Title
Block of neuronal nicotinic acetylcholine receptors by organophosphate insecticides
Author
Smulders, C.J.G.M.
Bueters, T.J.H.
Vailati, S.
van Kleef, R.G.D.M.
Vijvergberg, H.P.M.
Publication year
2004
Abstract
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
Subject
Neuronal nicotinic acetylcholine receptor
Organophosphate pesticides
Rat brain acetylcholnesterase
Two-microelectrode voltage clamp
Xenopus oocytes
brain protein
chlorpyrifos
dipeptidyl carboxypeptidase
disulfoton
nicotinic receptor
organophosphate insecticide
parathion
animal cell
animal experiment
animal model
animal tissue
article
binding site
brain nerve cell
cognitive defect
concentration (parameters)
controlled study
desensitization
environmental exposure
enzyme inhibition
male
neurologic disease
nonhuman
oocyte
protein binding
protein expression
rat
receptor blocking
voltage clamp
Xenopus laevis
Algorithms
Animals
Bicyclo Compounds, Heterocyclic
Binding, Competitive
Brain
Cholinesterase Inhibitors
Dose-Response Relationship, Drug
Electrophysiology
Humans
Insecticides
Kinetics
Ligands
Male
Models, Biological
Nicotinic Agonists
Nicotinic Antagonists
Oocytes
Organophosphorus Compounds
Patch-Clamp Techniques
Pyridines
Rats
Rats, Wistar
Receptors, Nicotinic
Xenopus laevis
Xenopus laevis
To reference this document use:
http://resolver.tudelft.nl/uuid:f872b897-7a39-4c1e-bdcb-b13da4328194
DOI
https://doi.org/10.1093/toxsci/kfh269
TNO identifier
238217
ISSN
1096-6080
Source
Toxicological Sciences, 82 (2), 545-554
Bibliographical note
Correspondence Address: Vijverberg, H.P.M.; Inst. for Risk Assessment Sciences, Utrecht University, PO Box 80176, NL-3508 TD Utecht, Netherlands; email: H.Vijverberg@iras.uu.nl
Document type
article