1.A.9.4.2
Glutamate-gated chloride channel (GluClα or Glc-1) (α-subunits when mutated confer resistance to the antiparisitic drug, avermectin (ivermectin) (Dent et al., 2000)). A naturally occurring 4-aa deletion in the ligand binding domain of Glc-1 confers resistance to avermectin (Ghosh et al., 2012). Several 3-d structures are known (3RIF; Hibbs and Gouaux, 2011). Ivermectin (avermectin; IVM), an anthelmintic drug, inhibits neuronal activity and muscular contractility in arthropods and nematodes, activating glutamate-gated chloride channels at nanomolar concentrations (Lynagh and Lynch, 2012; Calimet et al. 2013; Degani-Katzav et al. 2017). Ivermectin resistance has been studied in Haemonchus contortus (the Barber pole worm) leading to the conclusion that mutations to ivermectin resistance affected the intrinsic properties of the receptor with no specific effect on IVM binding (Atif et al. 2017). Glutamate binding triggers a rapidly reversible current in heteromeric channels formed by Glc-1 and Glc-2, while the anti-helmintic drug ivermectin and other avermectins trigger a permanently open channel configuration. Channels containing only Glc-1 are activated by ivermectin, but not by glutamate alon, and Glutamate binding triggers a rapidly reversible current in heteromeric channels formed by Glc-1 and Glc-2, while the anti-helmintic drug ivermectin and other avermectins including ibotenate trigger a permanently open channel configuration. Channels containing only Glc-1 are activated by ivermectin, but not by glutamate alone. The channel is blocked by picrotoxin and flufenamic acid (Cully et al. 1994; Das and Dillon 2005). A database of glutamate-gated chloride (GluCl) subunits across 125 nematode species reveals patterns of gene accretion and sequence diversification (O'Halloran 2022). The gene encoding this protein is expressed at varying levels in response to the presence of ivermectin (Dube et al. 2023).