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ToxSci Advance Access published online on August 25, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh261
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 30, 2004
Accepted August 18, 2004

Neurotoxicology

A Noncompetitive, Sequential Mechanism for Inhibition of Rat {alpha}4{beta}2 Neuronal Nicotinic Acetylcholine Receptors by Carbamate Pesticides

Chantal J. G. M. Smulders 1, Regina G. D. M. Van Kleef 1, Aart de Groot 1, Cecilia Gotti 2, Henk P. M. Vijverberg 1*

1 Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80176, NL-3508 TD Utrecht, The Netherlands
2 CNR, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy

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


  Abstract

The mechanism by which carbamate pesticides inhibit rat {alpha}4{beta}2 nicotinic ACh receptors (nAChRs) expressed in Xenopus laevis oocytes has been investigated using the two-electrode voltage clamp technique. Carbaryl, EPTC and fenoxycarb inhibit ACh-induced ion currents in a concentration-dependent way. EPTC and fenoxycarb inhibit ion currents induced by 1 mM ACh with 3- to 5-fold higher potency than ion currents induced by 1 µM ACh. The potency of carbaryl appears independent of ACh concentration. Fenoxycarb displaces [3H]-epibatidine bound to {alpha}4{beta}2 nAChRs with a Ki of 750 µM, which is much higher than the functional IC50 of 2.3 - 11 µM. This shows that the inhibition of ion current by the carbamate is a noncompetitive effect. Inhibition by fenoxycarb is independent of the state of the ion channel. The rate of onset of inhibition is enhanced and the rate of reversal of inhibition is reduced when the concentration of fenoxycarb is increased. The rate of reversal of inhibition is also reduced when the period of exposure to fenoxycarb is increased. The time- and concentration-dependent inhibition of nAChR-mediated ion current by fenoxycarb is accounted for by a two-step mechanism involving a rapid blocked state and a sequential more stably blocked or desensitized state.

Keywords: neuronal nicotinic acetylcholine receptor; carbamate pesticide; noncompetitive inhibition; voltage clamp; Xenopus oocyte; epibatidine binding.
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