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Eating
spicy food can seem like having fire in your mouth.
Interestingly
enough, some people do that. Fire eaters do
not
use “cold flames” or anything in their mouths other
than
spit. One fire eater famously said that the key to being
a
good fire eater is the ability to endure pain.
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Not long after my first bites, the burn started in my mouth. I began to
sweat and my eyes watered. My nose ran and the area around my mouth and nose
turned red. I looked like I was attending my best friend’s funeral on a sunny 110˚F
afternoon. This was not the impression I was hoping for.
Little did I know that I was demonstrating one of the body's
most amazing receptors, TRPV1, the capsaicin ion channel. To this day, even though
I now appreciate the biology of the experience, I have nightmares where little
Thai chilies grow large: towering over the child-like me on a dream playground, the
peppers twist my arm, take my lunch money, and give me a wedgie.
TRPV1 stands for the transient
receptor cation channel subfamily V (vanilloid) member 1. That’s a
mouthful; let's see if we can make it easier. Transient means that it is not activated all the time, something
has to come along to activate it. Cation
channel means that when activated,
the receptor allows for the flow of positive ions (cations) from the outside of
the cell to the inside.
There are many cations in the body, but TRPV1 is especially
good at letting calcium (Ca++) ions flow into the cell. Calcium
movement is at the heart of many of the functions we will talk about in the
coming posts.
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Here
all the known members of the human TRP family,
including
all the subfamilies. There six members of the
TRPV
subfamily; our discussion will be about TRPV1.
The
lone member of the ankyrin subfamily, TRPA1 will be
a
big player in the weeks to come. Likewise, TRPM8 is a
cold
receptor and we will talk about it extensively. I don’t
know much about the P, C, and ML subfamily members.
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TRPV1 is expressed on many cell types, but is most often
found on nociceptive (pain sensing)
neurons of the class-C type (these are small and respond to only some types of
noxious stimuli). The class-C nociceptive neurons are found in the peripheral
nervous system, like in your skin and mucosa, but also in the central nervous
system, especially those parts that interpret pain signals. Those TRPV1
receptors located in tissue cells and neurons can lead to some bizarre
functions, and we will talk about those in later posts.
TRPV1 is a primarily a heat sensor, but there are other heat-sensing
members of the TRPV subfamily. TRPV3 is activated by temperatures around 33˚C
to 39˚C, while TRPV4 senses temperatures in the 27-34˚C range.
Since TRPV1 is also a pain transducer, it senses heat that
would cause pain, specifically, temperatures above 43˚C (110˚F). Because TRPV1 transduces (changes) the heat into a signal for pain, you pull your hand back when you stick it in
hot water because it is painful. If you didn’t, the water could do damage to
your tissues; the pain from TRPV1 activation is an effort to prevent tissue
damage.
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Both
Adelta and C neurons carry pain signals to the
brain.
Adelta nerves are large than C fibers, and they
transmit
information much faster. A delta fibers
signals
travel about 5-35 meters/second, while
C
fibers depolarize at only0.5 to 2 mm/s. However,
the
signal is also shorter lasting. C fibers give a longer
sense
of pain, called second pain. C fibers also carry
signals of chemical pain, while Adelta fibers do not.
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Capsaicin is a vanilloid type molecule. So is vanilla. You
taste vanilla, so why not capsaicin too? Supertasters seem to have more neurons
with TRPV1 channels, so they taste more and
they sense more capsaicin. Some drugs that interfere or kill taste buds also
make hot foods not so spicy. So who’s to say we aren’t tasting capsaicin?
During my thai chili/dating incident, I noticed that I was only getting the pain and the burn, I
wasn’t tasting my food much. It might have been due to the excruciating pain ruining my dining experience, or it might be that capsaicin can suppress some tastes.
A 2009 paper showed that mice that were fed capsaicin seemed
to crave sugar more strongly. The idea we talked about during our taste posts
was that if you taste it less, you need more to satisfy a craving. So perhaps
the mice tasted less sugar after having been fed capsaicin.
This is supported by a 2010 study that showed that TRPV1
receptors are expressed in taste receptor cells of the circumvallate papillae,
and are often co-localized (are on
the same cell) with sweet or bitter taste receptors. The authors hypothesized
that activation of TRPV1 by capsaicin modulates taste receptors to suppress
(not eliminate) sweet and bitter tastes.
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Some
high mineral foods can give a metallic taste in
the
mouth, but more often this is the result of metals
on
their own or disease. Gum disease is common cause,
but
drugs are a more common cause. Some uncommon
antibiotics
give a metallic taste as do many cancer drugs.
Lithium,
used to treat bipolar disorder, tastes like
metal
because it is a metal.
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It seems that even if we don’t taste capsaicin itself, it can change what
it is we do taste. So capsaicin is
involved in our sense of taste. But perhaps we can go further. TRPV1 knockout
mice (genetically engineered mice with no TRPV1 receptors) still have changes in taste for sweet, bitter and metal. So at
least some of the capsaicin signaling is occurring via the taste receptors
themselves – and we could call that tasting capsaicin.
Let the tasting arguments begin, and you might want to include
the following in the discussion. If TRPV1 activation by heat results in the
same signaling as with capsaicin, does
it follow then that we taste heat?
Let’s talk more about TRPV1 as a noxious heat sensor. When
activated by high heat, TRPV1 signals your brain (particularly the
hypothalamus) that your body is too hot. Your brain then activates mechanisms
to increase the release of heat from your body to the environment. This might
include sweating, breathing faster… things like that.
When you eat spicy foods, the message to the brain via TRPV1
is exactly the same. The capsaicin tricks your brain into believing your body
is overheated, and kicks in the cooling mechanisms. This is why people in hot
regions of the world eat spicy food - it helps cool them off. The truth of this
comes from those same TRPV1 knockout mice. They never get the signal to cool
the body because they never sense that they are too hot. Therefore, these mice
tend to suffer from hyperthermia (hyper
= excess, and thermia = heat). People
with TRPV1 problems are hyperthermic too.
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On
top is a cartoon demonstrating the key in lock model for
protein/ligand
interactions. On the bottom is a cartoon
showing
the difference between protein denaturation by heat,
and
protein conformation change by heat. TRPV1 can undergo
the first and third scenarios.
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But how can heat fit into a ligand binding site on the TRPV1
ion channel? It’s just a physical state, not a solid object. New research is showing that the heat changes the shape of TRPV1, and this conformation (con = together, and form = shape) change activates the ion channel. In isolated
receptors with no extra proteins around, heat alone was enough to activate the
receptor, so the conformation change is all that is needed to have the ion
channel open.
Heat changing the shape of a protein is common; that’s what
happens when you cook food. Roasting, pan frying, poaching, toasting - in every
kind of cooking the protein becomes denatured (de = without, and nature
= form). Proteins lose all shape and function when cooked. In the case of TRPV1
and noxious heat, the protein changes conformation, but is not denatured;
therefore, it can be activated by the heat.
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On
the left is a myotonic arm and hand. This is a state of hyper-
excitation.
One contraction leads to repeated action potentials
and
waves of contraction. The action potentials occur in the
muscle
fibers, not in the neurons that lead to the muscle. On the
right
is paramyotonia. You see the hand/arm is in a pan of cold
water
– well, take my word for it, it’s called. This is the opposite
of
myotonia, in this case the relaxation is extended and the
muscle
won’t contract. It can be brought on by cold.
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A certain sodium channel (SCN4A) is mutated and the mutation
makes the sodium channel thermosensitive. At higher temperatures, the protein
changes shape and makes it harder for the muscles to relax. For example, a
person with myotonia might take a longer than normal time to release their grip
on an object. In cold temperatures, SCN4A changes to a different shape and is
almost non-functional, so relaxation is hard to overcome and contraction of a
muscle is slow and weak.
In this case the mutation has an unwanted result, but one can
see how TRP channels probably evolved from similar mutations. Once again, evolution
shows itself to be non-directed; mutations can be good, bad, or indifferent - they only survive through generations if they confer an
advantage. At some point, being able to sense heat via TRPV channels became advantageous. It must
have been early in evolution, because yeast, insect, higher animals, and even
plants have mechanisms to sense heat.
Next week, let’s meet a couple of animals that just won’t
play by the rules. Heat and capsaicin don’t act on their TRPV1 the way it
does for everyone else.
For
more information or classroom activities, see:
Capsaicin
–
TRPV1
–
Thermoregulation
–
Myotonia/paramyotonia
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A debt of gratitude is in order for your glorious posting! I very delighted in understanding it.
ReplyDeleteI am very excited to share my discovery with you and hopefully have a discussion. In short, my product activates the TRPM8 receptor, causing neurological modulation when the TRPV1 or TRPA1 are activated. www.drbselixir.com
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