A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors

Abstract

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.