Tetrodotoxin is a weakly basic, low molecular weight (319.27 Da) neurotoxin, consisting of a positively charged and poisonous guanidinium moiety. Existing as a zwitterion in acidic solutions, tetrodotoxin is highly polar as a result of the abundance of OH and NH groups. The particularly potent neurotoxin is a selective inhibitor of voltage-gated sodium channels (VGSCs), leading to symptoms of numbness, paralysis, and hypotension, as well as ultimately death (Chau et al., 2011).
First isolated from the pufferfish of the genus Tetraodontidae. tetrodotoxin has since been found in a variety of other species, including newts of the genus Taricha, toads of the genus Atelopus, octopuses of the genus Hapalochlaena, and sea stars of the genus Astropecten. In fact, since its initial discovery, the presence of tetrodotoxin has been reported in at least six phyla of organisms, including the Chordata, Mollusca, Echinodermata, Chaetognatha, Arthropoda, and Platyhelminthes (Chau et al., 2011). The wide distribution of the neurotoxin amongst unrelated species has led to the emergence of different theories regarding the biogenic origins of the molecule.
A possible explanation for the origin of tetrodotoxin is that it is a product of a bacterium, acquired via the food chain or by bacterial symbiosis, a mutualistic relationship existing between bacteria and other organisms. Particularly common in marine animals, the symbiotic bacteria live within organs where the conditions are optimum for the production of secondary metabolites, which are ultimately used by the host organism for chemical defence (Chau et al., 2011). Supporting the theory of bacterial symbiosis is the vast variety of tetrodotoxin-producing bacteria, which have been isolated from the large variety of species reported to contain the neurotoxin. For instance, species of the bacterium genus Vibrio have been found to occur in Atergatis floridus (Noguchi et al., 1983), Fugu vermicularis vermicularis (Noguchi et al., 1987), Fugu vermicularis radialis (Lee et al., 2000), Hapalochlaena maculosa (Hwang et al., 1989), Astropecten polyacanthus (Narita et al., 1987), Nassarius semiplicatus (Wang et al., 2008), and Niotha clathrata (Cheng et al., 1995). However, no evidence of symbiotic bacteria has been found in newts, thus demanding explanations of non-bacterial origin (Chau et al., 2011).
Mode of Action
Tetrodotoxin binds to amino acid residues on receptor site 1 of voltage-gated sodium channels (VGSCs). As key proteins in the initiation and propagation of action potentials, VGSCs are abundant in many different types of tissue. However, there exist nine different VGSC subtypes in mammals, each with distinct properties, and as a result, certain VGSC subtypes are more sensitive to tetrodotoxin than others (Nieto et al., 2012). The extent to which tetrodotoxin is able to block each VGSC subtype depends on its concentration; while nanomolar concentrations are sufficient to block subtypes Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7, micromolar concentrations are required for Nav1.5, Nav1.8, and Nav1.9 (Nieto et al., 2012).
By blocking VGSCs, tetrodotoxin is able to reduce the permeability of sodium ions in axon membranes without affecting the diffusion of potassium ions, thereby blocking the transmission of signals from the central nervous system (Fuhrman, 1967). It is this inhibition of the ion channel and interference with conduction that ultimately leads to paralysis, a common symptom of tetrodotoxin poisoning.
Potential Therapeutic Use
VGSCs are essential components of nociception due to the transmission of nerve impulses depending largely on the protein. However, as each VGSC subtype has specific properties and thus contributes to a specific type of pain, it is essential that drugs be produced to block each channel selectively. Due to tetrodotoxin being a selective blocker of the protein, its potential to be used as a painkiller has been researched extensively. Nevertheless, before it can be used as a common local anaesthetic, it must be made more selective for specific VGSC subtypes (Fuhrman, 1967).
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- Cheng, C.A., Hwang, D.F., Tsai, Y.H., Chen, H.C., Jeng, S.S., Noguchi, T., Ohwada, K., Hashimoto, K., 1995. Microflora and tetrodotoxin-producing bacteria in a gastropod, Niotha clathrata. Food Chem. Toxicol. 33, 929–934.
- Fuhrman, F.A., 1967. Tetrodotoxin. Scientific American. 217(2):60-71.
- Hwang, D., Arakawa, O., Saito, T., Noguchi, T., Simidu, U., Tsukamoto, K., Shida, Y., Hashimoto, K., 1989. Tetrodotoxin-producing bacteria from the blue-ringed octopus Octopus maculosus. Mar. Biol. 100, 327–332.
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- Narita, H., Matsubara, S., Miwa, N., Akahane, S., Murakami, M., Goto, T., Nara, M., Noguchi, T., Saito, T., Shida, Y., 1987. Vibrio alginolyticus, a TTX-producing bacterium isolated from the starfish Astropecten polyacanthus. Nippon Suisan Gakk. 53, 617–621.
- Nieto, F.R., Cobos, E.J., Tejada, M.A., Sánchez-Fernández, C., González-Cano, R., Cendán, C.M., 2012. Tetrodotoxin (TTX) as a Therapeutic Agent for Pain. Mar. Drugs. 10, 281-305.
- Noguchi, T., Hwang, D., Arakawa, O., Sugita, H., Deguchi, Y., Shida, Y., Hashimoto, K., 1987. Vibrio alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu vermicularis vermicularis. Mar. Biol. 94, 625–630.
- Noguchi, T., Uzu, A., Koyama, K., Hashimoto, K., 1983. Occurrence of tetrodotoxin as the major toxin in xanthid crab Atergatis floridus. Bull. Jpn. Soc. Sci. Fish. 49, 1887–1892.
- Wang, X., Yu, R., Luo, X., Zhou, M., Lin, X., 2008. Toxin-screening and identification of bacteria isolated from highly toxic marine gastropod Nassarius semiplicatus. Toxicon 52, 55–61.
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