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Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-05-08 , DOI: 10.1021/acschemneuro.8b00665 Barbara Chruścicka 1, 2 , Shauna E Wallace Fitzsimons 1, 2 , Dasiel O Borroto-Escuela 3 , Clémentine Druelle 1, 2 , Panagiota Stamou 1 , Kenneth Nally 1 , Timothy G Dinan 1, 4 , John F Cryan 1, 4 , Kjell Fuxe 3 , Harriët Schellekens 1, 2
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-05-08 , DOI: 10.1021/acschemneuro.8b00665 Barbara Chruścicka 1, 2 , Shauna E Wallace Fitzsimons 1, 2 , Dasiel O Borroto-Escuela 3 , Clémentine Druelle 1, 2 , Panagiota Stamou 1 , Kenneth Nally 1 , Timothy G Dinan 1, 4 , John F Cryan 1, 4 , Kjell Fuxe 3 , Harriët Schellekens 1, 2
Affiliation
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The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor-receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2A in vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases.
中文翻译：
催产素和5-羟色胺2A受体信号通过新型异体受体的形成而减弱。
催产素受体（OTR）和5-羟色胺2A受体（5-HTR2A）在相似的大脑区域表达，调节对社会和认知相关行为至关重要的中央通路。它们的内源性配体催产素（OT）和5-羟色胺（5-羟色胺，5-HT）之间的信号串扰突出了这两个神经递质系统之间的复杂相互作用，并可能表明异源受体复合物的形成以及随后的下游信号变化。在这项研究中，我们评估了OTR-5HTR2A异聚体在活细胞中的可能形成以及该受体-受体相互作用的功能性下游后果。首先，我们使用基于流式细胞仪的FRET方法和共聚焦显微镜证明了OTR和5-HTR2A在体外存在物理相互作用。此外，我们使用邻近结扎测定法（PLA）研究了脑切片中这种特定异源受体复合物的离体形成。OTR-5HTR2A异源受体复合物在边缘区域（包括海马，扣带回皮层和伏隔核），与认知和社会相关行为有关的关键区域中被鉴定。接下来，用于评估OTR-5HTR2A下游信号串扰的基于细胞的功能性测定表明，OT介导的Gαq信号传递的OT和OTR合成激动剂，羧苄青霉素和WAY267464的效力和功效均降低。同样，内源性激动剂5-HT对5-HTR2A的激活也显示Gαq介导的信号传导减弱。最后，证实了细胞内受体运输的改变，表明了OTR / 5-HTR2A对的共同贩运。全面的，
更新日期：2019-04-30
中文翻译：
催产素和5-羟色胺2A受体信号通过新型异体受体的形成而减弱。
催产素受体（OTR）和5-羟色胺2A受体（5-HTR2A）在相似的大脑区域表达，调节对社会和认知相关行为至关重要的中央通路。它们的内源性配体催产素（OT）和5-羟色胺（5-羟色胺，5-HT）之间的信号串扰突出了这两个神经递质系统之间的复杂相互作用，并可能表明异源受体复合物的形成以及随后的下游信号变化。在这项研究中，我们评估了OTR-5HTR2A异聚体在活细胞中的可能形成以及该受体-受体相互作用的功能性下游后果。首先，我们使用基于流式细胞仪的FRET方法和共聚焦显微镜证明了OTR和5-HTR2A在体外存在物理相互作用。此外，我们使用邻近结扎测定法（PLA）研究了脑切片中这种特定异源受体复合物的离体形成。OTR-5HTR2A异源受体复合物在边缘区域（包括海马，扣带回皮层和伏隔核），与认知和社会相关行为有关的关键区域中被鉴定。接下来，用于评估OTR-5HTR2A下游信号串扰的基于细胞的功能性测定表明，OT介导的Gαq信号传递的OT和OTR合成激动剂，羧苄青霉素和WAY267464的效力和功效均降低。同样，内源性激动剂5-HT对5-HTR2A的激活也显示Gαq介导的信号传导减弱。最后，证实了细胞内受体运输的改变，表明了OTR / 5-HTR2A对的共同贩运。全面的，
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