Tetrodotoxin sodium channels

Figure 11. Comparative potencies of several saxitoxins and tetrodotoxin in the mouse bioassay, displacement of radiolabelled saxitoxin from rabbit brain, and block of single batrachotoxin-treated rat sarcolemmal sodium channels incorporated into planar lipid bilayers. The horizontal axis is the log of the potency relative to saxitoxin. Compound numbering corresponds to that in Figure 1. Data from Ref. 10, 94, 95.

Tetrodotoxin (TTX) and saxitoxin (STX) are potent sodium channel blockers that are found in phylogenetically diverse species of marine life. The wide distribution of TTX and STX has resulted in speculation that bacteria are the source of these toxins. Recently, investigators have reported isolation of marine bacteria, including Vibrio Alteromonas, Plesiomonas, and Pseudomonas species, that produce TTX and STX. This chapter details the methods and results of research to define bacterial sources of TTX and STX. 

The tetrodotoxins (TTXs) and saxitoxins (STXs) have in common the ability to block sodium channels of excitable membranes (1—5), Saxitoxin and tetrodotoxin are some of the most potent non-proteinaceous neurotoxins known and are responsible for significant human morbidity and mortality (6, 7). Although for many years the biosynthetic origin(s) of TTXs and STXs has not been identified, recent evidence indicates that bacteria may be a source. 

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. 

Ginsburg KS, Narahashi T (1993) Differential sensitivity of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels to the insecticide allethrin in rat dorsal root ganglion neurons. Brain Res 627 239-248... 

Song JH, Narahashi T (1996) Differential effects of the pyrethroid tetramethrin on tetrodotoxin-sensitive and tetrodotoxin-resistant single sodium channels. Brain Res 712 258-264... 

Tabarean IV, Narahashi T (1998) Potent modulation of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels by the type II pyrethroid deltamethrin. J Pharmacol Exp Ther 284 958-965... 

There appear to be at least two kinds of sodium channels, the common ones which are blocked by tetrodotoxin and alternate ones which are not affected by tetrodotoxin (57,58). It seems reasonable that species with a preponderance of this alternate type of sodium channel might evolve as the predominate form in response to the presence of tetrodotoxin. It is completely reasonable that in the presence of tetrodotoxin, species would be selected in which the nerve... 

The puffer fish is probably the best known neurotoxic fish. Several related species of fish, as well as other marine life, such as some frogs, starfish, octopus, and others, contain tetrodotoxin. Many people consider this fish a delicacy despite the occasional death from poor preparation. Tetrodotoxin is heat stable but water soluble, so careful preparation is necessary to limit neurological effects. Symptoms of poisoning include a rapid onset of numbness in the lips and mouth, which then extends to the fingers and toes, followed by general weakness, dizziness, and respiratory failure, leading to death. The mechanism of action is similar to that of saxitoxin and affects sodium channel permeability. 

Fish Puffer fish (fugu) blowfish, toadfish. . . some frogs, starfish, ocopus Tetrodotoxin Nervous system numbness, paralysis, respiratory failure, death Decreased sodium channel permeability... 

Action potential propagation Local anesthetics, tetrodotoxin,1 saxitoxin2 Nerve axons Block sodium channels block conduction... 

Several isoforms of the sodium channel have been identified, and they have differing sensitivities to channel-blocking drugs such as tetrodotoxin. There is also evidence that some sodium channels are much more sensitive to local anesthetics than the classic channels associated with axonal transmission. 

Apart from AP-A, the best characterized of these polypeptides with respect to its biological activity is Anemonia sulcata toxin II (ATX II) [19]. This molecule is also cardioactive [28], as would be expected from its similarity to AP-A. Renaud et al. [29] have compared the activities of a number of sea anemone and scorpion toxins on isolated rat atria and found that anthopleurin-B (AP-B, also known as Ax II) had the highest potency and the greatest margin between the concentrations necessary for maximal inotropic activity and for provoking arrhythmias (0.3 versus 10 n . It was also found that sodium channels of rat cardiac cells in culture, which have a low affinity for tetrodotoxin (TTX), have a particularly high affinity for Type 1 anemone toxins [29], whereas Type 2 toxins [30] and scorpion toxins [31] had similar affinities for TTX-sensitive and TTX-insensitive channels in rat neuroblastoma cells and skeletal myotubes, respectively. 

A variety of toxins that modulate voltage-gated sodium channels have been used to probe channel function. They can be classified on the basis of five discrete binding sites (Table 1). These binding sites are commonly found on all a-subunits and are being characterized at the molecular level. The sensitivity to the puffer fish poison tetrodotoxin (TTX) has been used to subdivide voltage-gated sodium channels (Table 3). 

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