Abstract
Acetylcholine receptors are pentameric ligand–gated channels involved in excitatory neuro-transmission in both vertebrates and invertebrates. In nematodes, they represent major targets for cholinergic agonist or antagonist anthelmintic drugs. Despite the large diversity of acetylcholine-receptor subunit genes present in nematodes, only a few receptor subtypes have been characterized so far. Interestingly, parasitic nematodes affecting human or animal health possess two closely related members of this gene family, acr-26 and acr-27 that are essentially absent in free-living or plant parasitic species. Using the pathogenic parasitic nematode of ruminants, Haemonchus contortus, as a model, we found that Hco-ACR-26 and Hco-ACR-27 are co-expressed in body muscle cells. We demonstrated that co-expression of Hco-ACR-26 and Hco-ACR-27 in Xenopus laevis oocytes led to the functional expression of an acetylcholine-receptor highly sensitive to the anthelmintics morantel and pyrantel. Importantly we also reported that ACR-26 and ACR-27, from the distantly related parasitic nematode of horses, Parascaris equorum, also formed a functional acetylcholine-receptor highly sensitive to these two drugs. In Caenorhabditis elegans, a free-living model nematode, we demonstrated that heterologous expression of the H. contortus and P. equorum receptors drastically increased its sensitivity to morantel and pyrantel, mirroring the pharmacological properties observed in Xenopus oocytes. Our results are the first to describe significant molecular determinants of a novel class of nematode body wall muscle AChR.
Highlights
Parasitic nematodes have a major impact on both human and animal health worldwide
Using the Xenopus laevis oocyte as an expression system, we showed that these receptors are composed of subunits encoded by two closely related genes, acr-26 and acr-27 that are widely distributed in parasitic nematodes infecting humans and animals
Using the Haemonchus contortus acr-26 deduced amino-acid sequences as a query, tBLASTn searches against H. contortus genomic data available at the Sanger Institute allowed the identification of a partial sequence encoding a distinct acetylcholine receptor (AChR) subunit for which no clear homolog could be identified in Caenorhabditis elegans
Summary
In the absence of an efficient alternative strategy such as vaccination, the control of these parasites relies mainly on three major classes of anthelmintic compounds including the benzimidazoles, the macrocyclic lactones and the agonists or antagonists of ligand-gated acetylcholine receptors. During the past 50 years, both the widespread and indiscriminate use of the available anthelmintics has led to the selection of resistant parasites. This is currently a major concern for the husbandry of small ruminants where highly pathogenic species such as Haemonchus contortus have developed resistance to the three major anthelmintic families [1, 2]. There is an urgent need for a better understanding of anthelmintic mode of action and identification of novel anthelmintic targets to control resistant parasites and optimize drug application strategies [13]
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