Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes

PLoS Pathogens

Debra J. Woods¹  Elise Courtot²  Adrian J. Wolstenholme²  Robin N. Beech²  Vincent O’Connor²  Lindy Holden-Dye³  Cedric Neveu⁴  Nicolas Peineau⁵  Claude L. Charvet⁵  Abdallah Harmache⁵ 

[1] Department of Infectious Disease and Center for Tropical and Emerging Global Disease, University of Georgia, Athens, Georgia, United States of America;INRA, UMR1282 Infectiologie et Santé Publique, Nouzilly, France;Institute of Parasitology, McGill University, Macdonald Campus, Sainte Anne de Bellevue, Québec, Canada;School of Biological Sciences, University of Southampton, Southampton, United Kingdom;Université de François Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, Tours, France

关键词: Caenorhabditis elegans;    Xenopus oocytes;    Nematoda;    Sequence motif analysis;    Sequence alignment;    Sequence databases;    Acetylcholine;    Larvae;   

DOI  :  10.1371/journal.ppat.1005267

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY