What is neurotoxin and where does it come from?

Neurotoxin is the collective term for toxins that attack the nervous system. However, the structure and the mechanism by which the toxins affect nerve cells varies greatly within this class. Neurotoxins can be anything from small organic molecules to larger proteins. A common feature for these molecules is their interference with the nervous system, preventing communication between nerve cells. This can lead to brain damage, developmental disability or paralysis because the brain loses communication with the muscles. In the worst case scenario, the paralysis can affect the respiratory muscles, resulting in death by suffocation.

Cyanobacteria, also known as blue-green algae, can be found in lakes and coastal areas during the summer (Figure 6A). The Cyanobacteria make the water green and murky, but they also produce various toxins. The toxins formed by blue-green algae are collectively called cyanotoxins. These small organic molecules have a range of toxicity mechanisms. Two of these toxins are highly effective at attacking the nervous system (neurotoxins). These two toxins are anatoxin-a, also known as Very Fast Death Factor, and saxitoxin, which was investigated as a potential chemical weapon by the CIA until it became illegal to manufacture or acquire under the UN Weapons Convention. These toxins prevent nerve cells from communicating properly with each other by binding on the surface of nerve cells, to receptors or ion channels respectively. Because of the cyanotoxins, it can be extremely dangerous to bath in water infected with blue-green algae, and therefore the growth of these Cyanobacteria is closely monitored by health authorities.

Neurotoxins are also found in the plant kingdom and (Figure 6A), plant neurotoxins are often based on small organic molecules, like the Cyanobacteria . The plant-neurotoxins are found in many different species, including the Nightshade family and the Umbellifer family. For example the poisonous plant hemlock is in the Umbellifer family (Figure 6B). Poison hemlock produces the toxic molecule coniin, which binds to a receptor on nerve cells. If hemlock is ingested, symptoms such as visual impairment, muscle fatigue and paralysis occur quickly. Hemlock originates from Mediterranean countries, but it is very versatile and has become an invasive species in many countries. It can now be found in most parts of the world. This creates a major problem, especially for grazing livestock such as cows, horses and sheep, as hemlock is toxic to all mammals.

Figure 6. A: Cyanobacteria can sometimes be seen as a green carpet on the water when temperatures are high. Image by U.S. Army Corps of Engineersunder the license CC BY 2.0. B: During the summer months, hemlock blooms with white flowers. Image by John Tann under the license CC BY 2.0.

But why do bacteria, plants and animals produce neurotoxins in the first place? In all cases, the reason is to improve their chances of survival in the wild. But how the neurotoxins are used to serve this purpose is very different. Plants, such as hemlock, use their poison as a means of defense to make it less attractive for herbivores to eat them. In the previous section, we presented an animal that has a similar defense mechanism, the poison dart frog. The mechanism can also be found in other animals, such as pufferfish. Pufferfish have a peculiar defense mechanism of inflating like a water balloon, pufferfish and hedgehogfish also contain one of the most potent neurotoxins. This neurotoxin, tetrodotoxin, is produced by symbiotic bacteria living in the fish and works by blocking ion channels on the nerve cell. Tetrodotoxin is extremely toxic (Table 1). Since there is no antidote, poisoning can lead to death within hours. Tetrodotoxin is what makes the Japanese delicacy Fugu extra exciting. Actually, it is a matter of life or death, as there is a risk of being poisoned if the fish is not cooked to perfection.

In addition to using neurotoxins as a defense mechanism, several animals have developed neurotoxins that can be used as a weapon to capture prey. For snakes, neurotoxins are an extremely useful weapon, as prey is often paralyzed after just one bite. This ensures, that the snakes only need contact with their prey for a shortly, minimizing the risk of injury during the hunt.

Another group of animals that utilize potent neurotoxins to capture prey are cone snails. These slow snails feed on fast small fish, which may sound like an impossible task. To successfully catch their fast prey, the snails are equipped with a small harpoon that can be fired at high speed over short distances. When the fish are speared by the harpoon, they are injected with a potent neurotoxin consisting of several different “conotoxins” (from name “conesnails”). The conotoxins paralyze the fish almost instantly and the snail can then slowly retrieve the harpoon and the meal is secured. You can watch a video clip of the phenomenon here.

Where and how does neurotoxin affect the body?

As mentioned earlier, neurotoxins affect nerve cells, but the way the nerve cells are affected varies greatly depending for different neurotoxins. There are three main mechanisms that neurotoxins apply to attack nerve cells (Figure 7): 1) By binding to ion channels and blocking their function. 2) By binding to ion pumps and blocking their function. 3) By creating holes in the cell membrane of the nerve cell, allowing ions to freely diffuse in and out, rendering the nerve cell unable to send electrical signals.

Figure 7. Neurotoxins generally have one of three main mechanisms to attack the nerve cell. 1) Toxins can prevent the ion channels in the cell membrane from opening. 2) Toxins can bind to ion pumps, blocking its function or activation. 3) Toxins can form pores in the cell membrane, allowing ions to freely diffuse in and out of the cell.

A healthy nerve cell, with the signal on the way to the muscles

Every time a nerve cell is activated, every time you move a muscle in your body, this is orchestrated by signals that travel from the brain down to the muscles via the nerve cells. The brain sends a signal, e.g. “move your finger”. This signal is delivered to the muscles using nerve cells. To carry the signal, the nerve cell uses different ions. Inside a resting nerve cell, the concentration of sodium ions (Na+) is low, while the concentration of potassium ions (Ka+) is high (Figure 8, Box 1). When the nerve cell is activated to transmit a signal, sodium ions flow into the nerve cell, while potassium ions flow out (Figure 8, Box 2). The movement of ions creates an electrical current, that travels along the nerve cell and is perceived at the end of the nerve cell. When the signal is percieved, calcium ion channels open and calcium ions (Ca2+) enter the cell, allowing the signal to be transmitted (Figure 8, Box 3). The signal is transmitted using various transmitters, including a small molecule called acetylcholine. The nerve cell that relays the signal releases the acetylcholine, which transmits the signal to the next nerve cell. As acetylcholine binds to its specific receptor, the nicotinic acetylcholine receptor (nAChR), on the next nerve cell. This way, the signal is continued in the this cell, and by this mechanism, the signal is relayed until it reaches the muscle that needs to contract. After the signal is sent from the nerve cell, the original concentration of ions is restored so that the cell is ready to receive and transmit a new signal.

So it takes many different mechanisms to get the signal “move your finger” from the brain to your finger muscle. And all of these mechanisms can be attacked by neurotoxins.

(If you want to know more, you can watch videos about nerves and communication here.)

Figure 8. Box 1. A Na+ and K+ channel in the resting state. Box 2. A Na+ and K+ channel in the signaling stage. The signaling runs along the entire nerve fiber, as seen in the nerve cell at the top of the figure, until it reaches the nerve end (Box 3). Box 3. When signaling reaches its end, Ca2+ channels are activated, sending Ca2+ into the nerve cell, resulting in vesicles with neurotransmitters (e.g. acetylcholine) being released from the nerve cell. These neurotransmitters pass the signal on by binding to neuroreceptors on the next nervecell. These neuroreceptors are neurotransmitter-dependent ion channels that allow ion flow into the cell upon contact with the correct neurotransmitter, and the signalling process repeats in the new nerve cell.

Snail venom prevents ion transport

Conotoxins are small peptides that bind very specifically to ion channels responsible for the transport of sodium and potassium ions. When the toxins bind to their respective ion channels, the transport of the ions in and out of the nerve cell is prevented (Figure 9). Thus, the conotoxins prevent the nerve signal from being relayed, as the signal cannot be passed on through the nerve cell. As a result, conotoxin leads to paralysis, as the nerve cells can no longer transmit signals and communicate with the muscles.

Figure 9. Conotoxins bind to ion channels and prevent ion transport. When this figure is compared to figure 8, you can see the far-reaching consequences for the nerve cell’s ability to signal.

Spider venom makes holes in the cells

The black widow spider and other spiders in the same family produce a venom containing α-latrotoxin. When α-latrotoxin comes into contact with the cell membrane of a nerve cell, α-latrotoxin inserts itself into it and forms a pore. This allows Ca2+ to move freely in and out of the nerve cell (Figure 10). This causes the nerve cell to lose control of Ca2+ levels across the cell membrane. Therefore, Ca2+ can not control the release of acetylcholine and other neurotransmitters. This means that the nerve cell loses the ability to relay vital signals. When α-latrotoxin binds and forms its pore (Figure 10), a large amount of Ca2+ ions will flow into the nerve cell and release a large ammount of neurotransmitters. However, after a period of time, there will be no more neurotransmitters left in the nerve cell, so even though there is still a lot of Ca2+ present, not enough neurotransmitters are released to relay a signal.

Figure 10. The figure shows how α-latrotoxin disrupts normal signaling (left) by inserting itself into the nerve cell so that the control of Ca2+ ions is not maintained anymore (center). The short-term effect of this is increased nerve signaling, as all the neurotransmitters are released from the cell. The long-term effect is, that the nerve cell runs out of neurotransmitter and cannot signal as normal.

A bite from a cobra

A highly potent neurotoxin called α-cobra toxin can be found in cobra venom. This neurotoxin binds to the same receptor (nAChR) that acetylcholine (neurotransmitter) binds to, thereby preventing acetylcholine from binding its receptor. Since acetylcholine cannot bind and thus open nAChR, sodium and potassium concentrations inside the cell remain unchanged. Similar to the conotoxins, the nerve cells cannot signal to the muscles and paralysis is the consequence. This paralysis can spread and if it reaches the respiratory muscles, you can die from suffocation, due to lacking function of the breathing muscles around the lungs.

Task: In the figure below, draw where and how α-cobratoxin affects the nerve cell and tick which processes no longer function. Remember that acetylcholine is a neurotransmitter. Then click on the box here to see the answer.

The solution is shown in the image below:

 

Neurotoxin used as a death sentence

Throughout history, many people have been killed by neurotoxins. As far back as ancient Greece, neurotoxins were used as a method of execution. In 399 BCE. the philosopher Socrates was accused and sentenced to death for not believing in the gods of Athens and corrupting the youth of the city. The death sentence was carried out by having Socrates consume a drink made from hemlock and opium. Like many other neurotoxins, the coniine in hemlock affects nAChR. More specifically, coniine blocks the binding of acetylcholine to the receptor, thereby preventing the activation of nAChR. After Socrates consumed the drink, he walked around his prison cell until his feet were paralyzed and he couldn’t walk anymore. Ultimately, it was suffocation that killed Socrates as the paralysis spread from his feet and up through his body, eventually reaching the respiratory muscles.

Working questions

  1. Which receptor is blocked by the snake toxin α-cobratoxin?
  2. Which three ions do nerve cells use to transmit signals?
  3. Describe how the spider venom α-lactotoxin affects the nerve cell.
  4. Name an animal that uses neurotoxins as a defense mechanism against predators.
  5. Name an animal that uses neurotoxins as an attack mechanism to capture prey.
Answer

1. The snake toxin α-cobratoxin blocks the nicotinic acetylcholine receptor (nAChR).

2. Nerve cells use sodium (Na+), potassium (K+), and calcium (Ca2+) ions to transmit signals.

3. Example: The spider venom α-lactotoxin affects the nerve cell by binding to and blocking calcium (Ca2+) channels, preventing calcium entry and affecting the release of neurotransmitters needed for signal transmission.

4. Example: Pufferfish and the pilgrimage frog

5. Example: Snakes and cone snails