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トウガラシの「辛さ」って、植物の防御のはずなのに、人間が娯楽にしちゃった話。鳥だけOKの設計図まであって、自然の戦略が妙に賢い。 → https://yp-kyo.com #yp_kyo #やっぱりキョウは小市民 #初心者歓迎 #食べ物の起源 #トウガラシ #唐辛子

#TRPV1 #カビ真菌 #カプサイシン #キョウのブログ #トウガラシ #唐辛子 #小市民視点 #種子散布 #良性マゾヒズム #辛いなぜ #辛味進化 #鳥辛さ感じない

Controlling Body Temperature in Response to Fight or Flight

New research suggests that blocking TRPV1 protein causes an increased release of noradrenaline, leading to an increase in core body temperatures.

The research is in FASEB Journal. (full access paywall)

Research: "The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature" by Khadija M. Alawi, Aisah A. Aubdool, Lihuan Liang, Elena Wilde, Abhinav Vepa, Maria-Paraskevi Psefteli, Susan D. Brain, and Julie E. Keeble in The FASEB Journal doi:10.1096/fj.15-272526

Image: The researchers found that the "fight or flight" response in the mice was reduced, including after administration of amphetamine, which is known to increase levels of noradrenaline. Image is for illustrative purposes only and shows the structure of noradrenaline.

#neuroscience #science #genetics #trpv1 #noradrenaline #sympathetic nervous system #body temperature

Understanding Salicylate Intolerance: Symptoms and Coping

This applies to TRPV1-mediated salicylate intolerance, which I will explain at the end.

After consuming something high in salicylates, you:

feel the subjective experience of overheating

may start to sweat

may feel dizzy

may be shaky

will soon get diarrhea

will soon develop a low-grade fever that could last for several hours (or longer)

may also experience chills with said fever

will not sweat during said fever

will lose your appetite for the remainder of the day (or longer)

may experience anxiety or brain fog

may feel fatigued

will feel malaise

may get abdominal cramps and discomfort

To deal with the symptoms, first DO NOT TAKE ASPIRIN. Aspirin is acetylsalicylic acid, which will only make things worse. To kill the fever you need to sweat. When the TRPV1 receptor gets inhibited by salicylic acid, you get hyperthermia. TRPV1 is involved in regulating body temperature and, when activated, tells your body to cool itself down. So when you block the TRPV1 receptor with salicylic acid, your body doesn't get the signal to cool itself down, which makes you overheat. The main way your body cools itself down is through sweating.

I am not sure how safe exercise would be in this instance. And I have no experience with saunas during post-salicylate fever.

#salicylate sensitivity #salicylate intolerance #own stuff #overheating #trpv1

What’s So Repelling About Repellents?

Biology concepts – thermosensing, repellent, odor receptors, gustatory receptors, semiochemcials

Science explains our world, and then technology and engineering

build a model of that for our use. The better we know how our

universe works, the better we can make use of it. In the 1985

film Real Genius, this difference is stated when the scientist

students ask what a 6 megawatt laser might be for, one student

says, “Let the engineers figure out a use for it.” In this case, they

used it to fill a house with popcorn.

Science exists to describe our universe in terms of rules and mechanisms; what is and how it comes to be. Knowing that something exists is only half the equation. Science seeks to explain how something exists in terms of the rules of the universe. Observation is good, but it only shows us the question – mechanisms of action and interactions show us the answers.

As an example – we know that certain naturally occurring oils and well as some man made chemicals keep mosquitoes from feeding on us. This is the observation. But the question is – how do mosquito repellents work? The answer is more interesting and more complicated than you would initially think. Repellents rarely repel.

Investigating how chemicals keep us from getting bitten will teach us about how the living systems work, will give us a better understanding of our universe, and then give us better insect repellents. Don’t think that’s important? Consider the hundreds of millions of people who are infected every year (several million die) with mosquito-borne diseases (malaria, encephalitis, dengue fever, yellow fever, filiariasis). So yes, we need more repellents.

Mosquito borne diseases can be unpleasant at best. Top left is

filariasis, a worm is transmitted via mosquito and it clogs up

your lymphatic vessels, so that body parts swell from excess

fluid. Top right – malaria can result in so much red blood cell

lysis that your spleen (the guy who cleans them up) can

rupture. Bottom left – Dengue fever is often called breakbone

fever, the pain is not something an image can express. But the

hemorrhagic form of the disease can produce some bleeding

in weird places. Oh, and it can kill you too. Bottom right –

yellow fever is caused by a virus transmitted by mosquito. Your

liver breaks down and causes your whole body to turn yellow

and you bleed into your skin.

We should start with the repellents for which we have good ideas of their mechanism of action. But there aren’t any. We have some hypotheses and working ideas of the modes of action of mosquito repellents, but nothing is definitive yet. Let’s look at two of them and see if we can find some common pathways.

Citronella oil

Citronella is a combination of many different natural oils produced in lemongrass plants (Cymbopogon nardus and Cymbopogon winteratu). As a natural oil and a flavoring in Asian cooking, one would think that citronella oil would be considered just about the safest insect repellent this side of a slap with an open palm.

But no, Canada says that one small component of citronella oil called methyleugenol, can increase the likelihood of tumor formation in rats. Of course this was when methyleugenol was distilled from the oil, given by itself in large doses, and introduced directly into the stomach. But Canada is still in the process of banning citronella oil as an insect repellent. Of course, you can still eat thai food in Canada, which is often flavored with lemongrass.

The EU, on the other hand, said that the repelling function of citronella oil hadn’t been proven and it was deemed illegal to use in the EU in 2006. Oh, you could eat it, and use it soap or perfumes, you just couldn’t use it to keep mosquitoes away. They reconsidered in 2014 and some restricted uses of citronella oil as a repellent are now allowed.

Citronella oil comes from the lemongrass plant (Cymbopogon

nardus or Cymbopogon winteratu). There are two major species

for acquiring the oil, and the oil from each is a little different in

the percentage of each chemical. Lemon grass is also used in

cooking, the woody stalks are used with extra long cook times.

The torches that burn citronella oil work pretty well, but you

have to stay in the volatilized cloud of oil for them to be efficient.

Despite these issues, the U.S. Environmental Protection Agency (EPA) says citronella is safe and effective as an insect repellent. One weird side issue – you can take all the lemongrass you want from the US to Canada, where its oil is under attack, but you can’t bring any lemongrass from Canada to the US, where it is considered safe. Hmmmm.

