Wednesday, May 7, 2014

Everybody Wants To Be Cool

Biology concepts – TRPM8 cold sensor, menthol, evolution, cold pleasure

The old ads for menthol cigarettes are fascinating, from a biology
point of view. The “cool” and the “refreshing” aspects were reflected
by using spring and summer outdoor pictures, most often with lots of
cool water. At the end of today’s post, we see why this was so. We
also see an African American, since menthol cigarettes were targeted
much more strongly urban African Americans. They were newer
smokers and in typically hotter environments, so the coldness and
soothing abilities of the menthol were great selling points.
In 1924, Lloyd “Spud” Hughes patented the menthol cigarette. Not a big deal in the beginning, Hughes sold his patent to a cigarette manufacturer who marketed them as Spud cigarettes in 1927. They became the fifth largest seller, although there still wasn’t much in the way of profit. Kool cigarettes came along in 1933 and advertised the menthol casket nails as “soothing to the throat” and claimed they were actually medicinal.

The menthol cooled the feel of the smoke in the mouth and throat (much more next week on hos menthol feels cool). Menthol made it feel as though you weren’t sucking hot smoke into your lungs. And menthol deadened the discomfort that cigarettes could generate by irritating the lining of the throat and lungs.

These days, almost 90% of cigarettes contain some menthol, even if they don’t advertise themselves as menthol cigarettes. Why? The “cool” factor lends itself to novice smokers, while the throat analgesia appeals to the seasoned addict. But that may not be the main reason. A study from 2004 showed that menthol slows the metabolism of nicotine.

Slowing the metabolism of nicotine, menthol results in nicotine staying in the system longer and at greater concentrations - just perfect for developing a physical addiction. This, combined with the ability to comfortably smoke more cigarettes because of the slight throat numbing and apparent cooling of hot smoke would encourage more consumption, more addiction, and therefore more profit.

There is now (2013-2014) a push by the US Food and Drug Administration to ban or regulate menthol cigarettes. Did you know that menthol addition to shampoo is federally regulated but its addition to cigarettes is not? Let’s look at some of the reasons a change is being considered.

The tobacco plant has supplied cells that are used to show the
danger of menthol cigarettes. I just love that. But tobacco has been
involved in science in other ways as well. New efforts are
underway to have genetically modified tobacco produce medicines
or biodisel. And the tobacco mosaic disease actually led to the
discovery of viruses and the coining of the word “virus.” This same
virus was instrumental in establishing the fields of
virology, plant virology and all of molecular biology.
A 2013 series of experiments showed that menthol-containing cigarette smoke is more toxic to cells than non-mentholated cigarette smoke. Menthol alone had no toxic effect on the cells, so it is the combination of menthol and cigarette smoke that kills cells at a higher rate. In the most delicious irony imaginable, the two cell types that the researchers used to monitor cell death after smoke exposure were human lung cells and tobacco plant cells!!!

Additional recent evidence suggests that menthol interacts with the nicotine receptor in the brain. Brody and his co-workers showed that menthol cigarette smoke up regulates the number of nicotine receptors in the brain more than regular cigarette smoke. This might explain why it is harder for menthol cigarette smokers to quit smoking and why more of them fail in their efforts to quit.

Another 2013 study showed that menthol decreased the activity of the nicotine receptor, so that more nicotine was necessary to reach the same level of activation. Once again, this would contribute to a physical addiction.  Just a bit of information if you are considering taking up the habit - the “cool” factor and refreshing cold of mentholated smoke just may contribute to your death.

So sensing cool or cold has its place in biology and in society. Chili peppers are sensed as burning hot because they just happen to bind to and activate the TRPV1 heat sensing ion channel – it’s the biological joke being played on us that we have talked about before. TRPV1 a receptor that reacts to both environmental (temperature, pH) conditions and food substances.

On the other end of the scale is the sense of cold. Do organisms sense cold like they sense heat? Isn’t cold just a lack of heat, so that a feeling of cold is just a lack of activation of TRPV receptors? Nope. There are receptors specifically designed to sense cool or cold. Are there exceptions in cold sensing like there were for heat? You should know that answer by now.

