Tetrodotoxin and Saxitoxin

Tetrodotoxin (TTX, 1) is one of the best known marine toxins and exhibits potent neurotoxicity by specifically blocking the sodium channels of excitable cell membranes. The etiology of TTX has been an interesting topic because of the wide distribution of the toxin among genetically 

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Terlau, H., Heinemann, S. H., Stiihmer, W. et al. Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II. FEBS Lett. 293,93-96,1991. 

Lembi CA (2003) Control of nuisance algae. In Wehr JD, Sheath RG (eds) Freshwater algae of North America ecology and classification. Academic, San Diego, CA, pp 805-834 Lipkin GM, Fozzard HA (1994) A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel. Biophys J 66 1-13... 

Yamamori, K., Nakamura, M., Matsui, T., and Hara, T. J. (1988). Gustatoiy responses to tetrodotoxin and saxitoxin in fish a possible mechanism foravoiding marine toxins. Canadian Journal of Fisheries and Aquatic Science 45,2182-2186. 

Physiological studies show that monensin is a sodium ionophore (15), that induces inotropic effect on guinea pig atria (17). The polyether toxins including ciguatoxin, okadaic acid, and the recently characterized brevetoxin (5, 16) also induce inotropic effect on guinea pig atrial tissue in vitro (17). Additionally, partially purified CTX has been implicated in the depolarization of nerve cells in vitro, which can be reversed by high concentrations of Ca tetrodotoxin and saxitoxin (18). 

The extreme toxic potential of marine metabolites often prevents their application in medicine. However, a number of metabolites proved to be valuable tools in biochemistry, cell and molecular biology. For instance the neurotoxic maitotoxin [109-112] (interaction with extracellular calcium enhancement of calcium influx [113]), the neurotoxic brevetoxin B [114] (interaction with the binding-site-5 of voltage-sensitive sodium channels [115]), tetrodotoxin and saxitoxin (voltage clamp analysis to study sodium channels and excitatory phenomena [116] tetrodotoxin abolishes brevetoxin B activity [117]), okadaic acid [118-120] (analysis of phosphorylation and dephosphorylation processes in eukaryotic cell metabolism [121]), and palytoxin (stimulation of arachidonic acid metabolism synergistically with TPA-type promoters [122]). 

Figure 3. Drugs that selectively interact with ion channels a,b - tetrodotoxin and saxitoxin for Na channels c -tetraethylairanonium for K"" channels d - nifedipine for Ca channels.

Several studies employing oocytes of the clawed frog, Xenopus laevis, for the in vitro translation of sodium channel encoding mRNAs (53-55) suggest that this experimental system may be particularly useful toward this end. The biophysical properties of sodium channels expressed in oocytes following injection of rat brain mRNA were similar to those of sodium channels in their native membrane environment, and were specifically inhibited by the sodium channel blockers tetrodotoxin and saxitoxin (i5.). Sodium channels encoded by mRNAs from rat skeletal muscle and eel electroplax have also been expressed in Xenopus oocytes (56-57). To date the expression of insect sodium channels in the Xenopus oocyte has not been reported, but the utility of this system for the translation and expression of insect acetylcholine receptor mRNA has recently been demonstrated (58). Successful application of this methodology to the expression of insect mRNAs encoding functional sodium channels offers a novel method to test some of the hypotheses for the molecular basis of the kdr mechanism. 

LSnnendonker U (1989) Use-dependent block of sodium channels in frog myelinated nerve by tetrodotoxin and saxitoxin at negative holding potentials. Biochim Biophys Acta 985 153-160... 

Figure 4. The chemical structures of tetrodotoxin and saxitoxin. The numbering refers to the specific position of atoms within the molecule and is cited in the text. The guanidinium group is critical for the toxicity of these compounds and its formula is also shown.

From what has been presented on tetrodotoxin and saxitoxin, it can be appreciated what a two-edged sword these toxins are. On the one hand they have proven to be invaluable probes for the biochemist in the quest for understanding the workings of the nervous system and on the other, they are impressively efficient "molecules of death" with no antidote. Better in the test tube than in the stomach ... 

Kaufman B, Wright DC, Ballou WR, et al. Protection against tetrodotoxin and saxitoxin intoxication by a cross-protective rabbit anti-tetrodotoxin antiserum. Toxicon 29 581-587, 1991. 

Hille, B. 1975. The receptor for tetrodotoxin and saxitoxin. A structural hypothesis. Biophys. J. 15, 615-619. 

Narahashi, T. 1988b. Mechanism of tetrodotoxin and saxitoxin action. In Handbook of Natural Toxins, Vol. 3. Marine Toxins and Venoms (A.T. Tu, ed.), pp. 185-210. Marcell Dekker, Inc., New York. 

The high specificity of tetrodotoxin and saxitoxin for sodium channels in excitable ihembranes makes them suitable ligands with which to undertake binding studies on excitable membranes. From such studies, it is expected to demonstrate the presence of a saturable binding component with an affinity for the toxins comparable with the affinity determined indirectly from inhibition studies. This has proved to be so, although some early difficulties were experienced on two fronts. First, it is essential that an accurate specific activity is known for the radioactive toxin. If radioactive impurities (i.e. radioactivity un-... 

In the aquatic enviromnent, a number of other chiral pollutants are available and they differ in their enantioselective toxicities. Tetrodotoxin and saxitoxin (Figure 4.13) are the best examples of this. Tetrodotoxin... 

Figure 4.13 The chemical structures of tetrodotoxin and saxitoxin pollutants.

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