Block of Neuronal Nicotinic Acetylcholine Receptors by Organophosphate Insecticides
| Autor: | Regina G.D.M. van Kleef, Tjerk J. H. Bueters, Henk P.M. Vijverberg, Silvia Vailati, Chantal J. G. M. Smulders |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Insecticides Patch-Clamp Techniques Pyridines Nicotinic Antagonists Receptors Nicotinic Pharmacology Ligands Toxicology Binding Competitive Models Biological Xenopus laevis chemistry.chemical_compound Organophosphorus Compounds medicine Animals Humans Nicotinic Agonists Rats Wistar Nicotinic Antagonist Acetylcholine receptor Dose-Response Relationship Drug Chemistry Organophosphate Brain Environmental exposure Bridged Bicyclo Compounds Heterocyclic Acetylcholinesterase Rats Electrophysiology Kinetics Nicotinic agonist Biochemistry Epibatidine Oocytes Cholinesterase Inhibitors Algorithms Acetylcholine medicine.drug |
| Zdroj: | Toxicological Sciences. 82:545-554 |
| ISSN: | 1096-0929 |
| DOI: | 10.1093/toxsci/kfh269 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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