Tetrodotoxin (TTX) is a neurotoxin found in many pufferfish species. Pufferfish are considered a delicacy and consumed in many countries around the world, with Japan being the primary consumer. It is believed that the toxin is actually produced by a number of different bacterial species that have a symbiotic relationship with pufferfish. Studies have shown that non-toxic pufferfish become toxic after being fed a bacteria-enriched diet. The reverse is also true: toxic pufferfish become non-toxic after being fed a bacteria-free diet. The toxin itself is found in the liver, gonad, and skin of the pufferfish, and it is heat stable so cooking does not destroy it. As a result, extreme care by an experienced chef is required to prepare it.
TTX is an inhibitor of voltage-gated sodium channels (VGSCs). VGSCs open and close according to the membrane potential and are essential for the propagation of action potentials. The pervasiveness of these channels is conducive to the variety of symptoms that TTX induces. Inhibition of action potentials initially causes paresthesia of the mouth, while TTX’s effect on skeletal muscle eventually causes motor paralysis. The leading of cause of death is respiratory failure as TTX acts on the smooth muscle of the diaphragm and stops its contraction. In some cases, prompt respiratory support has been able to save patients from TTX poisoning.
It is believed that TTX inhibits VGSCs by entering the pore and physically occluding the channel. The ability of guanidine to replace sodium and sustain a current has been established before, and TTX has a guanidinium moiety of its own (Figure 1). Therefore, it’s theorized that the guanidinium group enters the channel like a sodium ion, but the bulky structure of TTX blocks the channel. The extreme binding efficiency could be further explained by other interactions between TTX and the channel that stabilize the molecule.