Special Issue "Tetrodotoxin"

Guest Editor
Dr. Peter C. Ruben
Department of Biomedical Physiology & Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada
Website: http://www.sfu.ca/bpk/faculty_directory/ruben/
E-Mail:
Interests: voltage-gated ion channels; toxins; evolution

Dear Colleagues,

Toxins, and their actions on target molecules, provide insight into predator/prey interactions, co-evolutionary arms races, molecular properties, and structure/function relationships. Toxins also hold promise for therapeutic interventions and serve as a template for rational drug design. Tetrodotoxin is a ubiquitous toxin with highly specific actions. Tetrodotoxin’s ability to block voltage-gated sodium channels has been a fruitful area of research for many years and has led to a number of insights from the molecular level through to the grand scale of evolution. It even has epicurean significance, sometimes with lethal results. Tetrodotoxin has been used as a tool to map the structure and the biophysical properties of voltage-gated sodium channels, and is routinely used to differentiate between sodium channel orthologs.

This special issue of the journal Marine Drugs focuses on tetrodotoxin and seeks to emphasize the importance of the toxin as a research tool, as a potential therapeutic agent, and as a key for understanding animal behavior and natural selection. It is my honor to serve as Guest Editor for this special issue, and to invite scientists to report recent advances on the full spectrum of research questions associated with tetrodotoxin. I eagerly anticipate working with you towards a successful special issue of Marine Drugs dedicated to this important toxin.

Dr. Peter Ruben
Guest Editor

Submission

All papers should be submitted to marinedrugs@mdpi.org with a copy to the Guest Editor. Papers will be published continuously until the deadline and will be listed together at the special issue website. Research articles and review articles are both invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editors for announcement on this website.

Submitted papers should not have been published previously, nor be under consideration for publication elsewhere. All papers are refereed through a peer-review process. A guide for authors, sample copies and other relevant information for submitting papers are available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed quarterly journal published by Molecular Diversity Preservation International.

Please visit the Instructions for Authors page before submitting a paper. Open Access Article Processing Charges are 1000 CHF per paper. English correction fees (250 CHF) will be added in certain cases (1250 CHF per paper for those papers that require extensive additional formatting and/or English corrections.). Starting 1 January 2010, Article Processing Charges are of 1400 CHF per accepted article for Marine Drugs.

• voltage-gated sodium channels
• chemical defense
• ionic currents
• puffer fish
• selectivity filter

Type of Paper: Article
Title: Distribution of TTX Analogs in Fugu Niphobles Collected at the
Southern Coast of Korea
Authors: Jun-Ho Jang, Jong-Soo Lee and Mari Yotsu-Yamashita
Affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi 981-8555, Japan; E-Mail: myama@biochem.tohoku.ac.jp (M.Y.-Y.)
Abstract: will be added soon

Type of Paper: Review
Title: The Outer Vestibule of the Na Channel – Toxin Receptor and Modulator of Permeation as well as Gating
Authors: René Cervenka, Touran Zarrabi, Peter Lukacs and Hannes Todt
Affiliation: Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; E-Mail: hannes.todt@meduniwien.ac.at
Abstract: The outer vestibule of voltage-gated Na channels is formed by extracellular loops connecting the S5 and S6 segments of all four domains (“P-loops”), which fold back into the membrane. Classically, this structure has been implicated in the control of ion permeation and in toxin block. However, conformational changes of the outer vestibule may also result in alterations in gating, as suggested by several P-loop mutations that gave rise to gating changes. Moreover, partial pore block by mutated toxins may reverse gating changes induced by mutations. Therefore, toxins that bind to the outer vestibule can be used to modulate channel gating.

Type of Paper: Article
Title: The Biophysical Costs Associated with Tetrodotoxin Resistance in the Garter Snake, Thamnophis sirtalis
Authors: Paul Lee and Peter C. Ruben
Affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6 Canada; E-Mails: paul0313@gmail.com, pruben@sfu.ca
Abstract: Tetrodotoxin (TTX) is a potent toxin that specifically binds to voltage gated sodium channels (Na_V). TTX binding physically blocks the flow of sodium ions through Na_V, thereby preventing action potential generation and propagation. TTX has different binding affinities for different Na_V isoforms. These differences are imparted by amino acid substitutions in positions within, or proximal to, the TTX binding site in the channel pore. These substitutions confer TTX resistance to a variety of species. Populations of the garter snake Thamnophis sirtalis have evolved TTX-resistant sodium channels over the course of a co-evolutionary arms race, allowing some populations of snakes to feed on tetrodotoxic newts, including Taricha granulosa. Different populations of the garter snake have different degrees of TTX-resistance, which we have previously shown to correlate with the number of amino acid substitutions as well as the kinetics of action potentials recorded from skeletal muscle. In the present study, we tested the voltage dependence, kinetics, and ion selectivity of Na_V containing sequence from different garter snake populations including: Bear Lake, Idaho; Warrenton, Oregon; and Willow Creek, California. We observed significant changes in gating properties of the TTX resistant Na_V. In addition, ion selectivity of the most TTX-resistant Na_V was significantly different from that of TTX-sensitive channels. These results suggest TTX resistance comes at a cost to channel performance caused by changes in the gating properties and/or ion selectivity of the TTX resistant Na_V.

