Ligand-gated chloride channels, including the glutamate-(GluCl) and GABA-gated channels, are the targets of the macrocyclic lactone (ML) family of anthelmintics. Changes in the sequence and expression of these channels can cause resistance to the ML in laboratory models, such as Caenorhabditis elegans and Drosophila melanogaster. Mutations in multiple GluCl subunit genes are required for high-level ML resistance in C. elegans, and this can be influenced by additional mutations in gap junction and amphid genes. Parasitic nematodes have a different complement of channel subunit genes from C. elegans, but a few genes, including avr-14, are widely present. A polymorphism in an avr-14 orthologue, which makes the subunit less sensitive to ivermectin and glutamate, has been identified in Cooperia oncophora, and polymorphisms in several subunits have been reported from resistant isolates of Haemonchus contortus. This has led to suggestions that ML resistance may be polygenic. Possible reasons for this, and its consequences for the development of molecular tests for resistance, are explored.

The glutamate-gated chloride channels (GluCls) are members of the ligand-gated ion channel superfamily that are thought to be involved in the mode of action of ivermectin and mechanism of resistance. Using reverse-transcriptase PCR techniques, 2 full-length GluCl cDNAs, encoding GluClα3 and GluClβ subunits, were cloned from Cooperia oncophora, a nematode parasite of cattle. The two sequences show a high degree of identity to similar subunits from other nematodes. The C. oncophora GluClα3 subunit is most closely related to the Haemonchus contortus GluClα3B subunit, while C. oncophora GluClβ subunit shares high sequence identity with the H. contortus GluClβ subunit. Using single-strand conformation polymorphism, the genetic variability of these two genes was analysed in an ivermectin-susceptible isolate and an ivermectin-resistant field isolate of C. oncophora. Statistical analysis suggested an association between the C. oncophora GluClα3 gene and ivermectin resistance. No such association was seen with the GluClβ gene.