AWD 3302: Project Files

What, basically, is going on?

Understanding how neurotoxins work relies on a basic understanding of neurobiology. Nerve cells in the body, be they in the brain, spinal cord, or connecting to your muscles, rely on a combination of chemical and electrical signals to transmit information from one cell to the next and one part of the body to the next. Cells in the body exist in a fluid matrix that contains all sorts of different chemicals, and the concentration of these chemicals is often different inside and outside of the cell's membrane that separates it from the rest of the world. Many of these particles are ions, meaning they lack or possess extra electrons, effectively giving them an electric charge. When the concentration of these ions is different inside and outside of the cell, it creates a difference in potential charge, called the Resting Membrane Potential.Cells possess tiny channels in their membranes that allow these ions to travel into and out of the cell, which effectively changes the electrical potential difference between the inside and the outside of the cell. These channels can be opened either by a change in the electrical potential in the membrane, or by the presence of a particular chemical that causes them to change shape and open or close them. The act of opening or closing many of these channels at once results in a sudden transfer of ions into or out of the cell, which often changes the balance of charge that was maintained and therefore causing the voltage across the membrane to spike. The key ions used by neurons are potassium ions and sodium ions.

The core unit of transmission is called the Action Potential, in which there is a sudden change in this electric potential in a local area of the cell, and the arrangement of channels in the cell membrane allows for this local change in potential to propagate, or travel down, the length of the cell membrane. Neurons contain a long extension called an axon, which allows this current to travel a relatively far distance before reaching the end of the cell. Once it reaches the end of the cell, the current arrives at a synapse, or a gap between the current cell and the next one. The current has no place left to go, as it has reached the end of its cell, but at the synapse there are structures that can secrete chemicals called neurotransmitters.

These neurotransmitters can leave the cell, travel through the intercellular space, and make contact with the cell on the other side by interacting with receptors on the next cell's membrane. These receptors respond uniquely to the neurotransmitters they are designed to bind with, but it is important to note that what is occurring is an interaction between complementary shapes, meaning that if a different molecule had a region that was similar in shape to the neurotransmitter in question, it too would interact with the receptor.

Imagine the shape-fitting toys that toddlers play with, where you insert a triangle or a circle piece into various cutouts, trying to match the correct shape with the correct hole. The neurotransmitter is the inserted piece, and it only inserts into the correct hole, or receptor. As an example, let's say the neurotransmitter dopamine is a triangle piece, and serotonin is a circle. Dopamine will only fit in the triangle receptor, and serotonin will only fit in the circle receptor^[i.n.]. Once activated, the receptor continues the signal cascade in the next cell, either chemically or electrically, furthering the transmission of the signal to its destination, whether it be to the brain to signal something, or to a muscle to tell it to move.

Now consider a modified version of the shape matching toy mentioned earlier where instead of falling through the hole, the insert has a larger block connected to it, so the piece inserts where the shapes match but the rest of the piece hangs out. The natural neurotransmitter is a triangle inserted into a triangle hole successfully, but there can be other chemicals that can interact with the board too. Another piece with a triangle that fits the hole is referred to as an agonist (one that binds successfully to the receptor), and a piece that partially fits the hole but doesn’t fit perfectly and prevents other pieces from fitting is referred to as an antagonist (obscures the receptor without activating it).

Neurotoxins are molecules that affect the chemical transmission between neurons, by affecting the cell transmitting the chemicals (pre-synaptic) or receiving them (post-synaptic). Some neurotoxins like tetrodototoxin (TTX), which is found in pufferfish and poison dart frogs, acts by blocking the sodium channels in the pre-synaptic cells. TTX is a large chemical (compared to a sodium ion) that attaches to the channel and stops it like a cork for tens of seconds at a time. This blockage prevents sodium ions from entering the cell, and as a result, the cell can no longer transmit action potentials. Contact to your hands would cause paralysis, as even though your brain is telling your hand to move, the message stops upstream of the muscles, and they do nothing. The toxin becomes fatal when it reaches critical tissue like the heart or lungs, where the stoppage of the involuntary nerve impulses that tell your lungs to expand and contract or your heart to beat causes those organs to become paralyzed. Then you die.^[i.n.]

Other toxins can interact with other ion channels or receptors to produce various effects, some of which can become very complicated and involved. Some toxins like tetanus bind to presynaptic inhibitory interneurons (neurons that release chemicals to other neurons to prevent them from firing action potentials), resulting in repeated muscle spasms because they can't "turn off" the muscular neurons. This ultimately leads to paralysis. Overall, most neurotoxins lead to paralysis in one way or another, and nature has come up with creative ways to cause this from perceivably every angle that it possibly can.^[i.n.]

Why some animals are immune or resistant to toxins, animals like the mongoose that can sustain repeated cobra bites, comes down to shape, once again^[i.n.]. These animals have evolved channels and/or receptors that have a slightly different shape that prevent the toxin from interacting, while continuing to allow the normal molecules to do their thing. Let's return to our original analogy. Imagine if the triangle hole now had a circular bump around it that prevented larger pieces from staying in place. The normal piece can still fit fine, but now the toxin piece can no longer fit properly because of the bump. Toxin can't bind, toxin can't block the channel, toxin can't prevent the cell from signaling, and the mongoose goes on its merry way getting bit by cobras. It's not immune, as given enough toxin pieces, eventually as soon as one comes off, another toxin piece takes its place, and the cell can't take in sodium fast enough for an action potential, but the animal is at least resistant to a few bites.

So, how does venom work?

Venom is a chemical compound that interacts with receptors and channels in nerve cell membranes that disrupt the transmission of messages, namely via action potentials, between the neurons. This often results in paralysis in some way or another, as the messages from the brain or spinal cord can no longer get to the muscle tissue. The result, a paralyzed animal that either can't move and is much easier to kill, an animal who suffocates to death because their lungs can't move, or a potential predator that now has a paralyzed arm or tentacle and won't come near you ever again (or probably survive much longer). Animals can resist these toxins by changing the shape of their receptors or channels so that the toxins can no longer bind to them or block them.

^[i.n.]