Citronella oil probably works in a couple of ways. It's strong and sweet smelling, so it covers up and dilutes the odors that mosquitoes use to find you. If they’re detecting all the citronella in the air, then they aren’t smelling you. But research also shows that citronella oil activates TRPA1 ion channels. In us, they detect cold and noxious chemicals and are interpreted as pain. It is very possible that the detected signals in mosquitoes just come through as something unpleasant and to be avoided.

In this way, citronella would be an actual repellent. It repels on contact as well, as the taste is thought to activate bitter taste receptors and contact greatly reduces feeding time.

But citronella only seems to work when you are in the cloud produced by burning the candles or torches, or within the area of the spray. And if you’re using an oil or cream with citronella, it should really be reapplied every 30-45 minutes - not the most user-friendly method for discouraging pests.

DEET

World War II in the Pacific was an insect nightmare for the US Army. In response to the plethora of insect-borne disease that ran through the allied forces, defense scientists starting looking for better insect repellents. In 1946, their efforts produced N,N-Diethyl-meta-toluamide, or DEET.

Just how they came up with DEET is a mystery to me, it must have been a massive exercise in trial and error. Why? Because we know less about how DEET works than we do about citronella oil. And that’s with the benefit of 40 years of research. They didn’t have a clue how it worked or even what systems it was targeting when developed in the 40’s.

Guess which hand has been treated with DEET. The

mosquitoes come very close to the hand that was treated,

but don’t land on it. This argues that DEET is less repelling,

than it is disguising. On the right, the structure of DEET is

similar to several human semiochemicals, it fits into the lock

and key system of several odor receptors and activates or

inhibits them.

Originally it was believed that DEET disrupted the mosquito’s ability to detect semiochemicals(octenol) produced by mammals, especially humans, so mosquitoes couldn’t find a mammalian host to feed on. Then they played around with the idea that it blocked detection of CO2.

More recent studies have been more rigorous, but haven’t helped solve the puzzle. A 2008 study suggested that DEET was actually repellent; the mosquitoes didn’t like the smell and would avoid it. But other studies have shown different mechanisms of action.

A study in the journal Nature in 2011 found that mosquito odor receptors could be confused by DEET. The receptors for octenol were less responsive in the presence of DEET, but other receptors more more responsive. The conclusion of the study was that odorants from humans could be detected, but their pattern was confused, so the mosquito didn’t recognize the target as a target. It’s as if we disappear from the mosquitoes radar when we wear DEET.

A 2010 study showed similar results. DEET activated certain odor receptors but not others when given alone, but the opposite effects were seen when DEET was given in the presence of things from human sweat that would normally attract a mosquito. Once again, the signals were confused. This is really more of a chemical disguise for us, not a repellent. Next time your kids go outside, you should insist that they apply their mosquito confusant.

However, a 2013 study in the Journal of Vector Ecology found that heat and moisture were critical elements for recognition of targets by female mosquitoes, and that DEET messed not with odor, but with detection of heat and/or moisture. Different from the other studies, but still more of a masking than a repellent.

Something a little disturbing. Mosquitoes can learn to ignore

DEET. Most mosquitoes will be confused by DEET and never

find you. But if they do and then are repelled by the taste, they

learn from that and the second taste is not repellent. Hopefully

they just don’t find you a second time.

There was an interesting study from 2013that showed that if you mutate or knock out Orco, one of the co-receptors (a protein that works with many different odor receptors so that they can function properly), then two things happened. One, DEET didn’t have any effect on the mosquitoes, and two, mosquitoes that normally preferred humans greatly would then settle for any mammal.

Weird - Orco is needed for both DEET to work and for mosquitoes to find humans more attractive. I haven’t figured that one out yet. The researchers showed that DEET only maintained an effect on the Orco mutant mosquitoes when they landed on a DEET covered surface, and then they didn’t like it at all.

This suggested that DEET might have more than one mechanism, confusion in the air and repellent taste on contact. Older studies supported this idea, as a couple of studies in 2005 and 2006 showed that contact with DEET would reduce feeding behavior in mosquitoes and one in 2010 showed that fruit fly bitter taste receptors are activated by DEET.

So, we have studies that say DEET is a confusant rather than a repellent, others that say it is a true obnoxious smell that they can’t stand, and yet others that say DEET is confusing to the smell and repellent to the taste. But there are more. Other studies suggest that DEET actually inhibits the smelling of anything, while others say that it inhibits an important protein called cytochrome p450.

Used commercially since the 1950’s, DEET has been the gold standard for efficiency for many years. Although it has to be used at fairly high concentrations, it can keep mosquitoes away for 4-6 hours at concentrations where citronella oil might work for less than an hour. At 100% concentration, DEET is active for more than 12 hours. What’s more, if you combine DEET with 5% vanillin, it works two hours longer!

A lime with cloves stuck in it as a mosquito repellent – really?

Well, lime is kind of like citronella oil, and clove has eugenol,

which acts on TRPV1 ion channels. But how many would you

have to have, or do you wear them like earrings? Penny royal

contains menthol and mosquitoes stay away from it. But it

also has toxins that will kill you.

As good as DEET is, people still question whether it’s safe. The EPA in a 2014 review said that DEET is safe for human use and poses no identifiable risks for human health, even in children. But this doesn’t keep people from suspecting chemical usage of carrying negative effects.

On the other hand, DEET dissolves plastic, foam rubber, spandex, gore-tex, and nylon. I can see where this might make people leery about slathering it on their skin for hours at a time. And a few people are allergic to DEET, so the best current repellent isn’t without some negatives.

One last point – a newer repellent called picaridinis almost as effective as DEET and doesn’t eat your back packing equipment and clothes. The interesting point is that picaridin is a synthetic version of piperine, the spicy chemical in black peppercorns. Add to this that menthol is also a fairly decent mosquito repellent, and we have some good arguments that TRP receptors might be involved in repelling activity – as with citronella oil. Piperine is a TRPV1 agonist, and menthol activates TRPM8 and TRPV1. All our talk about spicy food and heat/cold receptors has an impact even in the spread of malaria and other deadly diseases!

Next week, another question to answer - do sunflowers really turn with the sun?

