Biology concepts – thermoregulation, TRPM8,
vasoconstriction, brown adipose tissue, agonists/antagonists
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Pep-O
Mint was the first Lifesaver flavor, invented
in
1912. This was followed quickly by the Lifesaver
car
in 1918. Built on a Dodge truck chassis, the
important
word was dodge, since the car didn’t have
a
windshield and the driver had to stick his head out
the side window to see ahead.
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Now put the candy in your mouth like normal and suck on it for a
minute or two – don’t chew it up.
Swallow to get the saliva out of your mouth and take out the candy. Now
take in a long slow breath of air. How does it feel? Did the room get colder in
the last two minutes?
If you are like most people, the air feels colder in your mouth now that you've eaten menthol (peppermint). Just like capsaicin can make
hot things seem hotter via TRPV1, the cold sensing channel we talked about last week, TRPM8, can make room temperature air seem colder.
The TRPM8 cold sensing ion channel is important for keeping
our body temperature in a normal range. Just like TRPV1 senses when we are too
warm and initiates cooling mechanisms, TRPM8 tells us we are cold and institutes
procedures to make us warmer. One way is to stimulate vasoconstriction, so less heat is lost from the blood through our
skin. I’m sure you have noticed that your skin is paler when you are out in the
cold. This is from vasoconstriction limiting the amount of blood moving into
the surface vessels.
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When
your core temperature varies from your skin
temperature
by too much, TRPM8 will institute
heat
conserving and/or generating mechanisms.
For
heat conservation, more of the blood (left
cartoon)
that goes the skin can be shunted through
the
capillaries before it gets to the surface. This
helps
reduce the amount of heat loss via radiation
of
the heat in the blood. On the right is the effect of
the
arrector pili muscles. When cold, they contract
and
raise the hairs, trap air, and therefore trap body
heat
against the skin so less heat is loss. The
contraction also mounds up the skin – goosebumps.
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TRPM8 can also stimulate shivering and the burning of fat to
generate warmth. Through the sensations and reactions of TRPV1 and TRPM8,
animals learn to maintain a more or less constant body temperature, seeking out
temperatures that are good for physiology and avoiding temperatures that would
change their core temperature by too much. This was shown in a series of
studies described in a 2013 paper, where mice without temperature sensing receptors
TRPV1 and/or TRPM8 would not avoid hot or cold temperatures and were prone to
hyperthermia and or hypothermia.
So how does the TRPM8 channel sense cold? We saw that with
TRPV1 the heat induced a conformation change that caused the channel to open
and calcium to flow in and start a neural action potential. Could cold induce a
conformation change as well? Maybe. What was seen in a 2011 study was that
TRPM8 neurons started firing when the temperature dropped to 28.4˚C (83 ˚F). As
the temperature dropped, the neurons would fire more and more strongly, so it
could act as a thermostat.
When the temperature dropped severely (to 10˚C) the core
temperature changed little, but skin temperature dropped considerably. The
TRPM8 thermostat was targeted to keeping the organs and brain warm, not the
skin. It accomplishes this by
diverting heat via the blood away from the skin. A 2012 study showed
that TRPM8 antagonists brought a systemic hypothermia, but repeated use of the
antagonist reduced the magnitude of the temperature drop – so unlike most TRPV1antagonists (that bring bad hyperthermia), TRPM8 antagonists might be helpful in medicine.
But this still doesn’t answer the questions as
to how TRPM8 can detect cool
temperatures. It may or may not be a conformation change, but what does occur
is an alteration in the apparent
temperature threshold of the neuron. The cold temperature should inhibit firing
(cold slows metabolism and chemical activity), but here it increases the
metabolism and biochemical activities. TRPM8 makes the neuron seem warmer so
that the firing is easier, and this transfers information that the area is in
fact colder! That’s an exception.
It seems that TRPM8 can stimulate the burning of
fat to produce heat. We talked about this before with capsaicin as well. Brown
adipose tissue has more mitochondria and more of a protein called UCP1
(uncoupling protein). UCP separates mitochondrial energy burning from ATP
production; all the energy goes to making heat.
