γ-Aminobutyrate- and Glutamate-gated Chloride Channels as Targets of Insecticides

gamma-Aminobutyrate (GABA)- and glutamate-gated chloride channels (GABACls and GluCls) are members of the Cys-loop receptor channel family. Both channels are widely distributed in the nervous system of invertebrates and function as neurotransmitter receptors to mediate inhibitory synaptic transmission. These receptor channels are important targets for widely used insecticides and parasiticides. Diverse noncompetitive antagonists, including the phenylpyrazole insecticide fipronil, inhibit inhibitory neurotransmission by binding to a site deep within the pentameric channel. Macrocyclic lactones, such as the insecticide/parasiticide avermectin, activate GluCls by irreversibly binding to the subunit interfaces. Recent genome sequencing and molecular biology studies have revealed a diversity of subunit isoforms arising from the duplication, alternative splicing, and RNA editing of the genes encoding these channels in various insect species, which may lead to physiological and pharmacological diversification of the receptor channels. Fipronil resistance due to target-site insensitivity in GABACIs is a growing concern in several insect pest species. Nevertheless, identification of new chemistry and multiple potential binding sites for agonists, antagonists, and modulators in these channels suggests potential for developing novel pest control chemicals.