A novel G protein-coupled receptor of Schistosoma mansoni (SmGPR-3) is activated by dopamine and is widely expressed in the nervous system.
A novel G protein-coupled receptor of Schistosoma mansoni (SmGPR-3) is activated by dopamine and is widely expressed in the nervous system.
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DOI：
10.1371/journal.pntd.0001523
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发表时间：
2012
影响因子：
3.8
通讯作者：
Ribeiro P
中科院分区：
文献类型：
--
作者：
El-Shehabi F;Taman A;Moali LS;El-Sakkary N;Ribeiro P
血吸虫有一个发达的神经系统，几乎可以协调寄生虫的所有活动，因此被认为是化疗干预的一个有希望的目标。神经递质受体，特别是参与神经肌肉控制的神经递质受体，在其他蠕虫中已被证实是药物靶点，但在血吸虫中发现的这些受体很少，对它们在蠕虫生物学中的作用知之甚少。在这里，我们描述了一种新的曼氏血吸虫G蛋白偶联受体（命名为SmGPR-3），该受体被克隆，异源表达，并被多巴胺激活，多巴胺是血吸虫神经系统的一种成熟的神经递质。SmGPR-3属于“孤儿”胺样受体的新分支，存在于血吸虫中，而不存在于哺乳动物宿主中。对重组蛋白的进一步分析表明，SmGPR-3也可以被其他儿茶酚胺激活，包括多巴胺代谢物，epine，与哺乳动物受体相比，它具有不同寻常的拮抗剂特征。特异性肽抗体共聚焦免疫荧光实验表明，SmGPR-3在血吸虫的神经系统中大量表达，特别是在主要的神经索和体壁肌肉的周围神经支配中。此外，我们发现多巴胺、肾上腺素和其他多巴胺能药物对培养的血吸虫幼虫的运动有很强的影响。总之，这些结果表明SmGPR-3是一种重要的神经元受体，可能参与血吸虫运动活动的控制。通过同源性建模和虚拟配体对接模拟，首次对SmGPR-3的结构进行了分析。这项研究已经确定了SmGPR-3和宿主多巴胺受体之间潜在的重要差异，这些差异可以用于开发新的寄生虫选择性抗血吸虫药物。血吸虫属的血吸虫是人类血吸虫病的病原体，这是一种使人衰弱的疾病，全世界有2亿多人受到影响。目前还没有针对血吸虫病的疫苗，治疗严重依赖于吡喹酮这一单一药物。最近关于吡喹酮耐药性的报告引起了人们对未来控制该病的关注，并表明开发新的抗血吸虫药物的重要性。本研究的重点是模型吸虫的神经系统，曼氏血吸虫。许多杀虫剂和抗寄生虫药物通过与神经元蛋白相互作用而起作用，因此神经系统是化疗干预的一个特别有吸引力的靶点。在这里，我们描述了一种新的受体S. mansoni被多巴胺激活，一个重要的血吸虫神经系统的神经递质。这项研究首次对这种受体进行了深入分析，并表明它在控制肌肉功能和运动中起着重要作用。我们还表明，血吸虫受体在结构和功能特性方面与哺乳动物宿主的多巴胺受体有本质上的不同。我们建议这种新蛋白可以用于开发新的血吸虫特异性药物，旨在破坏宿主内寄生虫的运动。
Schistosomes have a well developed nervous system that coordinates virtually every activity of the parasite and therefore is considered to be a promising target for chemotherapeutic intervention. Neurotransmitter receptors, in particular those involved in neuromuscular control, are proven drug targets in other helminths but very few of these receptors have been identified in schistosomes and little is known about their roles in the biology of the worm. Here we describe a novel Schistosoma mansoni G protein-coupled receptor (named SmGPR-3) that was cloned, expressed heterologously and shown to be activated by dopamine, a well established neurotransmitter of the schistosome nervous system. SmGPR-3 belongs to a new clade of “orphan” amine-like receptors that exist in schistosomes but not the mammalian host. Further analysis of the recombinant protein showed that SmGPR-3 can also be activated by other catecholamines, including the dopamine metabolite, epinine, and it has an unusual antagonist profile when compared to mammalian receptors. Confocal immunofluorescence experiments using a specific peptide antibody showed that SmGPR-3 is abundantly expressed in the nervous system of schistosomes, particularly in the main nerve cords and the peripheral innervation of the body wall muscles. In addition, we show that dopamine, epinine and other dopaminergic agents have strong effects on the motility of larval schistosomes in culture. Together, the results suggest that SmGPR-3 is an important neuronal receptor and is probably involved in the control of motor activity in schistosomes. We have conducted a first analysis of the structure of SmGPR-3 by means of homology modeling and virtual ligand-docking simulations. This investigation has identified potentially important differences between SmGPR-3 and host dopamine receptors that could be exploited to develop new, parasite-selective anti-schistosomal drugs. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. There is no vaccine for schistosomiasis and treatment relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new anti-schistosomal drugs. The focus of this research is on the nervous system of the model fluke, Schistosoma mansoni. Many pesticides and antiparasitic drugs act by interacting with neuronal proteins and therefore the nervous system is a particularly attractive target for chemotherapeutic intervention. Here we describe a novel receptor of S. mansoni that is activated by dopamine, an important neurotransmitter of the schistosome nervous system. The study provides a first in-depth analysis of this receptor and suggests that it plays an important role in the control of muscle function and movement. We also show that the schistosome receptor is substantially different from dopamine receptors of the mammalian host, both in terms of structure and functional properties. We propose that this novel protein could be used to develop new, schistosome-specific drugs aimed at disrupting parasite motility within the host.
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影响因子：
4
作者：
Kimber MJ;Sayegh L;El-Shehabi F;Song C;Zamanian M;Woods DJ;Day TA;Ribeiro P
通讯作者：
Ribeiro P
影响因子：
1.5
作者：
Larsen, Mads B.;Fontana, Andreia C. K.;Mortensen, Ole V.
通讯作者：
Mortensen, Ole V.
影响因子：
2
作者：
GUSTAFSSON, MKS;ERIKSSON, K
通讯作者：
ERIKSSON, K
影响因子：
2.4
作者：
Kohn, AB;Moroz, LL;Greenberg, RM
通讯作者：
Greenberg, RM
影响因子：
2
作者：
GUSTAFSSON, MKS
通讯作者：
GUSTAFSSON, MKS