DeGennaro M, McBride CS, Seeholzer L, Nakagawa T, Dennis EJ, Goldman C, Jasinskiene N, James AA, & Vosshall LB (2013). orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET. Nature, 498 (7455), 487-91 PMID: 23719379

Stanczyk NM, Brookfield JF, Field LM, & Logan JG (2013). Aedes aegypti mosquitoes exhibit decreased repellency by DEET following previous exposure. PloS one, 8 (2) PMID: 23437043

Klun JA, Kramer M, & Debboun M (2013). Four simple stimuli that induce host-seeking and blood-feeding behaviors in two mosquito species, with a clue to DEET's mode of action. Journal of vector ecology : journal of the Society for Vector Ecology, 38 (1), 143-53 PMID: 23701619

#zoology #TRPV1 #TRPA1 #thermosensing #taste #smell #repellents #odor receptors #insect #gustatory receptors #exception #DEET #citronella oil #animal

They Can See The Blood Running Through You

Biology concepts- thermosensors, TRPV1, hematophagy, taste sense, alternate splicing, echolocation

All three species of vampire bat live in Central to South

America, the common vampire bat (Desmodus rotundus),

the hairy-legged vampire bat (Diphylla ecaudata), and

the white-winged vampire bat (Diaemus youngi).

Any idea what the picture to the left shows? A hint – this may be the most sophisticated piece of machinery ever devised by nature. Together with the organism to which it’s attached, this piece of evolutionary engineering is capable of almost everything a billion dollar jet can do.

It’s the nose of the common vampire bat (Desmodus rotundus). These bats belong to the family Phyllostomidae, one of three families of leaf-nosed bats (Rhinolophidae and Megadermatidae being the other two families). One of the exceptional skills mediated by this nose makes use of the same receptor that makes our mouths burn when we eat chili peppers. Vampire bats can detect the hot blood in your veins from far away!

It’s the noseleaves of the vampire bat that are so amazing, but maybe we should include the rest of the bat head as well. The ears, teeth, mouth, and eyes all work with the nose to give this bat some jet fighter skills.

Leaf nosed bats come in some very odd varieties. The picture on the below and right will give you some idea of the shapes and sizes possible. The question is – what’s the reason for these bizarre growths and why isn’t one odd shape enough? The answer will best be found if we know what their function is, because in biology – form follows function (except for proteins, see this post).

Here are some different leaf nosed bats. Top middle is the Ridley’s leaf

nose bat; bottom left is the Honduran white bat. Top right is the

Commerson’s leaf nose bat and the middle bottom is the greater

spear-nosed bat. The bottom right image is of the cleaf nosed bat of

Vietnam, a more newly discovered variety. It was first described in

2008, but it took 4 years to determine if it was a new species or just

a variant of another species.

Two basic needs of the bat are to find food and find its way. Whether it's a fruit bat, an insectivorous bat, or a vampire bat, a bat must be able to negotiate obstacles within its environment and find a source of nutrition.

To accomplish these tasks, especially given that most bats are nocturnal, they use echolocation. They send out a high-pitched sound, and it bounces off objects and returns to their ears. This is very much like the radar used in airplanes. But this isn’t all they use. Bats can see just about as well as humans; the phrase “blind as a bat” might as well be “blind as a Bob.”

We said most bats are nocturnal. This is Livingstone’s fruit bat

or Comoro flying fox. It is a fruit eating bat of the Comoros

Islands in the western Indian Ocean (just northwest of Madagascar)

and is at least partially diurnal. Other bats may be seen during

the day, but it almost always because they have been disturbed

in their hiding place or they were disturbed in their

feeding the night before.

Bats can also smell their way to food, especially fruit bats. But to answer the question about the noseleaves we have to return to echolocation. Vampire bat sounds emitted for echolocation come through their nose, not their mouth! According to a 2010 study, the leaves aren’t used to gather the returning sound, but to focus the outgoing sound so that the “pictures” formed by the returning echos will be most accurate.

Different shapes help to increase the difference in the reflectivity of objects in the area of focus as opposed to those in the periphery. This allows the various species to hone in what they need to discern and dismiss those things that are uninteresting. Different backgrounds and different needs require different nose leaf shapes.

This answers the question about the wild shapes of noses, but it brings up another question. If vampire bats find their food by echolocation, sight, and smell, then why do they have heat sensors?

To answer this new question, consider the sizes of the vampire bat and its intended prey. The bat weighs about 2.5 oz (71 g), but it needs blood for food (mammalian blood for common vampire bats, bird blood for hairy legged and white-winged species). In fact, vampire bats are the only mammals that completely depend on hematophagy (blood meals). Because of this, they often feed on animals that are over 1000x their size.

Pigs are a favorite source of blood for vampire bats. Here, a

sleeping pig has been bitten on the snout. Why the snout – read

on. Notice the bat can hold its weight with its wings, and that

there seems to be more blood than you would expect from

such a small bite. Again, read on to know why.

To get to the blood of say a cow or horse, vampire bats would have to have teeth so large that they couldn’t lift themselves for flight. No, they have to be very careful about where they bite a victim; somewhere that will bring enough blood to feed on, but won’t cause the huge animal to kill them. Vampire bat teeth are so sharp that prey animals rarely feel the bite, and since the bats are nocturnal, the victims are most often asleep at the time and stay asleep during the feed.

The bats need to locate a place on the sleeping animals where blood vessels are near the surface. This is where the heat sensing comes into play. Vessels close to the surface will give off the most heat to the environment, and vampire bats can “see” these vessels from up to 20 cm away!

The vessels in question need to be covered with less hair, so the bat almost always goes for the lower leg or snout. They will land on the ground, and walk or run up to the prey from behind the animal to make the bite. Vampire bats wings are much stronger than most other bats, so they have an easier time moving along the ground, supporting some of their weight on their wings.

On the left you can see the incisors of the vampire bat. The cheek

teeth and canines are used to shave off any hair from the site, but

the incisors do the cutting. The lack enamel, so they are always

razor sharp. On the right, the tongue is being used to take in the

blood. The tongue is deeply grooved, so the anticoagulant saliva

runs down into the wound and more blood can easily be lapped up.

Their teeth then cut a 5 mm x 5 mm gouge in the victim and they lap up the blood that comes out. It isn’t too common, but vampire bats do feed on humans. This leads us to another amazing skill. Instinct tells the vampire that a good feeding once will probably mean a good feeding again – if they can find the same animal. So how do they find the same animal several night is a row? They hear them.

A 2006 study showed that vampire bats do tend to feed on the same individual (be it human or cow) for several nights in a row. They can distinguish their previous victim by the sounds of their breathing! Every animal has a unique breathing pattern and sound profile, and the vampire bat can distinguish between individuals to find the one that matched a previous good meal. Imagine if we could find our favorite meal again by listening for the clinking of the right pans!

Returning to a good feeding spot each night, the vampire bat searches for a surface vessel to drink about 1-2 teaspoons of blood (4-5 ml). This isn’t enough to harm the animals, and is what allows them to go back several nights in a row.