Melastatin was the first TRPM protein discovered. The name
comes from melanin (the pigment in skin and hair cells) and
statin, which means to stop. It was important because it could stop
the invasion of tumors of melanin producing cells. We call this
maliganant melanoma, one of the deadliest cancers. Tumors with
more melastatin were less aggressive and invasive, while those with
little melastatin killed patients much sooner.
We learned recently that there are six different TRPV cation channels, and at least four of them are important for sensing different ranges of temperatures. In some cases, like with TRPV1, noxious heat (or capsaicin) results in a sensation of pain and burning, and the body’s mechanisms for cooling are turned on.

Another TRP family member, TRPM8, turns out to be the receptor channel that senses cool temperatures, from about 28˚C (82 ˚F) down to about 10˚C (50 ˚F) or even lower. The M stands for melastatin, a name for the first TRPM, before they knew it was a family of proteins. Now there are eight known members of the TRPM subfamily of TRP ion channels.

TRPM5 is particularly interesting for our recent discussion of taste, since it works to change the mechanical energy of taste particles + taste receptors into an electrical signal that is sent to the brain. Once again, we see the close relationship between the ion channels, like TRPV1 for capsaicin, and the taste sense. Maybe cold and TRPM8 also influence taste. We shall see.
Less is known about TRPM8 as compared to TRPV1 although they were discovered about the same time (early 2000’s). The pain associated with capsaicin and noxious heat aspects of TRPV1 made it sexier to study. I think we will see that TRPM8 and TRPA1 can be quite interesting in their own right.

Here’s a quick overview of the thermosensing by TRPs.
We will talk about it more next week. The TRPVs are
generally for warm temperatures, while TRPM8 is for
cool temp.s. TRPA1 will be our focus in a few weeks; it
senses painful cold. But notice, the garlic and wasabi
pictured with TYRPA1 also activate TRPV1, and the camphor
shown for TRPV1 also activates TRPM8 (next week). These are
related and complex systems.
First of all, TRPM8 is involved in thermoregulation, just as is TRPV1. In humans and other mammals (the naked mole rat excepted), when TRPV1 is activated, the body automatically thinks it is too hot and initiates cooling mechanisms. With TRPM8, the effect is the opposite. Stimulation of this ion channel tells the body that it is too cold, and mechanisms are initiated to increase the core temperature. We will talk about how TRPM8 helps to regulate body temperature next week.

The big question is why it’s important to sense cold as well as heat. For some reason, we sense cool/cold with some distinct proteins and heat with different proteins. Remember, evolution doesn’t follow a plan to make things complex, functional and efficient. Sometimes the functions occur at separate times and come from different pathways; there is no evolutionary goal or roadmap to a destination. It’s all chance.

A 2013 review has an interesting hypothesis as to why sensing cold/cold is so important, aside from just alerting us to the chance we might freeze to death. Based on mouse study results from as early as the 1970’s, and on the answers that human subjects give, it seems that coolness is an evolutionary plus. No- I don’t mean that The Fonz from Happy Days was an evolutionary leap into the future, I mean that cool sensations somehow help us survive and propagate.

We typically heat food because it increases aroma, increases taste, and reduces the work in digestion. These are all important for getting us the nutrients and the calories we need. Taste, as we said several weeks ago, is nature’s way of getting us to eat those things we need and avoid those foods that might harm us.

So why would cool foods or sensations be helpful? Cooling would decrease aroma and taste, so it must be something other than taste. The obvious reason for drinking something cold would be that it cools off our body – but it doesn’t work that way. As soon as you drink a cold drink, your body reacts to the cold by constricting the blood vessels near the cold surface so that heat is not lost. TRPM8 also invokes heating mechanisms after it is activated by the cold water or soda. So in truth, cold drinks don’t cool you off.

