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.