Block of neuronal nicotinic acetylcholine receptors by organophosphate insecticides
article
Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal α4β2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. Several OP pesticides, e.g., parathion-ethyl, chlorpyrifos and disulfoton, inhibited the ACh-induced ion current with potencies in the micromolar range. The potency of inhibition increased with increasing concentrations of the agonist ACh. Comparison of the potency of nAChR inhibition with the potency of AChE inhibition demonstrated that some OPs inhibit nAChRs more potently than AChE. Binding experiments on α 4β2 nAChRs showed that the OPs noncompetitively interact with nAChRs. The inhibitory effects on nAChRs are adequately described and explained by a sequential two-step mechanism, in which rapidly reversible OP binding to a separate binding site leads to inhibition followed by a stabilization of the blocked state or receptor desensitization. It is concluded that OPs interact directly with neuronal α4β2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal α4β2 nAChRs are additional targets for some OP pesticides. © Society of Toxicology 2004; all rights reserved. Chemicals / CAS: chlorpyrifos, 2921-88-2; dipeptidyl carboxypeptidase, 9015-82-1; disulfoton, 298-04-4; parathion, 3270-86-8, 56-38-2, 597-88-6; Bicyclo Compounds, Heterocyclic; Cholinesterase Inhibitors; epibatidine, 140111-52-0; Insecticides; Ligands; Nicotinic Agonists; Nicotinic Antagonists; Organophosphorus Compounds; Pyridines; Receptors, Nicotinic
Topics
Neuronal nicotinic acetylcholine receptorOrganophosphate pesticidesRat brain acetylcholnesteraseTwo-microelectrode voltage clampXenopus oocytesbrain proteinchlorpyrifosdipeptidyl carboxypeptidasedisulfotonnicotinic receptororganophosphate insecticideparathionanimal cellanimal experimentanimal modelanimal tissuearticlebinding sitebrain nerve cellcognitive defectconcentration (parameters)controlled studydesensitizationenvironmental exposureenzyme inhibitionmaleneurologic diseasenonhumanoocyteprotein bindingprotein expressionratreceptor blockingvoltage clampXenopus laevisAlgorithmsAnimalsBicyclo Compounds, HeterocyclicBinding, CompetitiveBrainCholinesterase InhibitorsDose-Response Relationship, DrugElectrophysiologyHumansInsecticidesKineticsLigandsMaleModels, BiologicalNicotinic AgonistsNicotinic AntagonistsOocytesOrganophosphorus CompoundsPatch-Clamp TechniquesPyridinesRatsRats, WistarReceptors, NicotinicXenopus laevisXenopus laevis
TNO Identifier
238217
ISSN
10966080
Source
Toxicological Sciences, 82(2), pp. 545-554.
Pages
545-554
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