Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from <em>Trichuris muris</em>

Abstract

The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug-target for oxantel, and highlights the pharmacological difference between Trichuris species.

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“…The cholinergic anthelmintics nicotine, levamisole, pyrantel, morantel and oxantel, have been used to characterize and distinguish different nAChR subtypes. Pharmacological characterization of the sensitivity of nAChRs to these cholinergic drugs has provided evidence to categorize different subtypes labeled including: L-, P-, N-, M-, and O- (Verma et al 2017;Hansen et al, 2021). Subtype sensitivities are determined by the nAChR composition of their protein subunits and individual amino acid substitutions on those subunits (Abongwa et al 2016).…”