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We
don’t yet know how cold activates TRPM8. In
warmth,
the channel is closed. With cooler
temperature
or menthol (M), the channel is open,
but
we don’t know if cold achieves this by a
conformation
change. If really cold, the regulatory
proteins
break away and the channel can’t work.
So
TRPM8 is active in a range of temperatures.
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However it manages the feat, TRPM8 is important for keeping
mammals warm. It might even help you lose weight. Chronic cold stimulates TRPM8
all the time, and this ramps up your heat production. A 2012 study showed that
for mice, chronic cold could actually prevent them from becoming obese.
Heat production takes energy, and burning more energy helps
you lose weight. But there is an important balancing act at work here. Our fat also
protects us against losing too much heat in the cold. Look at whales, they have
a layer of blubber all over their body to insulate them from the cold water. It
has been shown that people with an even layer of fat all over their body make
good cold weather swimmers, like Lynne Cox, who swam from her perfectly good
boat to the shores of Antarctica and across the Bering Strait in 4˚C (40˚F)
water.
On the other hand, bactrian camels keep their fat limited to
two humps (one for dromedaries) in order to prevent against having too much
insulation in their desert environment. Camels need to be able to dissipate lots
of heat. And no, the humps aren’t for storing water! Remember we said that one of the great things about fat is that you can store lots of energy in a small space precisely because can be stored without water.
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In
brown adipose tissue, there are ATP synthase
proteins
(for making ATP) and uncoupling proteins
(for
generating heat) in the inner mitochondrial
membrane.
When cold, the number of UCP proteins is
increased,
as is the number of mitochondria. About
65%
of the energy of the proto gradient formed by the
respiratory
chain can be converted to ATP by the ATP
synthase.
But using the UCP to allow protons back in
means
that 100% of the energy is changed to
heat,
no ATP is made.
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A 2014 study showed that chronic cold makes brown fat AND white fat upregulate UCP
and generate more mitochondria. It makes white fat more like brown fat and this
means that more fat is burned. In mice, this chronic cold is enough to keep
them from becoming obese, even on a high glucose diet. So if you want to stay
skinny, turn your thermostat way down all year round.
The study that showed that
chronic cold kept mice from getting fat wasn’t as cruel as it may sound. They
didn’t keep the mice at cold temperature all the time, they used a chemical that
could mimic the cold and make the TRPM8 channels fire all the time. What did
they use? Menthol.
With TRPM8, menthol (in mints) and some other
chemicals open the ion channels just as cool/cold temperatures would, and our
brains trick us into thinking the mouth or skin is colder than it really is.
That’s what is behind our lifesaver trick at the beginning of the post. The air
wasn’t any colder; your brain makes you think it was.
Take oil of wintergreen in BenGay for example. We showed that it was a
TRPV1 agonist, so it could induce analgesia by counter irritation. But it is
also a TRPM8 agonist. In the oral cavity at lower concentrations than used in
BenGay, it activates TRPM8 and desensitizes TRPV1. The lifesaver trick will
work with peppermint, spearmint, and wintergreen flavors; they all activate
TRPM8.
Pogorzala LA, Mishra SK, & Hoon MA (2013). The cellular code for mammalian thermosensation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (13), 5533-41 PMID: 23536068
Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, Vencato J, De Stefani D, Silvestrin V, Rizzuto R, Bassetto F, De Caro R, & Vettor R (2014). Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Molecular and cellular endocrinology, 383 (1-2), 137-46 PMID: 24342393
Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, Jin R, Ma L, Wang P, Zhu Z, Li L, Zhong J, Liu D, Nilius B, & Zhu Z (2012). Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. Journal of molecular cell biology, 4 (2), 88-96 PMID: 22241835
Selescu T, Ciobanu AC, Dobre C, Reid G, & Babes A (2013). Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin. Chemical senses, 38 (7), 563-75 PMID: 23828908
This is a good place to point out the similar exception for
TRPV1 and TRPM8. They are both proteins that can be activated by both
environmental factors and by
chemicals. We saw that TRPV1 is activated by capsaicin and other chemicals. The
opening of the channel and firing of the neurons in response to these chemicals
was interpreted exactly the same as if the neurons were exposed to damaging
heat.