Type of Paper: Review
Title: Effects of Tetrodotoxin on the Mammalian Cardiovascular System
Author: Thomas Zimmer
Affiliation: Institute of Physiology II, Friedrich Schiller University, 07740 Jena, Germany; E-Mail: thomas.zimmer@mti.uni-jena.de
Abstract: The human genome encodes nine functional voltage-gated Na⁺ channels. Three of them, namely Na_v1.5, Na_v1.8, and Na_v1.9, are resistant to nanomolar concentrations of tetrodotoxin (TTX; IC50 ≥ 1 µM). The other isoforms, which are predominantly expressed in the skeletal muscle and nervous system, are highly sensitive to TTX (IC50~10 nM). During the last decade, it has become evident that, in addition to the major cardiac isoform Na_v1.5, several of those TTX sensitive isoforms are expressed in the mammalian heart. Whereas immunohistochemical and electrophysiological methods demonstrated functional expression in various heart regions, the physiological importance of those isoforms for cardiac excitation in higher mammals is still debated. This review summarizes our knowledge on the systemic cardiovascular effects of TTX with a special focus on cardiac excitation and performance at lower concentrations of this marine drug.

Type of Paper: Review
Title: The Tetrodotoxin Receptor of Voltage-Gated Sodium Channels–Perspectives from Interactions with μ-Conotoxins
Authors: Robert J. French ¹, Baldomero M. Olivera ², Michael F. Sheets ³ and Doju Yoshikami ²
Affiliations: ¹ Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; E-Mail: french@ucalgary.ca (R.J.F.)
² Department of Biology, University of Utah, Salt Lake City, Utah, USA; E-Mails: olivera@biology.utah.edu (B.M.O.); yoshikami@bioscience.utah.edu (D.Y.)
³ The Nora Eccles Harrison Cardiovascular Research and Training Institute, 95 South 2000 East, Salt Lake City, UT 84112, USA; E-Mail: sheets@cvrti.utah.edu (M.F.S.)
Abstract: Receptor site 1, in the outer vestibule of the conducting pore of voltage-gated sodium (NaV) channels, was first functionally defined by its ability to bind the guanidinium-containing agents to tetrodotoxin (TTX) and saxitoxin (STX). Subsequent studies showed that peptide μ-conotoxins competed for binding at site 1. All of these natural inhibitors blocked single sodium channels in a 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 these different ligands have become more complex. Certain μ-conotoxin derivatives blocked single-channel current partially rather than completely, enabling the demonstration of interactions between the bound toxin and the channel’s voltage sensor. Most recently, variants of the relatively small μ-conotoxin KIIIA (16 amino acids) have exhibited 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 between NaV channels and these toxins.
Selected References: [1] Cruz, L.J.; Gray, W.R.; Olivera, B.M.; Zeikus, R.D.; Kerr, L.; Yoshikami, D.; Moczydlowski, E.Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J. Biol. Chem. 1985, 260, 9280 - 9288.
[2] French, R. J.; Prusak-Sochaczewski, E.; Zamponi, G.W.; Becker, S.; Kularatna, A.S.; Horn, R. Interactions between a pore-blocking peptide and the voltage sensor of the sodium channel: an electrostatic approach to channel geometry. Neuron 1996,16, 407 - 413.
[3] Zhang, M.M.; Green, B.R.; Catlin, P.; Fiedler, B.; Azam, L.; Chadwick, A.; Terlau, H.; McArthur, J.R.; French, R.J.; Gulyas, J.; Rivier, J.E.; Smith, B.J.; Norton, R.S.; Olivera, B.M.; Yoshikami, D.; Bulaj, G. SStructure/Function Characterization of μ-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels J. Biol. Chem. 2007, 282, 30699-30706.
[4] Zhang, M. M.; McArthur, J.R.; Azam, L.; Bulaj, G.; Olivera, B.M.; French, R.J.; Yoshikami, D. Synergistic and antagonistic interactions between tetrodotoxin and μ-Conotoxin in blocking voltage-gated sodium channels. Channels 2009, 3, 32-38.

Type of Paper: Review
Title: Biosynthesis of Tetrodotoxin and Structurally Related Molecules
Authors: Rocky Chau, John A. Kalaitzis and Brett A. Neilan
Affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia; E-Mails: rockx@hotmail.com (R.C.); b.neilan@unsw.edu.au (B.A.N.)
Abstract: The potent neurotoxin tetrodotoxin (TTX) posesses a unique cage-like structure whose biosynthesis has yet to be elucidated. Biosynthetic studies in the TTX-producing newt Taricha torosa, and in bacterial genera including Vibrio have proven inconclusive. Indeed, very few studies on the elucidation of the TTX biosynthetic pathway exist. This review will report on both chemical and genetic based biosynthesis studies of TTX undertaken to date and outline approaches which may be useful for expanding upon the current body of knowledge. The biosynthesis of structurally similar toxins, which may reveal clues into the biosynthetic pathway of TTX, will also be discussed.