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ToxSci Advance Access published online on September 1, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh269
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 24, 2004
Accepted August 25, 2004

Neurotoxicology

Block of Neuronal Nicotinic Acetylcholine Receptors by Organophosphate Insecticides

Chantal J. G. M. Smulders 1, Tjerk J. H. Bueters 2, Silvia Vailati 3, Regina G. D. M. van Kleef 1, Henk P. M. Vijverberg 1*

1 Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80176, NL-3508 TD Utrecht, The Netherlands
2 TNO Prins Maurits Laboratory, P.O. Box 45, NL-2280 AA Rijswijk, The Netherlands
3 CNR Center of Cellular and Molecular Pharmacology, University of Milano, Via Vanvitelli, 32, I-20129 Milano, Italy

* To whom correspondence should be addressed. E-mail: H.Vijverberg{at}iras.uu.nl.


  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 {alpha}4{beta}2 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}4{beta}2 nAChRs showed that the OPs non-competitively 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 directly interact with neuronal {alpha}4{beta}2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal {alpha}4{beta}2 nAChRs are additional targets for some OP pesticides.

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