Neuronal ion channels as the target sites of insecticides.
Certain types of neuronal ions 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 GABAA receptor chloride channel complex. With the exception of organophosphate and carbamate insecticides which inhibit acetylcholinesterases, most insecticide commercially developed act on the sodium channel and the GABA system. Pyrethroids show 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 (approximately 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 action 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 GABAA system, the initial transient stimulation being followed by a suppression. The stimulation requires the presence of the gamma 2 subunit. The suppression of the GABA system is also documented by Cl- 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.
Narahashi
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Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611-3008, USA.
D000818:Animals; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity; D007306:Insecticides / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011722:Pyrethrins / Q000633:toxicity; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018118:Chloride Channels; D007306:Insecticides; D011722:Pyrethrins; D011963:Receptors, GABA-A; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane