Neurotransmission and Neurotoxins #2

Neurotransmission and Neurotoxins II

Image Source

Target I: the Sodium Channel

The voltage-gated sodium channel is target of numerous neurotoxins, e.g. Tetrodotoxin. This compound occurs in several parts of the well-known puffer fish and specifically blocks the sodium channel, hence prohibits depolarisation and therefore signal transmission along an axon. In Japan puffer fish is known as "fugu" and is a delicacy that may only be prepared by certified chefs, trained in puffer fish anatomy. Nonetheless there are roughly 100 deaths per year due to false preparation of the fish by untrained chefs and amateurs.

Another potent sodium channel inhibitor is Saxitoxin, which is produced by marine dinoflagellates, a type of plankton known as the "red tide" (see image to the right). The toxin may be concetrated many-fold by filter-feeding shell fish to such an extent, that a small mussel can contain sufficient saxitoxin to kill up to 50 people!
Saxitoxin and Tetrodotoxin both have a guanidino group (highlighted in red) and both are effective only if applied to the neuron extracellularly. Hence it is concluded that the guanidino group binds to carboxylate groups at the outside entry of the sodium channel and hereby blocks it.

To stick with the sodium channel inhibitors, Batrachotoxin is discussed next: This is the most potent venom (toxin of an animal) known and has an LD50 = 2 μg/kg.
Batrachotoxin is a steroidal alkaloid, which is secreted by the skin of Phyllobates aurotaenia, a Columbian arrow-poison frog from the tropical Coco region. Although batrachotoxin also inhibits the sodium channel specifically it has a different mode of inhibition: In contrast to the previous presented ones, it renders the axonal membrane highly permeable to sodium, hence causes a permanent depolarisation. In fact this effect is reversed by tetrodotoxin! - They appear to be competitive ligands.

To finish the first part about sodium channel inhibitors it shall be mentioned, that American scorpions produce neurotoxic proteins - with a lenght between 60 - 70 amino acids - which also specifically bind to the sodium channel. However these proteins do not compete with tetrodotoxin and hence must have a different binding site.

Target II: the Release Mechanism of Acetylcholin

The black widow spider, Latrodectus mactans, produces a neurotoxic venom protein called α-Latrodoxin. The protein inserts into the presynaptic plasma membrane and acts as a calcium-ionophore. This leads to a massive, uncontrolled release of Acetylcholin (ACh) into the synaptic cleft. The structure of this toxin is shown in the next image and exhibits a central pore, through which the calcium ions can enter the presynaptic cell in an uncontrolled fashion, hence without any corresponding stimulus (arriving action potential).

The black widow spider inhabits most warmer regions of the world. Its' venom is 15-times more toxic that that of the female prairie rattlesnake. However, due to only small amounts of injected venom the bites are usually not fatal.

In contrast to α-Latrodoxin, Botulinus toxin inhibites the release of ACh at the neurotransmitter junction. Botulinus toxin is a large protein and is produced by the anaerobic gram-positive bacterium Clostridium botulinum.
This compound now is the most toxic substance known to man with an LD50 = 1 - 2 ng/kg!

Clostridium botulinum - Image Source

The bacterium is responsible for the deadly food poisoning called botulism. For an illustration of the structural setup of the toxin, have a look at the sketch to the right. After cleavage into a light and heavy chain the toxin enters the axon terminal. Inside, the disulfide bond is reduced and the light chain, a zinc-metalloprotease, released. The selective destruction of proteins implicated in exocytosis of vesicles impairs the release of neurotransmitters into the synaptic cleft.

Target III: The ACh Receptor

The ACh receptors of the postsynaptic cell are target of some of the most deadly known neurotoxins. Death occurs typically as a result of respiratory failure due to the inhibition of neuromusculuar junctions.
As the first example the harlequin poison frog (Dendrobates histrionicus) with its' secreted neurotoxin, a piperidine alkaloid called Histrionicatoxin, shall be mentioned. It is a very potent antagonist to ACh and prevents the ACh receptor channel opening.

Furthermore many poisonous snakes contain small, neurotoxic proteins in their venom. Examples are:

• α-Bungarotoxin (from kraits: Bungarus sp.)
• Erabutoxin (from sea kraits: Laticauda)
• Cobratoxin (from spitting cobra: Naja siamensis)

These proteins all bind to the ACh receptor and prevent channel opening. Also do the mentioned snake venom proteins all have a common fold: the snake-toxin like fold consists of a central antiparallel ß-sheet and several disulfide bonds (indicated in orange in the illustration below), that render the structure compact and rigid.

Not only sea snakes but also other creatures of the sea are venomous predators: Marine molluscs with more than 500 species in the Conus genera and over 50.000 suspected active compounds are most noticeable!

Also flora can produce very powerful neurotoxins: South American indians use curare (Tubocurarine), which is extracted from the vine Chondodendron tomentosum to coat the arrows of their blowguns. This substance very efficiently blocks the ACh receptor at neurotransmuscular junctions and hence causes relaxation and paralysis of muscules including respiratory organs!

I hope you liked this brief presentation of the most potent and famous neurotoxins and their point of action. Due to the similarities in content, I will soon write a short article about chemical warfare agents. If you have any questions or suggestions feel free to include them in the comments. I will respond to them as soon and complete as possible.

Best,
mountain.phil28

References:
Information and non-direct-cited images are taken from
"Molecular Physiology" lectures at the TU Graz.