Nicotinic acetylcholine receptors: expression demonstrates functional diversity in parasitic nematodes (844.4)

Abstract

Nicotinic acetylcholine receptors mediate fast neurotransmission in both vertebrates and invertebrates. Selective targeting of parasite nAChR by antiparasitic drugs requires functional and/or structural differences between the receptors of the host and the parasite. Anti‐parasitic drugs like levamisole, pyrantel, tribendimidine, and derquantel (cholinergic anthelmintics) selectively target the nAChRs of nematodes. Unfortunately, regular use of anthelmintics has resulted in increasing reports of resistance in livestock parasites. Our aim has been to understand the molecular pharmacology of the nAChRs in parasitic nematodes, to inform development of better anthelmintics. We have cloned homologues of the nAChR subunit genes unc‐29, unc‐38, unc‐63 and acr‐8 from Oesophagostomum dentatum, a pig GI parasite. By employing the Xenopus laevis oocyte expression system, we demonstrated that four, pharmacologically different receptor subtypes can be reconstituted with various combinations of the four subunits. Single‐channel properties of one of the reconstituted receptor subtypes matched with one of the four subtypes recorded in vivo from O. dentatum, demonstrating the physiological relevance of the reconstituted receptor subtypes. Comparing these results with reconstitution results from other nematodes demonstrates the diverse, plastic nature of nAChRs in parasitic nematodes.Grant Funding Source: Supported by NIH R01 AI047194‐12, R21AI092185‐01 and Chateaubriand Fellowship