, Harriet
催产素介导的功能的复杂性与其对其他神经传递系统的调节作用密切相关，包括血清素（5-羟色胺，5-HT）系统。催产素 (OT) 和 5-HT 之间的信号传导已在神经发育和特定情绪行为的调节过程中得到证实。有人认为，神经递质之间的串扰是由其特定受体之间的相互作用驱动的，特别是催产素受体 (OTR) 和 5-羟色胺 2C 受体 (5-HTR2C)，但缺乏这方面的证据以及随后的下游信号转导结果。考虑到OTR和5-HTR2C在某些内分泌功能和行为（包括饮食行为、社交互动和运动活动）中的重叠中心表达谱和共同参与，我们研究了功能活性OTR/5-HTR2C杂合物的存在。在这里，我们使用基于流式细胞术的 FRET (fcFRET) 证明了在体外细胞表达系统中 OTR 和 5-HTR2C 之间潜在物理相互作用的证据。我们可以通过单细胞转录组数据的计算机分析和离体邻近连接测定（PLA）在两种受体的内源表达水平下概括这一发现。接下来，我们表明 OTR/5-HTR2C 对的共表达导致 OTR 介导的 G α q 信号显着耗竭以及受体运输的显着变化。值得注意的是，在药物阻断 5-HTR2C 后，OTR 介导的下游信号传导的减弱得以恢复。最后，我们证明了这种新型异质复合物在体内的功能相关性，因为 5-HTR2C 拮抗作用增加了小鼠中 OT 介导的活动减退。总体而言，我们为功能活性 OTR/5-HTR2C 异质复合物的形成提供了令人信服的证据，从而使 OTR 和 5-HTR2C 信号功能的复杂性增加了另一个层次。本文是神经肽特刊的一部分。
The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated G alpha q-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality.This article is part of the special issue on Neuropeptides.