Wednesday, March 19, 2014

Maybe We Do Taste The Burn

Biology concepts – capsaicin, TRPV1, heat sensing, thermoregulation, taste, ligand

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.
Early in our dating experience, my wife and I visited a Thai restaurant in our old college town. As part of the ordering process, you were allowed to tell them just how hot you would like your food. Eager to impress, I asked for the hottest they had. Big mistake.

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.

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.
The fact that TRPV1 is a channel means that it is not a one to one ratio. Activation of the channel is like opening a gate, where many ions will flow through. Finally the fact that it is a subfamily means that there are many channels that are similar to it and this one is activated by molecules that look like vanillin, an alkaloid fatty acid - capsaicin is a vanilloid compound.

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.

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.
The signals from TRPV1 travel up several nerves to the brain, but seem to involve the trigeminal nerve centers most often. Noxious (noxa is Latin for harm, same root as for nociceptive) neural signals don’t travel to the gustatory centers of the brain. This is why it’s said that you don’t taste capsaicin, you merely perceive it as burning heat and pain. But this may be a misconception.

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.

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.
In addition, a 2009 study talked about how some compounds are sensed as metallic tastes, and these are mediated, in part, by TRPV1 signaling. This is part of the reason why humans and other animals avoid heavy metal tastes and why they can be uncomfortable as well. High concentrations of artificial sweeteners can give an uncomfortable metallic taste, again linking TRPV1 with sweet taste receptors.

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.

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.
This is today's exception - that TRPV1 is activated by such different mechanisms (heat and capsaicin), but that the activation results in exactly the same signaling. The receptor is a protein, and we have seen many times that receptors are activated by other molecules through the lock and key mechanism. The shape of the ligand (the molecule that binds or ligates to the receptor) matches exactly a pocket in the receptor, so they fit together like a key in a lock - and the receptor function is unlocked.

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.

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.
A protein that is thermosensitive is amazing, but apparently it has happened more than once in history. There is a condition in some humans (maybe other animals, but we haven’t asked them) where heat can induce myotonia (prolonged contraction) and cold can induce paramyotonia (prolonged relaxation, nearing paralysis). In 2000, a group in Japan described a family in which this condition is a dominantly-inherited, genetic disease.

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.

Cao E, Cordero-Morales JF, Liu B, Qin F, & Julius D (2013). TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron, 77 (4), 667-79 PMID: 23439120

Costa RM, Liu L, Nicolelis MA, & Simon SA (2005). Gustatory effects of capsaicin that are independent of TRPV1 receptors. Chemical senses, 30 Suppl 1 PMID: 15738113

Sugiura Y, Aoki T, Sugiyama Y, Hida C, Ogata M, & Yamamoto T (2000). Temperature-sensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis. Neurology, 54 (11), 2179-81 PMID: 10851391

Riera CE, Vogel H, Simon SA, Damak S, & le Coutre J (2009). Sensory attributes of complex tasting divalent salts are mediated by TRPM5 and TRPV1 channels. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29 (8), 2654-62 PMID: 19244541

For more information or classroom activities, see:

Capsaicin –


Thermoregulation –

Myotonia/paramyotonia -