A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants
A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants
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DOI：
10.1016/j.molbiopara.2011.01.006
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发表时间：
2011-05-01
影响因子：
1.5
通讯作者：
Mortensen, Ole V.
中科院分区：
文献类型：
--
作者：
Larsen, Mads B.;Fontana, Andreia C. K.;Mortensen, Ole V.
曼氏血吸虫（Schistosoma mansoni）是血吸虫病的主要病因，血吸虫病是一种被忽视的热带疾病，影响着2亿人。因此，确定治疗血吸虫病的新的治疗靶点具有极大的公共利益。儿茶酚胺、去甲肾上腺素（NE）和多巴胺（DA）是寄生虫生存所必需的，它们能使寄生虫的肌肉松弛和延长，从而控制寄生虫的运动。mansoni SmDAT在寄生虫的成虫形式和孢子囊形式（感染的蜗牛）中表达，并且还在卵和毛蚴阶段中表达。它是在尾蚴阶段缺席，但奇怪的是，一个转录丢失的外显子编码的跨膜结构域8被确定在这个stage.Heteroimmunohistochemistry表达的cDNA在哺乳动物细胞中导致饱和，多巴胺转运活性与多巴胺的明显亲和力相媲美的人多巴胺转运蛋白。外排实验显示显着更高的底物选择性相比，其哺乳动物的同行，安非他明是一个不太有效的外排诱导剂对SmDAT相比，人类DAT。SmDAT的药理学特性表明，大多数人类DAT抑制剂，包括精神兴奋剂，如可卡因显着不太有效的抑制SmDAT。与其他简单生物的DAT一样，SmDAT的药理学与人类去甲肾上腺素转运蛋白更相似。我们无法确定其他多巴胺转运载体内的完整的寄生虫基因组，我们假设SmDAT是唯一的儿茶酚胺转运体的寄生虫，可能是负责不仅清除DA，但也NE。(C)2011 Elsevier B.V.保留所有权利。
The trematode Schistosoma mansoni is the primary cause of schistosomiasis, a devastating neglected tropical disease that affects 200 million individuals. Identifying novel therapeutic targets for the treatment of schistosomiasis is therefore of great public interest. The catecholamines norepinephrine (NE) and dopamine (DA) are essential for the survival of the parasite as they cause muscular relaxation and a lengthening in the parasite and thereby control movement.Here we characterize a novel dopamine/norepinephrine transporter (SmDAT) gene transcript, from S. mansoni. The SmDAT is expressed in the adult form and in the sporocyst form (infected snails) of the parasite, and also in the egg and miracidium stage. It is absent in the cercariae stage but curiously a transcript missing the exon encoding transmembrane domain 8 was identified in this stage.Heterologous expression of the cDNA in mammalian cells resulted in saturable, dopamine transport activity with an apparent affinity for dopamine comparable to that of the human dopamine transporter. Efflux experiments reveal notably higher substrate selectivity compared with its mammalian counterparts as amphetamine is a much less potent efflux elicitor against SmDAT compared to the human DAT. Pharmacological characterization of the SmDAT revealed that most human DAT inhibitors including psychostimulants such as cocaine were significantly less potent in inhibiting SmDAT. Like DATs from other simpler organisms the pharmacology for SmDAT was more similar to the human norepinephrine transporter. We were not able to identify other dopamine transporting carriers within the completed parasite genome and we hypothesize that the SmDAT is the only catecholamine transporter in the parasite and could be responsible for not only clearing DA but also NE. (C) 2011 Elsevier B.V. All rights reserved.