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There
are many agonists for TRPM8, similar to TRPV1.
In
fact, some things that activate TRPM8 also activate
TRPV1.
An interesting one is the synthetic agonist called
icilin.
It is thousands of time more active on TRPM8 than
cool
temperatures. However, it binds to TRPM8 in a
completely
different way as compared to menthol and
cool
temperatures.
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Menthol is a terpene alkaloid contained in plants of the
genus Mentha (mint, from the Greek mintha). This genus includes 25 species
of aromatic herbs, such as peppermint, spearmint, and pennyroyals. Most mints
can be and are used in making foods and drinks, but the pennyroyals also
contain toxic compounds that will induce liver failure and kill you.
At low concentrations in the mouth or on skin, menthol
produces a pleasant cooling sensation, but higher concentrations produce
burning, irritation and pain (this has to do with how it activates TRPV1,
TRPV3, TRPM8, and TRPA1, depending on the concentration).
In the oral cavity, a small amount of menthol
actually desensitizes TRPV1 activation by heat and capsaicin, so chili peppers
might not seem so spicy. Biochemical evidence shows that menthol sparks a
release of glutamate from neurons. But an increase in glutamate
neurotransmitter can actually stop the type C nociceptive neurons from firing
(an inhibitory neurotransmitter in this case).
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Pennyroyal
is a member of the mentha genus (left). It, like
many
plants (right image is orange mint), has been used in
medicine.
It can be ground and drunk with water to settle a
sick
tummy or to induce perspiration. However, pennyroyal
has
to be used carefully. In addition to menthol, it contains a
chemical
called pulegone. Too much pulegone and here
come
the seizures, organ failure and death. Don’t confuse
the
two mints.
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At this same time, menthol (or other TRPM8 agonists) will
sensitize TRPM8 receptors, the combination of these two results means that
sucking in air after a wintergreen or peppermint candy will make the air seem
colder, but might also make a hot cup of coffee seem cold as well.
I think the only way to resolve these ideas is to start a
controlled experiment. What do you predict would happen if you froze a chili
pepper and then took a bite? How about eating peppermint laced with capsaicin,
or a strong peppermint flavored tea that has been heated to near boiling? Who
will win out, TRPM8 or TRPV1?
It may not be so easy to figure out. The agonists and
antagonists of the TRPs can have effects on multiple receptors and the effects
can be different at different concentrations. Menthol sensitizes TRPM8, but if
the temperature is above 37˚ C (98˚ F) it actually makes TRPV3, a heat sensor,
more active (2006).
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Camphor
comes from some species of laurel trees (left), as well as
from
some herbs of the mint family, like camphor basil (right).
Dried
rosemary leaves are up to 20% camphor. Camphor has
been
used for many things, including as a flavoring in asian
sweets,
an analgesic, an insect repellent, and a rust proofing
agent.
I find it hard to rectify those uses with one another.
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And then there’s camphor. Like menthol, camphor is terpenoid
chemical. Camphor can make things seem cool (by activating and sensitizing
TRPM8), but it’s more complicated. It actually potentiates both heat and cold sensations. A 2013 study shows
that it can sensitize or potentiate TRPV1 (painful hot) and TRPM8 (non-painful cool). Camphor can even activate the noxious
cold sensor TRPA1 that we will talk about in a couple of posts. This means that
it can be analgesic or painful, warming and cooling.
It becomes even more confusing when you realize that camphor
activates TRPM8, just like menthol, but can inhibit the activation of TRPM8 by menthol. Weird, right? Well, consider
this – Vick's VapoRub contains menthol and camphor as its active ingredients. Next week, we'll investigate how
they can work together to open your nose and make you feel both warm and fuzzy
while they cool and invigorate you at the same time.
For
more information or classroom activities, see:
Thermoregulation
–
https://www.khanacademy.org/science/mcat/organ-systems/muscular-system/v/thermoregulation-by-muscles
