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ToxSci Advance Access originally published online on September 1, 2004
Toxicological Sciences 2004 82(2):545-554; doi:10.1093/toxsci/kfh269
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.

Block of Neuronal Nicotinic Acetylcholine Receptors by Organophosphate Insecticides

Chantal J. G. M. Smulders*, Tjerk J. H. Bueters{dagger}, Silvia Vailati{ddagger}, Regina G. D. M. van Kleef* and Henk P. M. Vijverberg*,1

* Institute for Risk Assessment Sciences, Utrecht University, NL-3508 TD Utrecht, The Netherlands; {dagger} TNO Prins Maurits Laboratory, NL-2280 AA Rijswijk, The Netherlands; and {ddagger} CNR Center of Cellular and Molecular Pharmacology, University of Milano, I-20129 Milano, Italy

Received June 24, 2004; accepted August 25, 2004

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 {alpha}4ß2 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 {alpha}4ß2 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 {alpha}4ß2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal {alpha}4ß2 nAChRs are additional targets for some OP pesticides.

Key Words: organophosphate pesticides; neuronal nicotinic acetylcholine receptor; rat brain acetylcholinesterase; Xenopus oocytes; two-microelectrode voltage clamp.


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