Chloride channels as tools for developing selective insecticides

Abstract

Ligand-gated chloride channels underlie inhibition in excitable membranes and are proven target sites for insecticides. The gamma-aminobutyric acid (GABA(1)) receptor/chloride ionophore complex is the primary site of action for a number of currently used insecticides, such as lindane, endosulfan, and fipronil. These compounds act as antagonists by stabilizing nonconducting conformations of the chloride channel. Blockage of the GABA-gated chloride channel reduces neuronal inhibition, which leads to hyperexcitation of the central nervous system, convulsions, and death. We recently investigated the mode of action of the silphinenes, plant-derived natural compounds that structurally resemble picrotoxinin. These materials antagonize the action of GABA on insect neurons and block GABA-mediated chloride uptake into mouse brain synaptoneurosomes in a noncompetitive manner. In mammals, avermectins have a blocking action on the GABA-gated chloride channel consistent with a coarse tremor, whereas at longer times and higher concentrations, activation of the channel suppresses neuronal activity. Invertebrates display ataxia, paralysis, and death as the predominant signs of poisoning, with a glutamate-gated chloride channel playing a major role. Additional target sites for the avermectins or other chloride channel-directed compounds might include receptors gated by histamine, serotonin, or acetylcholine.The voltage-sensitive chloride channels form another large gene family of chloride channels. Voltage-dependent chloride channels are involved in a number of physiological processes including: maintenance of electrical excitability, chloride ion secretion and resorption, intravesicular acidification, and cell volume regulation. A subset of these channels is affected by convulsants and insecticides in mammals, although the role they play in acute lethality in insects is unclear. Given the wide range of functions that they mediate, these channels are also potential targets for insecticide development.

The cys-loop ligand-gated ion channel gene superfamily of the parasitoid wasp, Nasonia vitripennis

“…For example, nAChRs are targets of neonicotinoids, which have been the fastest-growing class of insecticides in modern crop protection (Jeschke and Nauen, 2008). In addition, GABA receptors, GluCls and HisCls are targets of fipronil and avermectins (Iovchev et al, 2002;Bloomquist, 2003).…”

Tissue-specific Proteogenomic Analysis of Plutella xylostella Larval Midgut Using a Multialgorithm Pipeline

“…In our laboratory, although we found that cadherin is not involved in P. xylostella Bt Cry1Ac resistance (52), we revealed that down-regulation of ALP, ABCC2, ABCC3, and a novel ABCG1 (white) genes are all associated with Cry1Ac resistance in P. xylostella (77,78). Acetylcholinesterase (AChE), as a hydrolase, which hydrolyzes the neurotransmitter acetylcholine was the target of organophosphorus insecticide; chloride channel was studied as insecticidal target (79). Ryanodine receptors (RyRs) are the major cellular mediator of calciuminduced calcium release in animal cells.…”

Immunologic and neurodevelopmental susceptibilities of autism

“…Fipronil's insecticidal activity is mediated primarily through its actions as a non-competitive antagonist of GABR. In this regard, fipronil was initially developed as an insecticide because of its higher selectivity for insect forms of GABR relative to mammalian GABR (Bloomquist 2003). However results from recent studies indicate that fipronil, like endosulfan and lindane, is indeed a high affinity noncompetitive antagonist for the mammalian β 3 -homopentameric GABR (GABRβ 3 ) (Chen et al,2006;Sammelson et al, 2004).…”