A [delta]-Conotoxin from Conus ermineus Venom Inhibits Inactivation in Vertebrate Neuronal Na super(+) Channels but Not in Skeletal and Cardiac Muscles

• Published in: The Journal of biological chemistry Vol. 279; no. 6; pp. 4680 - 4685
• Main Authors: Barbier, J, Lamthanh, H, Le Gall, F, Favreau, P, Benoit, E, Chen, H, Gilles, N, Ilan, N, Heinemann, SH, Gordon, D, Menez, A, Molgo, J
• Format: Journal Article
• Language: English
• Published: 06-02-2004
• Subjects: Anura; Conus ermineus; Marine
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309576200

We have isolated [delta]-conotoxin EVIA ([delta]-EVIA) sub(,) 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 [omega]-, [delta]-, mu O-, and [kappa]-conotoxins. However, it displays low sequence homology with the latter conotoxins. [delta]-EVIA inhibits Na super(+) channel inactivation with unique tissue specificity upon binding to receptor site 6 of neuronal Na super(+) channels. Using amphibian myelinated axons and spinal neurons, we showed that [delta]-EVIA increases the duration of action potentials by inhibiting Na super(+) channel inactivation. [delta]-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 [delta]-EVIA was confirmed by showing that a fluorescent derivative of [delta]-EVIA labeled motor nerve endings but not skeletal muscle fibers. In a heterologous expression system, [delta]-EVIA inhibited inactivation of rat neuronal Na super(+) channel subtypes (rNa sub(V)1.2a, rNa sub(V)1.3, and rNa sub(V)1.6) but did not affect rat skeletal (rNa sub(V)1.4) and human cardiac muscle (hNa sub(V)1.5) Na super(+) channel subtypes. [delta]-EVIA, in the range of concentrations used, is the first conotoxin found to affect neuronal Na super(+) channels without acting on Na super(+) channels of skeletal and cardiac muscle. Therefore, it is a unique tool for discriminating voltage- sensitive Na super(+) channel subtypes and for studying the distribution and modulation mechanisms of neuronal Na super(+) channels, and it may serve as a lead to design new drugs adapted to treat diseases characterized by defective nerve conduction.