HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 35, 36372-36381, August 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/35/36372    most recent M403096200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rayes, D. Articles by Bouzat, C. Search for Related Content PubMed PubMed Citation Articles by Rayes, D. Articles by Bouzat, C. Social Bookmarking                      What's this?

Molecular Basis of the Differential Sensitivity of Nematode and Mammalian Muscle to the Anthelmintic Agent Levamisole^*

Diego Rayes, María José De Rosa, Mariana Bartos, and Cecilia Bouzat

From the Instituto de Investigaciones Bioquímicas de Bahía Blanca, UNS-CONICET, B-8000FWB Bahía Blanca, Argentina

Levamisole is an anthelmintic agent that exerts its therapeutic effect by acting as a full agonist of the nicotinic receptor (AChR) of nematode muscle. Its action at the mammalian muscle AChR has not been elucidated to date despite its wide use as an anthelmintic in humans and cattle. By single channel and macroscopic current recordings, we investigated the interaction of levamisole with the mammalian muscle AChR. Levamisole activates mammalian AChRs. However, single channel openings are briefer than those activated by acetylcholine (ACh) and do not appear in clusters at high concentrations. The peak current induced by levamisole is about 3% that activated by ACh. Thus, the anthelmintic acts as a weak agonist of the mammalian AChR. Levamisole also produces open channel blockade of the AChR. The apparent affinity for block (190 µM at –70 mV) is similar to that of the nematode AChR, suggesting that differences in channel activation kinetics govern the different sensitivity of nematode and mammalian muscle to anthelmintics. To identify the structural basis of this different sensitivity, we performed mutagenesis targeting residues in the subunit that differ between vertebrates and nematodes. The replacement of the conserved Gly-153 with the homologous glutamic acid of nematode AChR significantly increases the efficacy of levamisole to activate channels. Channel activity takes place in clusters having two different kinetic modes. The kinetics of the high open probability mode are almost identical when the agonist is ACh or levamisole. It is concluded that Gly-153 is involved in the low efficacy of levamisole to activate mammalian muscle AChRs.

Received for publication, March 19, 2004 , and in revised form, May 28, 2004.

^* This work was supported by grants from Universidad Nacional del Sur, Agencia Nacional de Promoción Científica y Tecnológica, International Society for Neurochemistry, CONICET (to C. B.), and FIRCA Grant 1R03 TW01185-01 (to C. B. and Steven Sine, Principal Investigator of the FIRCA Grant, Mayo Clinic and Foundation, Rochester, MN). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Instituto de Investigaciones Bioquímicas de Bahía Blanca, UNS-CONICET, CC857, Camino La Carrindanga Km 7-B8000FWB Bahía Blanca, Argentina. Fax: 54-291-4861200; E-mail: inbouzat{at}criba.edu.ar.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Boulin, M. Gielen, J. E. Richmond, D. C. Williams, P. Paoletti, and J.-L. Bessereau Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor PNAS, November 25, 2008; 105(47): 18590 - 18595. [Abstract] [Full Text] [PDF]

				T.-Y. Wu, C. M. Smith, S. M. Sine, and M. M. Levandoski Morantel Allosterically Enhances Channel Gating of Neuronal Nicotinic Acetylcholine {alpha}3{beta}2 Receptors Mol. Pharmacol., August 1, 2008; 74(2): 466 - 475. [Abstract] [Full Text] [PDF]

				M. Bartos, D. Rayes, and C. Bouzat Molecular Determinants of Pyrantel Selectivity in Nicotinic Receptors Mol. Pharmacol., October 1, 2006; 70(4): 1307 - 1318. [Abstract] [Full Text] [PDF]