A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors.
Ivermectin exerts its anthelmintic effect by activating nematode Cys-loop glutamate-gated receptors. Here we show that a glycine residue at a specific transmembrane domain location is essential for high ivermectin sensitivity in both glycine- and glutamate-gated Cys-loop receptors. We also show that ivermectin sensitivity can be conferred on an ivermectin-insensitive receptor by introducing a glycine at this position. Furthermore, comparison of amino acid sequences of ivermectin-sensitive and -resistant receptors reveals that the presence of a glycine reliably predicts ivermectin sensitivity. By providing a means of identifying ivermectin-sensitive receptors, this finding should help in characterising ivermectin-resistance mechanisms and identifying new anthelmintic targets.
Lynagh
Timothy
T
Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia.
Lynch
Joseph W
JW
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000871:Anthelmintics / Q000378:metabolism* / Q000494:pharmacology; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000235:genetics* / Q000378:metabolism*; D004351:Drug Resistance; D005998:Glycine / Q000235:genetics*; D007559:Ivermectin / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009348:Nematoda / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment
D000871:Anthelmintics; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D007559:Ivermectin; D005998:Glycine