Macrocylcic lactone (ML) antihelmintics, insecticides and acaricids (e.g. abamectin and ivermectin) target the alpha subunits of the glutamate-gated chloride channels (GluCl) present in nematodes, arthropods, crustaceans (daphnia), and mollusks. The binding of the ML may result in directly opening the ion channel, or may potentiate the effects of the endogenous agonist, glutamate, resulting in increased chloride entry into the cell. With the increased influx of chloride ions, the cell becomes hyperpolarized (neuron) or depolarized (myocyte), resulting in paralysis and death. Mammals do not possess glutamate-gated chloride channels, but the structure of the GluCl channel is similar to the glycine === Background (optional) ===
Strong evidence exists for population decline in pest species (e.g., worms, ticks and mites) resulting from targeted glutamate-gated chloride channels, as well for non-target species (bees, butterflies). However, this AOP has been developed with minimal research. Given GluCl channels exist in several cell types, specific key events likely vary among species, which are not elucidated here. The review by Wolstenholme (2012) describes specific GluCl-controlled sensory inputs in worms and flies (e.g., behavioral responses to odour, temperature and light) which suggest pathways other than paralysis may be more sensitive. As such, this AOP should be considered putative with minimally-researched support.
Slimko, E.M., McKinney, S., Anderson, D.J., Davisodn, N., and Lester, H.A. (2002) Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373-7379.
Wolstenholm, A. (2012) Glutamate-gated chloride channels. J. Biological Chem. 287: 48, 40232-40238.