Skip Navigation


ToxSci Advance Access originally published online on August 25, 2004
Toxicological Sciences 2004 82(1):219-227; doi:10.1093/toxsci/kfh261
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
82/1/219    most recent
kfh261v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Smulders, C. J. G. M.
Right arrow Articles by Vijverberg, H. P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smulders, C. J. G. M.
Right arrow Articles by Vijverberg, H. P. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Toxicological Sciences vol. 82 no. 1 © Society of Toxicology 2004; all rights reserved.

A Noncompetitive, Sequential Mechanism for Inhibition of Rat {alpha}4ß2 Neuronal Nicotinic Acetylcholine Receptors by Carbamate Pesticides

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

* Institute for Risk Assessment Sciences, Utrecht University, NL-3508 TD Utrecht, The Netherlands; {dagger} CNR, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy

Received June 30, 2004; accepted August 18, 2004

The mechanism by which carbamate pesticides inhibit rat {alpha}4ß2 nicotinic acetylcholine (ACh) receptors (nAChRs) expressed in Xenopus laevis oocytes has been investigated using the two-electrode voltage clamp technique. Carbaryl, S-ethyl N,N-dipropylthiocarbamate (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-fold to 5-fold higher potency than ion currents induced by 1 µM ACh. The potency of carbaryl appears to be independent of ACh concentration. Fenoxycarb displaces 3H-epibatidine bound to {alpha}4ß2 (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.

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


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.