Abstract
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.
Highlights
The bloodfluke Schistosoma mansoni is one of three species of schistosomes that cause significant disease in humans
Recent drug screens conducted on cultured S. mansoni suggest that biogenic amine (BA) neurotransmitters may be suitable for development of antischistosomal drugs [5,6]
Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide
Summary
The bloodfluke Schistosoma mansoni is one of three species of schistosomes that cause significant disease in humans. Over 90% of all human schistosomiasis is due to S. mansoni. This species exists in Africa, the Middle East, South America and the Caribbean, in regions where the intermediate snail host, Biomphalaria glabrata, is present. Recent drug screens conducted on cultured S. mansoni suggest that biogenic amine (BA) neurotransmitters may be suitable for development of antischistosomal drugs [5,6]. Substances that normally disrupt BA neurotransmission, such as dopaminergic and serotonergic drugs were shown to halt larval development [5] and to produce aberrant motor phenotypes in culture [6]. More information is needed to elucidate the mode of action of these neurotransmitters and to identify potential targets for drug discovery
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