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J. Biol. Chem., Vol. 279, Issue 6, 4680-4685, February 6, 2004

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A -Conotoxin from Conus ermineus Venom Inhibits Inactivation in Vertebrate Neuronal Na⁺ Channels but Not in Skeletal and Cardiac Muscles^*

From the ^aLaboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040, CNRS, 91198 Gif-sur-Yvette cedex, France, the ^dDépartement d'Ingénierie et d'Etudes des Protéines, Centre d'Etudes Nucléaires/Saclay, 91191 Gif sur Yvette cedex, France, the ^gResearch Unit Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, D-07747 Jena, Germany, and the ^hDepartment of Plant Sciences, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel

We have isolated -conotoxin EVIA (-EVIA)_, a conopeptide in Conus ermineus venom that contains 32 amino acid residues and a six-cysteine/four-loop framework similar to that of previously described -, -, µO-, and -conotoxins. However, it displays low sequence homology with the latter conotoxins. -EVIA inhibits Na⁺ channel inactivation with unique tissue specificity upon binding to receptor site 6 of neuronal Na⁺ channels. Using amphibian myelinated axons and spinal neurons, we showed that -EVIA increases the duration of action potentials by inhibiting Na⁺ channel inactivation. -EVIA considerably enhanced nerve terminal excitability and synaptic efficacy at the frog neuromuscular junction but did not affect directly elicited muscle action potentials. The neuronally selective property of -EVIA was confirmed by showing that a fluorescent derivative of -EVIA labeled motor nerve endings but not skeletal muscle fibers. In a heterologous expression system, -EVIA inhibited inactivation of rat neuronal Na⁺ channel subtypes (rNa_V1.2a, rNa_V1.3, and rNa_V1.6) but did not affect rat skeletal (rNa_V1.4) and human cardiac muscle (hNa_V1.5) Na⁺ channel subtypes. -EVIA, in the range of concentrations used, is the first conotoxin found to affect neuronal Na⁺ channels without acting on Na⁺ channels of skeletal and cardiac muscle. Therefore, it is a unique tool for discriminating voltage-sensitive Na⁺ channel subtypes and for studying the distribution and modulation mechanisms of neuronal Na⁺ channels, and it may serve as a lead to design new drugs adapted to treat diseases characterized by defective nerve conduction.

Received for publication, August 28, 2003 , and in revised form, November 13, 2003.

^* This work was supported in part by Direction des Systèmes de Forces et de la Prospective Grant 02 60 65 093 (to J. M.), by European Community Grant QLK3-CT-2000-00204 (to A. M. and D. G.), by United States-Israel Binational Agricultural Research and Development Grant IS-3259-01 (to D. G.), and by Deutsche Forschungsgemeinschaft Grant HE 2993/5 (to S. H. H.). 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.

^b These authors contributed equally to this work.

^c Supported by a fellowship from DSP-CNRS.

^e Supported by a fellowship from CEN/Saclay. Present address: L'Oréal Recherche, 92583 Clichy cedex, France.

^f Present address: Atheris Laboratories, case postale 314, Ch-1233 Bernex, Switzerland.

ⁱ To whom correspondence should be addressed. Fax: 33-1-69-82-94-66; E-mail: Jordi.Molgo{at}nbcm.cnrs-gif.fr.

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