Potential acetylcholine receptor (AChR) mutants of the nematode are selectable by resistance to the neurotoxic drug levamisole, a probable cholinergic agonist. To determine which mutants may have achieved resistance through loss of levamisole receptor function, we have assayed mutant extracts for specific 3H-meta-aminolevamisole binding activity in the presence and absence of mecamylamine. We find that mutants in 3 of the 7 genes associated with extreme levamisole resistance are obviously deficient in saturable specific 3H-meta-aminolevamisole binding activity. Mutants of the 4 other genes have abnormal binding activities that fail to undergo the apparent allosteric activation of saturable specific 3H-meta-aminolevamisole binding activity caused by mecamylamine. Thus, all 7 genes appear to be required to produce a fully functional levamisole receptor. Mutants of several other genes associated only with partial resistance to levamisole have at least grossly normal receptor binding activities.

The free living nematode, C. elegans is understood at a level of detail equalled by few other organisms, and much of the cell biology and sequence information is proving of considerable utility in the study of parasitic nematodes. Already, C. elegans provides a convenient vehicle for investigating anthelmintic drug action and resistance mechanisms. Among the ionotropic receptors, with their important roles in the behaviour and development of the organism, are targets for anthelmintics. The subunits of nicotinic acetylcholine receptors of C. elegans form a large and diverse multigene family. Members of this family are among the 11 genes associated with resistance to the anthelmintic drug levamisole.