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The Tetrodotoxin Receptor of Voltage-Gated Sodium Channels—Perspectives from Interactions with μ-Conotoxins
Department of Physiology and Pharmacology, University of Calgary, and Hotchkiss Brain Institute, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada
Department of Biology; University of Utah; Salt Lake City, UT, USA
The Nora Eccles Harrison Cardiovascular Research & Training Institute and Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA
* Author to whom correspondence should be addressed.
Received: 2 June 2010; in revised form: 24 June 2010 / Accepted: 25 June 2010 / Published: 13 July 2010
Abstract: Neurotoxin receptor site 1, in the outer vestibule of the conducting pore of voltage-gated sodium channels (VGSCs), was first functionally defined by its ability to bind the guanidinium-containing agents, tetrodotoxin (TTX) and saxitoxin (STX). Subsequent studies showed that peptide μ-conotoxins competed for binding at site 1. All of these natural inhibitors block single sodium channels in an all-or-none manner on binding. With the discovery of an increasing variety of μ-conotoxins, and the synthesis of numerous derivatives, observed interactions between the channel and these different ligands have become more complex. Certain μ-conotoxin derivatives block single-channel currents partially, rather than completely, thus enabling the demonstration of interactions between the bound toxin and the channel’s voltage sensor. Most recently, the relatively small μ-conotoxin KIIIA (16 amino acids) and its variants have been shown to bind simultaneously with TTX and exhibit both synergistic and antagonistic interactions with TTX. These interactions raise new pharmacological possibilities and place new constraints on the possible structures of the bound complexes of VGSCs with these toxins.
Keywords: guanidinium toxins; conopeptides; pore block
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French, R.J.; Yoshikami, D.; Sheets, M.F.; Olivera, B.M. The Tetrodotoxin Receptor of Voltage-Gated Sodium Channels—Perspectives from Interactions with μ-Conotoxins. Mar. Drugs 2010, 8, 2153-2161.
French RJ, Yoshikami D, Sheets MF, Olivera BM. The Tetrodotoxin Receptor of Voltage-Gated Sodium Channels—Perspectives from Interactions with μ-Conotoxins. Marine Drugs. 2010; 8(7):2153-2161.
French, Robert J.; Yoshikami, Doju; Sheets, Michael F.; Olivera, Baldomero M. 2010. "The Tetrodotoxin Receptor of Voltage-Gated Sodium Channels—Perspectives from Interactions with μ-Conotoxins." Mar. Drugs 8, no. 7: 2153-2161.