Chemical Ecology (Session I 2001)
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Tetrodotoxin: Mode of Action


The flow of sodium ions into nerve cells is a necessary step in the conduction of nerve impulses in excitable nerve fibers and along axons. Normal axon cells have high concentrations of K+ ions and low concentrations of Na+ ions and have a negative potential. Stimulation of the axon results in an action potential which arises from a flow of Na+ ions into the cell and the generation of a positive membrane potential. Propagation of this depolarization along the nerve terminal presages all other events. The Na+ ions flow through the cellular membrane employing the sodium ion channel, a channel that is selective for sodium ions over potassium ions by an order of magnitude.

See these important sites: A review of ion channels and diseases .
Information on voltage-gated Na channels and neuronal action potential.

The structure of the sodium ion channel was determined by a group in Japan led by Shosaku Numa.* These scientists used Electrophorus electricus, the electric eel, as the source of sodium ion channels. The electric organ of the eel is a rich source of sodium ion channels in structures called electroplaxes, the source of the electrical discharge in the eels.

    Repeating Unit 
    Repeating Unit 


The channel itself is made up of a single peptide chain with four repeating units with each unit consisting of six trans-membrane helices. The trans-membrane pore is formed when the four units fold into a cluster with the center of the cluster the pore.

          Ion Channel (from outside cell)


Tetrodotoxin is the poison that is produced by the puffer fish and a number of other animals. It is a virulent poison, the LD50 for the mouse is 10 nanograms. It acts by blocking the conduction of nerve impulses along nerve fibers and axons. The victim eventually dies from respiratory paralysis.

Tetrodotoxin is quite specific in blocking the Na+ ion channel and therefore the flow of Na+ ions while having no effect on K+ ions. Binding to the channel is relatively tight (Kd =10-10 nM). Whereas the hydrated sodium ion binds reversibly on a nanosecond time-scale, tetrodotoxin is bound for tens of seconds.

Membrane with ion channels and hydrated sodium ion and tetrodotoxin


Tetrodotoxin, much larger than the sodium ion, acts like a cork in a bottle, preventing the flow of sodium until it slowly diffuses off. A mortal dose of tetrodotoxin is but a single milligram. Tetrodotoxin competes with the hydrated sodium cation and enters the Na+-channel where it binds. It is proposed that this binding results from the interaction of the positively charged guanidino group on the tetrodotoxin and negatively charged carboxylate groups on side chains in the mouth of the channel. Saxitoxin, a natural product from dinoflagellates, acts in a similar way and is also a potent nerve poison."

If we assume that there are carboxylate groups also on the intracellular side of the pore why doesn’t the tetrodotoxin also block Na+ from leaving the cell when the cell reestablishes equilibrium.?

If tetrodotoxin is such a powerful toxin why does it not poison the host? This is a common question in virtually all cases where a toxin is present. The obvious answer is that the sodium ion channel in the host must be different than that of the victim. It must not be susceptible to the toxin. It has been demonstrated for one of the pufferfish that the protein of the sodium ion channel has undergone a mutation that changes the amino acid sequence making the channel insensitive to tetrodotoxin. The spontaneous mutation that caused this structural change is beneficial to the pufferfish because it allowed it to incorporate the symbiotic bacteria and utilize the toxin it produces to its best advantage, A single point mutation in the amino acid sequence of the sodium-ion channel in this species renders it immune from being bound and blockaded by TTX. Suggest what this mutation might involve.

For important insights read these articles

*M. Noda, T. Ikeda, T. Kayono, H. Suzuki, H. Takeshima, M. Kurasaki, H. Takahashi, and S. Numa. Nature 320 (1986) 188.                                                **********