Selection at a gamma-aminobutyric acid receptor gene in Haemonchus contortus resistant to avermectins/milbemycins.
Gamma-aminobutyric acid (GABA) Type A receptors are inhibitory chloride channels in membranes of vertebrate and invertebrate neuromuscular cells. Gating of the channels by GABA leads to an influx of chloride ions into, and hyperpolarisation of, the cell. GABA receptors are believed to form channels by the association of five protein molecules of varying subunit types, with the second transmembrane (M2) domain of each protein molecule forming a central pore through which chloride ions can pass. We have analysed by single-strand conformation polymorphism the genetic variation of a GABA-receptor gene, HG1, from two sets of unselected and anthelmintic-selected strains of the parasitic nematode Haemonchus contortus. Significant differences in allele frequencies were detected between one unselected strain and its derived ivermectin-selected strain and between the other unselected strain and its derived ivermectin- and moxidectin-selected strains. In each set of strains, one allele increased substantially in frequency in the drug-selected strains relative to their respective unselected strains. The selected allele, however, differed between the two sets of strains. Similar analyses were performed on a phosphoenolpyruvate carboxykinase gene and a nicotinic acetylcholine receptor subunit gene. No significant differences were found in allele frequencies between the unselected and their derived anthelmintic-selected strains. These results indicate the GABA receptor as a possible site of action for avermectins and milbemycins, and suggest its involvement in resistance to these anthelmintics.
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D018509:DNA, Helminth / Q000032:analysis; D004351:Drug Resistance / Q000235:genetics; D005787:Gene Frequency; D006188:Haemonchiasis / Q000188:drug therapy / Q000469:parasitology / Q000662:veterinary; D006189:Haemonchus / Q000187:drug effects* / Q000235:genetics; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D018807:Polymorphism, Single-Stranded Conformational; D018079:Receptors, GABA / Q000235:genetics*; D012641:Selection, Genetic; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000469:parasitology
D000871:Anthelmintics; D018509:DNA, Helminth; D018942:Macrolides; D018079:Receptors, GABA; D007559:Ivermectin; C019264:avermectin; C027837:moxidectin