Parasitic
nematode infections are treated using
anthelmintic drugs, some of which target
nicotinic acetylcholine receptors (nAChRs) located in different parasite tissues. The limited arsenal of
anthelmintic agents and the prevalence of drug resistance imply that future defense against
parasitic infections will depend on the discovery of novel targets and
therapeutics. Previous studies have suggested that Ascaris suum ACR-16 nAChRs are a suitable target for the development of
antinematodal drugs. In this study, we characterized the pharmacology of the Ancylostoma caninum ACR-16 receptor using two-
electrode voltage-clamp electrophysiology. This technique allowed us to study the effects of
cholinergic agonists and antagonists on the nematode nAChRs expressed in Xenopus laevis oocytes. Aca-ACR-16 was not sensitive to many of the existing
cholinomimetic anthelmintics (
levamisole,
oxantel,
pyrantel, and
tribendimidine).
3-Bromocytisine was the most potent agonist (> 130% of the control
acetylcholine current) on the Aca-ACR-16 nAChR but, unlike Asu-ACR-16,
oxantel did not activate the receptor. The mean time constants of desensitization for agonists on Aca-ACR-16 were longer than the rates observed in Asu-ACR-16. In contrast to Asu-ACR-16, the A. caninum receptor was completely inhibited by DHβE and moderately inhibited by α-BTX. In conclusion, we have successfully reconstituted a fully functional homomeric nAChR, ACR-16, from A. caninum, a model for human
hookworm infections. The pharmacology of the receptor is distinct from
levamisole-sensitive nematode receptors. The ACR-16 homologue also displayed some pharmacological differences from Asu-ACR-16. Hence, A. caninum ACR-16 may be a valid target site for the development of
anthelmintics against
hookworm infections.