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Cloning and Expression of an Oxantel Sensitive Homomeric Nicotinic Acetylcholine Receptor of Trichuris, the TsuACR-16-like receptor
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International audience. Background and purpose: Anthelmintic resistance and/or decreased susceptibility to anthelmintics is a major global problem in parasitic nematodes of livestock and is of great concern, mainly in the Soil Transmitted Helminths (STHs), where decreased susceptibility to albendazole has already been reported for some parasites, amongst these, the human whipworm, Trichuris triciura. Trichuris is an interesting nematode genus due to its broad host spectrum and its low susceptibility to several anthelmintic drug classes. However, a noteworthy exception is the cholinergic agonist oxantel, which has a high efficacy against Trichuris spp. Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In Ascaris suum, oxantel has a low, but some effect on the homomeric nicotinic Ach receptor ACR-16 (Asu-ACR-16). Ascaris suum is a Clade III parasitic nematode, whereas Trichuris is included in Clade I. We therefore hypothesized that the sensitivity of Tsu-ACR-16 to oxantel is different from the Asu-ACR-16 and could be a target for oxantel within Trichuris.Methodology: A Tsu-acr-16-like receptor was identified, amplified by PCR, cloned, functionally expressed in Xenopus laevis oocytes and pharmacologically characterized under two-electrode voltage-clamp. Results: In electrophysiological experiments, oxantel produced a high and robust current response of the Tsu-ACR-16-like receptor whereas pyrantel activated the receptor moderately. The cholinergic anthelmintic compounds morantel and levamisole did not activate the receptor significantly and nAChR agonists, including epibathidine, nicotine, cytisine, dimethylpiperazine and 3-bromocytisine resulted in minor responses.Conclusion and perspective: The Tsu-ACR-16-like receptor is more sensitive to oxantel than Asu-ACR-16. This receptor may not be the only target of oxantel, but the functional expression of this Tsu-ACR-16-like receptor can prove a valuable screening tool to evaluate the effect of new synthetic or natural compounds against this genus.
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