On the left is a mint julep, famous in Kentucky and the Deep
South during the hot summers. It contains Kentucky bourbon,
which is why it is brownish. On the right is the mojito, also
good on hot days, but uses rum, so it is popular in the Caribbean
and Florida, where the rum is. The connection? They both use
mint (menthol) to increase the coolness and refreshing
characteristics of the drinks. TRPM8 hard at work to make
your Saturday evening a success. 
Yet they still feel refreshing on a hot day – what gives? Refreshing may be the key word here. People use many words that together make up “refreshing.” They say that cold drinks revive them, restore their energy, arouse them, reduce stress. All these feelings would promote survival behaviors in a hot environment. But we might also drink a cold drink on a cold day and deem it pleasant. In this case, pleasant can be equated to useful – and useful means promoting survival.

The 1970’s experiments showed that mice would lick a cold piece of metal when they were thirsty, showing that cold helps satisfy thirst. The more amazing thing was that the mice would lick the cold metal even if they could drink all they wanted. This meant that cold drinks were a reward; they activate a pleasure center in the brain. Many studies and experiments have shown these results to be true for humans as well.

So a cold drink on a cold day might be seen as unpleasant, while a cold drink on a hot day is very pleasant (useful). But more important, a cold drink on a cold day when you are thirsty is seen as pleasant and satisfying. It’s our brain helping us to garner the things we need; if cold water is all that’s available to a cold caveman, he better want to drink it. It works the same on skin, cold applied to the skin on a hot day – such as jumping into the pool on a warm day is seen as pleasant, even if it doesn’t cool the body all that much (see above). But the same cannonball on New Years day with the Polar Bear Club, is completely unpleasant.

Comedian and late night talk show host Jimmy Fallon took
the Polar Bear Plunge in Chicago this past New Years. Basically,
3000 people jump into a 34˚F (1˚C) Lake Michigan to support
Special Olympics. Some do it for the charity, some for the thrill,
some because they are unbalanced. For those with a heart
condition, it can kill you.

The brain is an amazing organ, it works with our body to get us what we need, and tricks us into doing it – that’s basically what pleasurable things are, evolutionary tricks. But remember – too much of a good thing can be bad in an environment where we can manipulate nature.

Unfortunately, evolution doesn’t look into the future, it only worries about what keeps us alive at this moment. This explains the danger of menthol in cigarettes – we find it pleasant even if it is bad for us in the long run.

We will talk more about the TRPM8 next week, about how menthol seems to cool you down, how TRPM8 is a lot like TRPV1, and how it may save your life.

Eccles R, Du-Plessis L, Dommels Y, & Wilkinson JE (2013). Cold pleasure. Why we like ice drinks, ice-lollies and ice cream. Appetite, 71, 357-60 PMID: 24060271

Noriyasu A, Konishi T, Mochizuki S, Sakurai K, Tanaike Y, Matsuyama K, Uezu K, & Kawano T (2013). Menthol-enhanced cytotoxicity of cigarette smoke demonstrated in two bioassay models. Tobacco induced diseases, 11 (1) PMID: 24001273

Brody AL, Mukhin AG, La Charite J, Ta K, Farahi J, Sugar CA, Mamoun MS, Vellios E, Archie M, Kozman M, Phuong J, Arlorio F, & Mandelkern MA (2013). Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 16 (5), 957-66 PMID: 23171716

Ashoor A, Nordman JC, Veltri D, Yang KH, Al Kury L, Shuba Y, Mahgoub M, Howarth FC, Sadek B, Shehu A, Kabbani N, & Oz M (2013). Menthol binding and inhibition of α7-nicotinic acetylcholine receptors. PloS one, 8 (7) PMID: 23935840     

In lieu of additional web sources, I suggest investigating the National Center for Biotechnology Information site ( from the National library of Medicine. This site has many resources, from looking at the amino acid or nucleotide sequences from any protein or gene you can imagine (GenBank, to scientific journal articles that may or may not be available to you. Look at PubMed Central (PMC, where all articles are available free to the public.