Neuronal Ion Channels as the Target Sites of Insecticides

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Abstract
Certain types of neuronal ion channels have been demonstrated to be the major target sites of insecticides. The insecticide‐channel interactions that have been studied most extensively are pyrethroid actions on the voltage‐gated sodium channel and cyclodiene/lindane actions on the GABAAreceptor chloride channel complex. With the exception of organo‐phosphate and carbamate insecticides which inhibit acetylcholinesterases, most insecticides commercially developed act on the sodium channel and the GABA system. Pyrethroids slow the kinetics of both activation and inactivation gates of sodium channels resulting in prolonged openings of individual channels. This causes membrane depolarization, repetitive discharges and synaptic disturbances leading to hyperexcitatory symptoms of poisoning in animals. Only a very small fraction (~1%) of sodium channel population is required to be modified by pyrethroids to produce severe hyperexcitatory symptoms. This toxicity amplification theory applies to pharmacological and toxicological actions of other drugs that go through a threshold phenomenon. Selective toxicity of pyrethroids between invertebrates and mammals can be explained based largely on the responses of sodium channels and partly on metabolic degradation. The pyrethroid‐sodium channel interaction is also supported by Na+uptake and batrachotoxin binding experiments. Cyclodienes and lindane exert a dual action on the GABAAsystem, the initial transient stimulation being followed by a suppression. The stimulation requires the presence of the γ2 subunit. The suppression of the GABA system is also documented by CI‐flux and ligand binding experiments. It appears that the sodium channel and the GABA system merit continuing efforts for development of newer and better insecticides. Nitromethylene heterocycles including imidacloprid act on nicotinic acetylcholine receptors. Insect receptors are more sensitive to these compounds than mammalian receptors. Single‐channel analyses of the nicotinic acetylcholine receptor of PC12 cells have shown that imidacloprid increases the activity of subconductance state currents and decreases that of main conductance state currents. This may explain the imidacloprid suppression of acetylcholine responses.

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