Abstract
Cys-loop ligand-gated ion channels (LGICs) mediate fast ionotropic neurotransmission. They are proven drug targets in nematodes and arthropods, but are poorly characterized in flatworms. In this study, we characterized the anion-selective, non-acetylcholine-gated Cys-loop LGICs from Schistosoma mansoni. Full-length cDNAs were obtained for SmGluCl-1 (Smp_096480), SmGluCl-2 (Smp_015630) and SmGluCl-3 (Smp_104890). A partial cDNA was retrieved for SmGluCl-4 (Smp_099500/Smp_176730). Phylogenetic analyses suggest that SmGluCl-1, SmGluCl-2, SmGluCl-3 and SmGluCl-4 belong to a novel clade of flatworm glutamate-gated chloride channels (GluCl) that includes putative genes from trematodes and cestodes. The flatworm GluCl clade was distinct from the nematode-arthropod and mollusc GluCl clades, and from all GABA receptors. We found no evidence of GABA receptors in S. mansoni. SmGluCl-1, SmGluCl-2 and SmGluCl-3 subunits were characterized by two-electrode voltage clamp (TEVC) in Xenopus oocytes, and shown to encode Cl−-permeable channels gated by glutamate. SmGluCl-2 and SmGluCl-3 produced functional homomers, while SmGluCl-1 formed heteromers with SmGluCl-2. Concentration-response relationships revealed that the sensitivity of SmGluCl receptors to L-glutamate is among the highest reported for GluCl receptors, with EC50 values of 7–26 µM. Chloride selectivity was confirmed by current-voltage (I/V) relationships. SmGluCl receptors are insensitive to 1 µM ivermectin (IVM), indicating that they do not belong to the highly IVM-sensitive GluClα subtype group. SmGluCl receptors are also insensitive to 10 µM meclonazepam, a schistosomicidal benzodiazepine. These results provide the first molecular evidence showing the contribution of GluCl receptors to L-glutamate signaling in S. mansoni, an unprecedented finding in parasitic flatworms. Further work is needed to elucidate the roles of GluCl receptors in schistosomes and to explore their potential as drug targets.
Highlights
Schistosomiasis, a disease caused by parasitic flatworms in the genus Schistosoma, is one of the most prevalent parasitic diseases in tropical and sub-tropical areas of the world
Schistosomiasis is a debilitating disease caused by blood flukes in the genus Schistosoma that afflicts over 200 million people worldwide
We characterized a novel family of glutamate-gated chloride channel (GluCl) receptors from S. mansoni that are pharmacologically and evolutionarily distinct from GluCls in nematodes, insects and snails
Summary
Schistosomiasis, a disease caused by parasitic flatworms in the genus Schistosoma, is one of the most prevalent parasitic diseases in tropical and sub-tropical areas of the world. S. mansoni is responsible for the majority of schistosomiasis infections in subSaharan Africa, the Middle East, the Caribbean and South America [1]. Global statistics for 2003 revealed that an estimated 207 million people were infected, of whom .85% live in Africa; 120 million people suffered from clinical disease and 779 million were at risk of infection [2]. Schistosomiasis leads to a chronic, often debilitating disease that impairs growth, development and productivity in infected individuals, and is strongly linked to extreme poverty, in sub-Saharan Africa [3,4]. In Africa alone, 280,000 deaths/year are attributed to the severe complications caused by schistosomiasis [5]. No vaccines are available against schistosome species, and schistosomiasis control relies almost entirely on a single drug, praziquantel. Growing concerns about sub-optimal efficacy of praziquantel and the prospect of drug resistance [6–10] highlight the need to identify targets for the discovery of new schistosomicidal drugs
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