Functional characterization of a novel class of morantel-sensitive acetylcholine receptors in nematodes

The control of parasitic nematode infections in humans, livestock and companion animals is critically dependent on anthelmintic treatment. However, the indiscriminate use of anthelmintic drugs has inevitably led to the selection of resistant parasites. In this respect there is currently an urgent need to increase our knowledge of the mode of action of available anthelmintics as well as to identify novel targets for the development of next generation anthelmintic compounds. In the present study we report the functional and pharmacological characterization of a novel subtype of nematode acetylcholine-gated ion channel in two distantly related parasitic nematode species: Haemonchus contortus and Parascaris equorum. 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. We further demonstrate that these receptors represent a molecular target for the anthelmintics morantel and pyrantel. The H. contortus and P. equorum receptors expressed as transgenes in the nematode model Caenorhabditis elegans both confer morantel and pyrantel sensitivity in-vivo. For parasitic nematodes of veterinary and medical importance, this novel class of cholinergic receptor is of prime interest for target-based drug screening and the development of relevant anthelmintic combinations