title: Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes.
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.
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.|Université de François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, Tours, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Courtot
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.|Université de François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, Tours, France.
authors.forename: Claude L
authors.initials: CL
authors.lastname: Charvet
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.|Institute of Parasitology, McGill University, Macdonald Campus, Sainte Anne de Bellevue, Québec, Canada.
authors.forename: Robin N
authors.initials: RN
authors.lastname: Beech
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.|Université de François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, Tours, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Harmache
authors.affiliation: Department of Infectious Disease and Center for Tropical and Emerging Global Disease, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Wolstenholme
authors.affiliation: School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
authors.affiliation: School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Connor
authors.affiliation: Université François Rabelais de Tours, Département de physiologie animale, Tours, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Peineau
authors.affiliation: Veterinary Medicine Research and Development, Zoetis LLC, Kalamazoo, Michigan, United States of America.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Woods
authors.affiliation: INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France.|Université de François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, Tours, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Neveu
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D001199:Ascaridoidea / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D006189:Haemonchus / Q000235:genetics / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009015:Morantel / Q000494:pharmacology; D009348:Nematoda / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*
chemical_list: D000871:Anthelmintics; D015801:Helminth Proteins; D011950:Receptors, Cholinergic; D009015:Morantel