The Mechanism of Action of Avermectins in Caenorhabditis Elegans: Correlation between Activation of Glutamate-Sensitive Chloride Current, Membrane Binding, and Biological Activity

Abstract

Xenopus laevis oocytes were injected with mRNA isolated from the free-living nematode Caenorhabditis elegans and the activation and potentiation of a glutamate-sensitive chloride current by a series of avermectin analogs and milbemycin D were determined. There was a strong correlation between the EC50 value determined for current activation in oocytes, the LD95 value for nematocidal activity, and also for the Ki value determined in a [3H]ivermectin competition binding assay. Four of the analogs were tested for potentiation of glutamate-sensitive current and the rank order for potentiation correlated with the EC50 for direct activation of current. We conclude that avermectins and milbemycins mediate their nematocidal effects on C. elegans via an interaction with a common receptor molecule, glutamate-gated chloride channels.

Distribution of glutamate‐gated chloride channel subunits in the parasitic nematode Haemonchus contortus

“…There is, however, a strong correlation between the biological activities of ivermectin on C. elegans and H. contortus , both pharyngeal pumping and motility being inhibited in both species (Bernt et al, 1989;Avery and Horvitz, 1990;Geary et al, 1993;Arena et al, 1995). It seems that nematodes contain more than one type of GluCl, and it is possible that differences in the expression of individual subunit genes between nematode species reflect their adaptation to different life styles.…”

Validação intralaboratorial de método quantitativo para determinação múltipla de resíduos de avermectinas em leite bovino por cromatografia líquida de alta eficiência com detecção de fluorescência

“…Estes compostos ativam os canais de cloreto dos neurotransmissores inibitórios ácido gama-aminobutírico e glutamato, provocando a paralisia dos parasitas 2,12,43 . Como o mecanismo de ação não é específico, as avermectinas podem afetar organismos não alvos 30 .…”

Biochemical Processes Related to Insecticide Action: an Overview

“…Examples include pyrethroids and DDT which affect sodium channels (Zlotkin 1999), polychlorocycloalkane fipronyl which blocks the chloride ion channels (Cole et al1993;Bloomquist 1994;Scharf and Siegfried 1999) and the avermectins which activate the GABA receptor (Deng and Casida 1992;Arena et al 1995;Jansson and Dybas 1998). Excellent reviews of GABA and glutamate receptors and of ion channels are presented by Bloomquist and Zlotkin (this Vol.).…”