Journal article
A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants
Molecular and biochemical parasitology, v 177(1)
May 2011
PMID: 21251927
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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▶ A catecholamine transporter (SmDAT), from Schistosoma mansoni. ▶ SmDAT is expressed in the adult and the sporocyst form of the parasite. ▶ The apparent affinity for dopamine of SmDAT is comparable to the human DAT. ▶ Cocaine and amphetamine are significantly less potent in inhibiting SmDAT. ▶ Amphetamine is dramatically less potent at evoking efflux through SmDAT.
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.
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Details
- Title
- A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants
- Creators
- Mads B Larsen - Department of Neurobiology, University of Pittsburgh School of Medicine, PA 15260, USAAndréia C.K Fontana - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USALizandra G Magalhães - University of Franca, SP, BrazilVanderlei Rodrigues - Department of Biochemistry and Immunology, Ribeirão Preto School of Medicine, University of São Paulo, SP, BrazilOle V Mortensen - Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
- Publication Details
- Molecular and biochemical parasitology, v 177(1)
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000289338000005
- Scopus ID
- 2-s2.0-79952444944
- Other Identifier
- 991014878388104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Parasitology