Chapter 3: Neurotoxins 61

With a ith a basic understanding of how neurons work, we can resume our
discussion of toxins versus medicines and look at some toxins that target the
nervous system, or neurotoxins. Since the nervous system is linked to so many
important functions, toxins that target neurons can have a wide range of effects in
people. Some toxins, like those from ants and hornets, cause extreme pain. Other
toxins, like those from some centipedes or snails, actually block pain. Still other
poisons from some. frogs block the neurons involved in breathing. Simply saying
that these toxins cause pain, block pain, or stop nerve function, however, really
undersells the molecular mechanisms of these interactions; it keeps them in the
realm of being magical. My goal in this section is to demystify neurotoxins and
help you understand exactly how they work.

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 Molecular machines

Neurotoxins are ligands that bind to receptors on the surface of your neurons.
Frequently these neurotoxin receptors are channel proteins. Neurotoxins most
often impact receptor function in one of two ways; either forcing channels to open
or forcing channels to close. Opening of the channel causes the neuron to
artifically depolarize, while closing the channel prevents the normal ligand from
opening the channel when needed. Channels can open and close because just like
the machines you see every day that mechanically turn on or off, or open and
close, receptor proteins are what I call "molecular machines." They have very
simple physical movements and mechanisms that make them mechanically open
or close. Instead of being built from metal, they are proteins that are built from
amino acids. And, just like any machine, if you throw a monkey wrench into its
gears, you are going to goof it up. Try to think of neurotoxins as molecular
monkey wrenches that stop these machines from working properly.

I'm going to use the TRPV1 and the Na 1.7 sodium channels as examples since
these proteins are some of my favorites and they have some extraordinary and
interesting functions in our bodies. But the lessons here could be extrapolated to
literally thousands of other proteins in your body or millions of other proteins
throughout biology. I'm going to show you actual pictures of these proteins that
were captured by X-ray diffraction, the imaging technique introduced in Chapter
1. These images are snap shots that capture the proteins as they really are (or
were) in a moment of time. These images show how these molecular machines
actually open and close during neuron firing. Then, finally, we will take a look at
how some toxins

Chapter 3: Neurotoxins 63
alter the activity of these channels. If you have ever wondered exactly how
medicines or toxins work, this next section should give you a really good
conceptual understanding.

TRPV1: The human heat sensor protein

The discovery of the TRPV1 (trip-vee-one) channel is a really nice example of

what is called basic science or basic research. Basic science is scientific
investigation that does not have an immediate application to human health. There
is no or immediate payoff for basic science investigations, so most of the time
basic science is funded by grants from various government And yet, these basic
science discoveries often form the foundation upon which future medicines or
real-world applications are based. You can think of basic science as the base upon
which a pyramid of science is built. At the apex of the pyramid are lifesaving
medicines (applied science), but they would never have been developed without
the basic science that built their foundation.

The scientists who discovered TRPV1 didn't actually set out with the goal of
discovering how we feel heat. In fact, they were studying a different topic
completely. They were actually interested in knowing why eating hot peppers
made peoples' mouths burn. They knew about capsaicin, the molecule/ligand in
peppers that makes them spicy, and they hypothesized that capsaicin must be
binding to a receptor to cause the heat associated with hot peppers. They searched
for a channel protein that capsaicin could bind to and activate, and they found
TRPV1 [9]. Originally this channel was called the capsaicin receptor, but it was
later renamed to TRPV1 since its structure was similar to a preexisting family of
other TRP channels. After

64 Chapter 3: Neurotoxins
scientists discovered TRPV1 and started studying it in more detail, they also
learned about its more important roles in pain and temperature sensation. With
this information in hand, more health-orientated research is now underway to
design new ligands to control the TRPV1 channel. This is a nice example of basic
science that started out just as curiosity but ended up as an important foundation
for medically related investigation. There is a highly recommended video of
David Julius on the "iBiology" website where he describes the discovery of
TRPV1. If you search for "iBiology David Julius" you should find it.

In order to understand how TRPV1 works, we need to zoom in and look at the
details of TRPV1 structure. The TRPV1 channel consists of four individual units
that are arranged around a central hole. Like I said before, imagine a donut. The
TRPV1 channel looks like a donut that was made by a very poor baker, The hole,
or channel, is the "business end" of the protein where calcium ions travel through
the protein when it is opened by heat or other stimulations. In figure 1 are four
images that each show the TRPV1 channel from a different perspective. In the
upper left side view, the regions of the protein that sit either within the cell
membrane (transmembrane region), or actually inside the cell (cytoplasmic
region), are indicated, but it is difficult to see all four subunits from the side.
When viewed from the top, however, (upper right), the four subunits are easily
seen (colored in different shades of gray). Notice how these four individual units
are arranged around the central pore/channel through which calcium is allowed to
pass. See? It's a really badly shaped donut.

Although there are no images of the open versus closed states of TRPV1, the pore
would most likely appear slightly bigger in