Rabies can be spread by bats, and they don’t have to bite you.

When a bat bites an infected animal, it takes in the virus. The

virus grows in the animal and gets distributed to the saliva as

well. Startled bats sometimes spit, and if this gets into your

eyes, mouth, nose, or an open wound, you could contract the

infection. It’s rare overall, but rabies kills about 60,000

people a year.

This doesn’t mean that feeding by vampire bats is without negative consequences. One, the idea of being fed on gives me the heebie jeebies. Two, the vampire bat is a common vector for rabies virus. And three, in the cattle of Latin America, repeated feeding by vampire bats is associated with reduced milk production in dairy cattle and reduced mass gain in beef cattle. So if you wake to find a vampire bat licking your ankle, best to shoo him away and try to breathe differently tomorrow night.

How do vampire bats locate that ankle vessel they need to feed on? Back we go to that amazing nose. The heat sensors of bats are called pit organs, just like in the pit vipers we talked about last week. There are three to four of these organs in the noseleaves of the bat, and a couple across the upper lip as well.

As opposed to the pit vipers, vampire bats have adapted a heat sensor, not a cold sensor to use as their infrared detector for blood vessels. TRPV1, the same receptor that is used for the capsaicin burn and heat regulation in mammals, is present in very high numbers in the neurons of the pit organs.

But this is no ordinary TRPV1. Mammals can’t detect heat from 20 cm away with a regular TRPV1 – this is a modified TRPV1. A 2011 study found that this version of the protein is missing the last three amino acids on the carboxy terminus (the end produced last). This small change increases the sensitivity of the receptor from 43˚C all the way down to 30˚C, so that small differences in heat can be noted from almost a foot away.

One more amazing fact - the bats have regular TRPV1 too. The two version of the protein come from the same gene and the normal one is used throughout the bat’s body for all the things we use TRPV1 for: heat regulation, reproduction, cancer inhibition, etc. Only in the neurons of the pit organs is the mRNA altered after it is transcribed from the gene (alternately spliced) to make the slightly shorter, more sensitive protein.

Here is a cartoon of how blood clots. On the bottom flow chart,

the first anti-co line is where desmolaris and draculin work.

The third line is where desmoteplase acts.

Now our bat friend has located a victim, found a surface vessel and taken a bite to let the blood flow. There’s yet another problem. Mammalian blood clots to prevent loss. The bats must either keep biting, which might wake their prey, or have a way to keep the blood flowing.

Their mouths have specialized salivary glands that make anticoagulants so no clot is formed. There is one anticoagulant that someone with a sense of humor named draculin. It acts to prevent blood clot formation. We have mentioned a second anticoagulant before, called desmoteplase. One of our Halloween posts talked about how it may be good for people that have had strokes. It dissolves any clots that may form.

A 2014 clinical trial is showing that desmoteplase is better than the tissue plasminogen activator clot busters now being used (rtPA), since they have a half-life of four hours (as opposed to 5 minutes for rtPA) and it’s breakdown products aren’t as toxic to nerves and the blood brain barrier as compared to rtPA.

A newer anticoagulant is called desmolaris. A 2013 study showed that it works on yet another part of the clotting system to prevent clot formation. And this isn’t all of them. A 2014 protein survey suggests that there may be dozens more anticoagulant proteins in vampire bat saliva.

Which flying machine is more complex and cool?

Lets add up the vampire bat’s technologies and compare them to an F16. The bat can fly and turn better. The bat has radar and infrared heat detection. It has high powered listening devices that can discriminate between two individuals. Finally, it has biological weapons that allow it to do its work without alarming the target.

All that in a “machine” that can fit into the palm of your hand. Defense aeronautical engineers must feel so embarrassed.

Next week, let’s take it just a bit further. Female mosquitoes aren’t just looking for you, they’re tasting and feeling for you. They use CO2 gradients as well as my prodigious heat to find me on a warm picnicking evening.

Vanderelst D, De Mey F, Peremans H, Geipel I, Kalko E, & Firzlaff U (2010). What noseleaves do for FM bats depends on their degree of sensorial specialization. PloS one, 5 (8) PMID: 20808438

Patel R, Ispoglou S, & Apostolakis S (2014). Desmoteplase as a potential treatment for cerebral ischaemia. Expert opinion on investigational drugs, 23 (6), 865-73 PMID: 24766516

Ma D, Mizurini DM, Assumpção TC, Li Y, Qi Y, Kotsyfakis M, Ribeiro JM, Monteiro RQ, & Francischetti IM (2013). Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo. Blood, 122 (25), 4094-106 PMID: 24159172

Gröger U, & Wiegrebe L (2006). Classification of human breathing sounds by the common vampire bat, Desmodus rotundus. BMC biology, 4 PMID: 16780579

Gracheva EO, Cordero-Morales JF, González-Carcacía JA, Ingolia NT, Manno C, Aranguren CI, Weissman JS, & Julius D (2011). Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature, 476 (7358), 88-91 PMID: 21814281

For more information or classroom activities, see:

Leaf-nosed bats –

http://animaldiversity.ummz.umich.edu/accounts/Phyllostomidae/

http://animals.jrank.org/pages/2868/American-Leaf-Nosed-Bats-Phyllostomidae.html

http://sandwalk.blogspot.com/2012/02/ugliness-of-leaf-nosed-bat.html

http://www.speciesconservation.org/case-studies-projects/ridleys-leaf-nosed-bat-ridleys-round-leafed-bat/3049

http://animals.jrank.org/pages/2860/Old-World-Leaf-Nosed-Bats-Hipposideridae.html

http://animaldiversity.ummz.umich.edu/accounts/Hipposideridae/

http://www.inaturalist.org/taxa/71378-Hipposideridae

http://www.ehow.com/about_6579902_leaf_nosed-bat.html

http://animaldiversity.ummz.umich.edu/accounts/Rhinolophidae/

http://kids.nationalgeographic.com/animals/vampire-bat.html

http://animaldiversity.ummz.umich.edu/accounts/Desmodus_rotundus/

Echolocation –

http://www.teachengineering.org/view_activity.php?url=collection/cub_/activities/cub_soundandlight/cub_soundandlight_lesson4_activity1.xml

http://www.exploresound.org/home/teachers-parents/

http://skramar.wikispaces.com/III.+Classroom+Activity

http://kindernature.storycounty.com/display.aspx?DocID=20097271336

http://www.unco.edu/nhs/physics/faculty/adams/Research/USB/Index_PS.htm

http://www.scholastic.com/teachers/lesson-plan/bat-cave-7-science-activities

https://www.youtube.com/watch?v=Hr-Y2Tt8gFE

http://channel.nationalgeographic.com/channel/brain-games/videos/echolocation/

http://www.bbc.co.uk/learningzone/clips/bats-catch-fish-using-echolocation/10517.html

https://www.youtube.com/watch?v=p08Y0oRAX3g

http://www.scientificamerican.com/article/how-do-bats-echolocate-an/

http://askabiologist.asu.edu/echolocation

http://nelson.beckman.illinois.edu/courses/neuroethol/models/bat_echolocation/bat_echolocation.html

Alternate splicing –

http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapter16/animation_-_exon_shuffling.html

https://www.youtube.com/watch?v=FVuAwBGw_pQ

http://www.dnalc.org/view/16938-3D-Animation-of-RNA-Splicing.html

http://www.dnalc.org/view/16940-Alternative-RNA-Splicing.html

http://bcs.whfreeman.com/thelifewire/content/chp14/1402001.html

http://www.hartnell.edu/tutorials/biology/splicing.html

http://www.eurasnet.info/education/alternate-splicing/what-is-alternate-splicing

http://www.premierbiosoft.com/tech_notes/gene-splicing.html

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CGoQFjAI&url=http%3A%2F%2Fwww.bioscience-explained.org%2FENvol4_1%2Fpdf%2Fspliceeng.pdf&ei=QfuYU-KCLsKayASduIDwCA&usg=AFQjCNGbbnWnBAbaDG1g-bbiPEOI0rRm0g&sig2=EUOIonqIgKKSeR4ogUEyfA&bvm=bv.68911936,d.aWw

http://www.nobelprize.org/educational/medicine/dna/a/splicing/splicing_alternative.html

Anticoagulants -

http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/TheImpactofCongenitalHeartDefects/Anticoagulation_UCM_307110_Article.jsp

http://www.nlm.nih.gov/medlineplus/bloodthinners.html

http://www.healthline.com/health/anticoagulant-and-antiplatelet-drugs

http://www.strokeassociation.org/STROKEORG/LifeAfterStroke/HealthyLivingAfterStroke/ManagingMedicines/Anti-Clotting-Agents-Explained_UCM_310452_Article.jsp

https://www.youtube.com/watch?v=cy3a__OOa2M

https://www.youtube.com/watch?v=9QVTHDM90io

http://www.hopkinsmedicine.org/hematology/coagulation.swf

http://www.allaboutbleeding.com/hcp/understanding-coagulation.aspx

#zoology #vampire bat #TRPV1 #pit organ #hematophagy #heat sensing #exception #echolocation #animal #alternate splicing

Cold Receptors Come In From The Cold

Biology concepts – thermosensing, cool sensing, allergy, cross-reactivity, cold allergy, sperm maturation, acrosome reaction, opiate withdrawal

You can be allergic to things that touch your skin – like poison ivy,

things injected, like bee venom, things eaten – like foods, or things

inhaled – like perfumes. But now we need to add something else

to this list – cold? On the right you see a common way to test for

allergy. Anything that produces a wheal and flare reaction

(blanched and raised surrounded by red) is considered positive.

But what if they’re just allergic to the metal needle?

Allergies can result when your immune system, specifically your mast cells, have an exaggerated response to something that should be innocuous. We have talked about the different kinds of immune hypersensitivity reactions before, but in general, allergy (or atopy, from Greek for out of place) occurs when your body produces a type of antibody (IgE) that recognizes foreign substances and causes your mast cells to release histamine.

Histamine release can lead to itching, watery eyes, runny nose, and even hives (urticaria, from Latin for nettle, see the post on nettle toxins). The IgE is good for helping you learn to avoid poisons and such, but what if your body makes and IgE to something that isn’t dangerous, like peanuts or latex?

Sometimes it isn’t even a case of building an antibody to something that is normally not deemed foreign. Sometimes a peanut molecule just looks enough like some other antigen that an IgE is tricked into binding to the peanut molecule or the banana molecule.

The fruit-latex syndrome is a good example of this. In many cases of people being allergic to latex (Hevea brasiliensis), they also have an allergy to avocados, kiwi fruit, bananas, or chestnuts. The IgE that recognizes the latex hevein protein cross reacts with a beta-glucanase enzyme protein from the fruits.

In the cases of cross-reacting antibodies, there are antibodies to innocuous antigens, your body reacts to them just like they were something dangerous. Histamine release results from IgEs grouping around an allergen and then attaching to a mast cell. If you have encountered this allergen before and have ramped up the number of IgEs that recognize this antigen, the mechanisms can lead to anaphylaxis. This life threatening condition is marked by inflammation that can cut off airways and a lowering of blood pressure that could kill the brain.

Spina bifida patients often develop latex and tropical fruit allergies.

Spina bifida is an incomplete closing of the spinal cord in the fetus

and can lead to severe difficulties in leg movement. It can range from

undetectable to very evident, like in the right image above. Lots of

treatment means lots of chances to develop latex hypersensitivity,

and almost 2/3 of spina bifida patients develop a latex allergy. A 2011

studysays that they first develop allergy to latex, and then this cross-

reacts with the fruit. So patients without latex allergy don’t have

to avoid the fruits.

People allergic to nuts or bee stings are forced to carry around injectors of epinephrine just in case their allergies are triggered. The epinephrine constricts blood vessels, increases the heart rate and the amount of blood moved, so your blood pressure won’t drop too far if you take it soon enough. It also dilates the airways and stops inflammation so you can keep breathing. These are all good things.

Like we said, this is how allergies can and sometimes dowork. But there are exceptions. Did you know that you can be allergic to cold weather? Yes, I hear you out there, chuckling that you’ve been allergic to shoveling snow for years. But what I’m talking about is a physical allergy – hives, breathing problems, itching, and cough – just because your skin and airways are exposed to cold air.

No – you can’t make an antibody to an environmental condition like cold – at least not as far as I know. But remember that TRPM8 is a cool sensor, stimulated by cold temperatures. What if your body skipped the antibody part and the cold temperature itself stimulated mast cell degranulation (release of histamine granules)? Maybe it does, but whether the cold acts via TRPM8 is another question.

Mast cells (in red) degranulate in response to allergens.

The allergen (1) is recognized and bound by the

appropriate IgE antibodies (2). The end of the antibody

opposite the allergen binding site has a receptor on the

mast cell surface (3). Crosslinking of more than one

surface recpeotr with Ab causes degranulation and

release of inflammatory mediators, like histamine (4)

from the granules usually stored in the cytoplasm (5).

There are only a couple of studies that have looked at TRPM8 and cold-induced urticaria. In 2010, a study using rat mast cells showed that they do express YRPM8 ion channels and that they do release histamine when exposed to cold or methanol (a TRPM8 agonist). The histamine release could be blocked, even at cold temperatures, by treating the cells with a TRPM8 antagonist. Pretty convincing, eh?

But the very next year, another study said it was unlikely that TRPM8 was responsible for cold-induced urticaria. This study used human mast cells and mice. Although they did find TRPM8 channels on the mouse mast cells, they didn’t release histamine in the presence of cold in their experimental model. And the researchers didn’t even find TRPM8 expressed on the human cells. This is a bit unusual, since mice are usually a great model for human physiology.

In mast cells from mice with no TRPM8 channels (TRPM8 knockout mice), the mast cell response to cold was normal, so this study concluded that TRPM8 is not involved in cold urticaria. Confusing, but a good opportunity to cheer the relentlessness of science. Study will continue until something is repeatable and can’t be proved wrong. Maybe it will be you – curing cold allergy might not make you rich, but cold-triggered asthma follows a similar stimulation – and solving that little problem will get you a Nobel Prize and a big fat check.

How about another exception? One important difference between TRPV1 warm/hot sensor and TRPM8 cool/cold sensor is that TRPV1 is often located on pain neurons, while TRPM8 is located on other types of neurons and other cell types. TRPM8 activation is not associated with pain sensation directly, since they don’t help depolarize pain neurons. But there is an exception – your teeth.

The left cartoon shows the dentinal pores and how they have

odontoblast processes in them. If the dentin is expose by

receding gums or by decay, the pores are then exposed. On

the right, different stimuli can cause the fluid in the pores to

move, which then puts strain or stretch on the processes, this

causes shifts in ions and that can cause the neurons to fire. These

neurons only carry one message – pain.

Inside the middle of each tooth is the pulp (in the pulp chamber), made up of a few layers of cells that can make more tooth material (odontoblasts), some blood vessels, and a set of nerves. Odontoblastsmake a product called dentin, which is hard, but not as hard as enamel. The enamel on your teeth is not very thick, most of the structure is dentin. As you age, insults to the tooth (like decay), can stimulate the laying down of additional layers of dentin inside the pulp chamber.

The dentin has minute pores that travel out from the middle to the base of the enamel layer. If decay or some other stimulus reaches the pore, processes (like fingers) of the odontoblasts in the pores can react to the stimuli. These then signal the neurons in the pulp. However, the pulp has onlypain sensing neurons. So every stimulus that reaches the pulp will be interpreted as pain.

The odontoblasts have TRPV1 channels, TRPM8 channels and TRPA1 channels (we will talk more about these next week). The hydrodynamic theory of tooth pain says that the changes in temperature that reach the odontoblast processes result in pressure changes and this puts mechanical stress (stretch or shear) on the membranes. These then trigger the channels and the signal is passed to the pain neuron.

A 2013 PLoS study says this is partially true. Their results seem to indicate that very cold and very hot stimuli do produce mechanical pressure on the membrane, so TRPV1 and TRPA1 are responsible for mechano-sensitive pain. But they suggest that in the case of TRPM8, cool/cold temperatures trigger the odontoblasts and neuron. The neuron only has one thing to say - pain – so when triggered by TRPM8 signals in the neighboring odontoblast, it responds the only way it knows how. Too bad, but it has spawned a million dollar industry in toothpastes for people with sensitive teeth.

This is a cartoon of the head of a sea urchin sperm, but many

of the concepts apply in humans as well. See all the red

arrows? Those represent the places where calcium flux is

important in maturation and function. And what do TRPV1

and TRPM8 move the best – calcium. The acrosome reaction

actually dissolved the membrane around the acrosome so that

it can more easily enter the ova. This has to be done at a proper

time; TRPM8 activation prevents it from happening too early.

Here’s another TRPM8 function that we will touch on only briefly. We talked about TRPV1 being important in sperm maturation and in entry into the egg. Well, it looks like TRPM8 is involved as well, only in the opposite direction. TRPM8 signaling, according to a 2011 study, TRPM8 activation preventssperm maturation. This is also important, you need the capacitation and the acrosome reaction to occur at the proper point because they shorten the sperm survival time.

TRPM8 signaling prevents the acrosome reaction, but when the egg is near, a chemical called CRISP4 is released from the egg or parts near there. CRISP4 is a TRPM8 inhibitor. When TRPM8 is inhibited, now TRPV1 can be stimulated to trigger the acrosome reaction.

The interesting part here is that up to the point of CRISP4 release, something is constantly stimulating TRPM8 activity in the sperm cell. I really doubt that there's a cold stimulus way up inside the uterus, so just what is activating TRPM8? We know about lots of endogenous activators of TRPV1, but there has only been one study saying that TRPM8 might have a body-produced agonist, a type of lipid called lysophopholipids. But I think we are missing a bunch of other agonists – maybe you could look for those someday.

OK, here’s the last weird function for TRPM8 today. Would you believe it works in morphine action and withdrawal (when addicted)? Opiates like morphine are analgesic andcold antinociceptive. You take morphine and you don’t sense cold – of course, you won’t sense much of anything else either. For cold, we know how it acts. Opiates cause the internalization of TRPM8 channels on neurons. If there are no exposed channels, they can’t be triggered to allow ions into the neuron.

It goes even further; this isn’t some byproduct or side effect. Menthol is known to create analgesia (one of the reasons they use it in cigarettes). But according to a 2013 paper, if you give naloxone (an opiate blocker) at the same time as menthol – no analgesia. TRPM8 internalization is required for morphine to work.

The term, “cold turkey” is fairly old, first appearing in print

around 1910. It means “without preparation,” but just where

it came from is a matter of question. It might refer to the fact

that cold turkey after Thanksgiving doesn’t need preparation.

It might also be related to “talk turkey, which means to get

down to business. But the way that drug addicts feel cold,

sweat, are pale and have goose bumps – the visual aspect is

not wasted. By the way – who would smoke a cold turkey?

This is important when you are trying to kick a morphine habit. As you stop taking the opiates, TRPM8 quickly relocates to the membrane of the cell and is very easily activated. This causes a cold hypersensitivity and hyperalgesia. People going through withdrawal feel cold because their TRPM8 channels are firing. This is one explanation for calling it, “going cold turkey.” It is uncomfortable and painful, and is one of the main reasons that patients fail detox.

The naloxone that is used to treat morphine addiction binds to the opioid receptor, but doesn’t produce the analgesia. It also allows the TRPM8 to remain externalized, so they don’t have the rebound feeling of cold and pain. Pretty impressive – and now you know how it works.

Next week – TRPM8 is for cold, then there’s the cold that hurts. That is a different receptor, called TRPA1. It makes cold hurt, abut it also saves you from the cold.

Gibbs GM, Orta G, Reddy T, Koppers AJ, Martínez-López P, de la Vega-Beltràn JL, Lo JC, Veldhuis N, Jamsai D, McIntyre P, Darszon A, & O'Bryan MK (2011). Cysteine-rich secretory protein 4 is an inhibitor of transient receptor potential M8 with a role in establishing sperm function. Proceedings of the National Academy of Sciences of the United States of America, 108 (17), 7034-9 PMID: 21482758

Shapovalov G, Gkika D, Devilliers M, Kondratskyi A, Gordienko D, Busserolles J, Bokhobza A, Eschalier A, Skryma R, & Prevarskaya N (2013). Opiates modulate thermosensation by internalizing cold receptor TRPM8. Cell reports, 4 (3), 504-15 PMID: 23911290

Medic N, Desai A, Komarow H, Burch LH, Bandara G, Beaven MA, Metcalfe DD, & Gilfillan AM (2011). Examination of the role of TRPM8 in human mast cell activation and its relevance to the etiology of cold-induced urticaria. Cell calcium, 50 (5), 473-80 PMID: 21906810 Cho Y, Jang Y, Yang YD, Lee CH, Lee Y, & Oh U (2010). TRPM8 mediates cold and menthol allergies associated with mast cell activation. Cell calcium, 48 (4), 202-8 PMID: 20934218

For more information or classroom activities, see:

Cold allergy –

http://www.accuweather.com/en/weather-news/allergic-to-cold-adapting-to-l/19934125

http://www.coldurticaria.info/

http://www.nbcnews.com/health/health-news/allergic-cold-gene-detectives-find-new-clues-f1C6435965

http://www.mayoclinic.org/diseases-conditions/cold-urticaria/basics/definition/con-20034524

http://usatoday30.usatoday.com/news/health/medical/health/medical/coldflu/story/2012-01-23/Allergic-to-cold-Its-a-real-condition-experts-say/52759906/1

http://www.drgreene.com/qa-articles/cold-allergies/

Hydrodynamic theory of tooth pain –

http://www.dentalcare.com/en-US/dental-education/continuing-education/ce200/ce200.aspx?ModuleName=coursecontent&PartID=1&SectionID=-1

http://www.wisegeek.com/in-dentistry-what-is-the-hydrodynamic-theory.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=14&sqi=2&ved=0CIwBEBYwDQ&url=http%3A%2F%2Fwww.mbfys.ru.nl%2Fstaff%2Fj.vangisbergen%2Fendnote%2Fendnotepdfs%2Fcolleges%2FTANDARTSEN%2FPLAATJES%2520EN%2520FILES%2Foral%2520neurophysiol%2520JUNGE%2Fhydrodynamic_theory_LECT06.doc&ei=W05IU7zCHaLCyQGTiYDQBQ&usg=AFQjCNEtK2R_BX3DAJj03Ep0_pPGB2ulwg&sig2=_F9lV6O4KCaixwoAnLugLw

http://www.drbui.com/artdentinhypersensitivity.html

http://www.juniordentist.com/theories-of-pain-transmission-through-dentin.html

Sperm maturation –

http://embryo.asu.edu/pages/sperm-capacitation

http://www.pbs.org/wgbh/nova/education/activities/2811_baby.html

http://www.keytoconceive.com/sperm-capacitation.php

http://www.glowm.com/section_view/heading/Sperm%20Transport%20and%20Capacitation/item/315

http://www.youtube.com/watch?v=rrFsTdfe2qw

http://www.wisegeek.org/what-is-sperm-capacitation.htm

http://www.youtube.com/watch?v=-J9deipbdSI

http://community.babycenter.com/post/a36676870/capacitation

http://education-portal.com/academy/lesson/acrosome-reaction-function-definition.html#lesson

http://www.youtube.com/watch?v=5-g8dLcERlM

http://www.youtube.com/watch?v=-jLyzWrSTOA

http://www.stanford.edu/group/Urchin/acrosome.htm

http://www.embryology.ch/anglais/dbefruchtung/akrosom02.html

http://worms.zoology.wisc.edu/urchins/SUfert_acrosome.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181525/

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/reprod/fert/fert.html

Drug withdrawal –

http://en.ria.ru/infographics/20100524/159134332.html

http://emedicine.medscape.com/article/819502-overview

http://www.addictionsandrecovery.org/withdrawal.htm

http://www.nlm.nih.gov/medlineplus/ency/article/000949.htm

http://www.hindawi.com/journals/tswj/2012/940613/

http://derekwmeyer.blogspot.com/2012/05/physical-component-of-opiate-withdrawal.html

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=16&ved=0CH8QFjAFOAo&url=http%3A%2F%2Fwww.drneurosci.com%2Fcurrentissues%2Fthephysiologicalbasisofdrugaddiction.pdf&ei=81JIU8akN-reyAHNi4GgCA&usg=AFQjCNFpwBNfSjgwuPQ02N4fRj7wKeaQdA&sig2=gihQYdc3hBHJak9mxCBh2g&bvm=bv.64542518,d.aWc

http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_095.htm

#zoology #TRPV1 #TRPM8 #thermoregulation #sperm maturation #opiate withdrawal #hydrodynamic theory of tooth pain #exception #animal #allergy

Capsaicin Receptors – Matters Of Life And Death

Biology concepts – cochlear amplification, capsaicin, tinnitus, neural plasticity, long term depression, sperm capacitation, acrosome reaction, apoptosis, reactive oxygen species, cancer

On the left are the Red Hot Chili Peppers. I am most interested in the

member on the right – Flea. Acknowledged as the second best rock

bassist of all time (right behind John Entwhistle), he gathers as much

or more attention for his name choice and his seeming inability to

wear a shirt. On the right is Donnie Thornberry, of the Wild

Thornberrys. He was a feral child raised by animals in Africa. His

character is voiced by Flea – ahhh, it’s starting to make sense.

I have never been a fan of the Red Hot Chili Peppers (sometimes known as RHCP). The music is nails on a chalkboard to me, and their bassist is named for a plague-carrying arthropod. But in the interest of fair play, I looked deeper. In late 2013, lead singer Anthony Kiedis and “Flea” produced a film intended to honor the life of jazz pianist Joe Albany. Add to this that Kiedis acted in an ABC After School Special when he was a teenager, and I now see that the Chili Peppers are more than just bad music.

I use this story to introduce today’s topic - there is so much more to the capsaicin in chili peppers than just heat and pain. We learned last week how capsaicin and other TRPV1 agonists can combat obesity and damage from stroke, but these abilities were related to the TRPV1 function in thermoregulation. Today let’s look at some functions that are so far outside normal TRPV1/capsaicin function that they can be considered exceptional – like jazz piano from the RHCP.

Hearing

We have explained the mechanism of hair cell action in hearing before. The inner hair cells are bent by the sound wave in the cochlea and converted to a neural impulse to be detected as sound. The outer hair cellswork to amplify the wave so that the sound is louder and can register a signal in the inner hair cells.

Scientists know that TRPV1 is expressed on the inner and outer hair cells, and works in the cochlear amplification system particularly. However, we don’t know its exact function(s) there. On the down side, we know that TRPV1 must work in a narrow range, because drugs and agonists that excite TRPV1 can lead to hearing problems.

Acoustic injury (acute or chronic loud noise), gentimicin (an antibiotic), and cisplatin (a cancer drug) can all cause hearing damage. A 2009 study of gentimicin damage to the cochlea showed that it increased TRPV1 expression in the outer hair cells. A 2008 study of cisplatin showed that its damage to the hair cells could be suppressed if you decreased TRPV1 activity.

Most often people think of tinnitus as a ringing in the

ears, but it doesn’t have to be. It can be clicking, buzzing,

hissing, or roaring sounds as well. If you hear voices –

well, that’s something completely different. Also, tinnitus

is usually characterized as a neural transduction issue,

often from damage to the hair cells, so only you hear it.

But there are problems in blood vessels, muscles, or

bones (TMJ) near the ear that produce soucnds other

can hear. This is called objective tinnitus.

A 2013 study indicates that TRPV1 is important for the uptake of the drugs into the hair cells, and then they do their damage. An older study shows that even without drugs to be taken up, increased TRPV1 expression is the cause of acoustic injury tinnitus (ringing) and hearing loss. Another paper showed that capsaicin itself blocks the action potential in the outer hair cells and dampens the cochlear amplification system. Why anyone would stick a chili pepper in his ear is beyond me.

So we see that a little TRPV1 activity is good, but too much is bad. This is not to say that eating a lot of peppers will harm your hearing; dietary capsaicin never gets to your cochlea unless you’re a horribly messy eater. We will return to this idea with TRPV1 and capsaicin; it can be an angel or a devil.

Memory and learning

Neural plasticity (the ability to change neural connections, building some, losing others) is important in learning and memory. We have discussed long-term potentiation (LTP) in terms of memory, where a reinforcement of action potentials between two neurons or in a pathway lead to a strong connection and a new item learned or remembered.

The flip side is long-term depression (LTD). This mechanism is what allows you to weaken and lose connections between neurons that aren’t being reinforced. You can’t learn something as well unless you keep reinventing the connections, including losing some. However, don’t get the idea that you have to forget some thing in order to remember something new, it is much more complicated than that.

This is a good carton because it helps me point out a

dichotomy. Many people say that your brain is a muscle,

if you don’t exercise it, you will lose it. This is like the

atrophy of your muscles if you don’t use them. But we are

reading in this post that losing some neural connections

is important for learning. Long term depression is similar

to not using your brain. Those connections that are not

reinforced are lost – but here it is a good thing,

a necessary thing.

TRPV1 acts in LTD. Without TRPV1 activity, all connections could continue to be strengthened, and a ceiling level of excitability would be reached. Then you wouldhave trouble adding new information.

TRPV1 acts at the level of the hippocampus (important for memory) through an endocannabinoid called anandamide. We already know that anandamide is a TRPV1 agonist. A 2008 study indicated that there was no LTD activity in mice that had no TRPV1 channels. This study found that TRPV1 was “necessary and sufficient” for LTD, meaning that it was needed and only it was needed for the effect.

Another 2008 study points out how this is important for us. Stress brings too much LTD and not enough LTP. When you’re stressed it’s harder to learn new things and easier to lose established knowledge. Amazingly, TRPV1 agonists like capsaicin can regulate this in stress. Stress + TRPV1 agonists led to reduced LTD and improved LTP. It seems that capsaicin and other TRPV1 agonists regulate synaptic plasticity in both directions, keeping us on balance and always learning.

Reproduction

Put simply, without capsaicin channels none of us are here to read this great stuff. TRPV1 activity, through various agonists, is important for sperm motility and fertilization of the egg. The sperm meets the egg and here we go - is that the whole picture? Nope. It takes a lot to arrange their introduction, and some of it involves TRPV1 channels.

You ever wonder why the testicles are kept outside the trunk of the body? It’s to keep the sperm cool – heat kills sperm. TRPV1 receptors sense high heat and institutes local reactions to cool the sperm. A 2008 study showed that TRPV1 knockout mice had much higher levels of sperm death in the testicle when the temperature was raised. It didn’t make the mice sterile, but it was close.

On left is a cartoon of sperm capacitation, making it ready tofertilize travel to the egg. The loss of the cholesterol coat isimportant for increasing motility and for finishing the signals that point out whee the egg is. The acrosome is also prepared here, but there are more acrosome changes in the right image showing the

acrosome reaction. Here, the spem head becomes a weapon, dissolving the outer layers of the egg and stabbing it for entry.

So TRPV1 is important for sperm even before they start their journey. The first thing that happens after the sperm enters the female reproductive tract is that they undergo a process called capacitation. These changes make the sperm ready to bind to the egg. TRPV1 and its agonist anandamide (same as in LTD) are important late in capacitation. They prepare the sperm for transfer of the DNA to the egg.

TRPV1 and endocannabinoid receptors are also responsible for the increase in sperm motility after capacitation. The sperm swim toward the egg, but how do they know where she is? There are many signals, including osmolarity differences, hormones, temperature changes, pH changes, and liquid currents. We have seen that several of these (pH, temp., hormones, osmosis) are sensed by TRPV1 channels.

It’s been shown that TRPV1 on the sperm post-acrosomal and head regions are important for sperm motility. A 2013 study showed that inhibiting TRPV1 slowed down fish sperm. And in a 2013 study of infertile men, the motility of the sperm in men with low levels of anandamide was decreased.

Strangely, even though capacitated sperm are thermotactic (swim toward higher temperatures), this is one time where it DOESN’T involve TRPV1/capsaicin receptors. It still involves calcium, but the flux is through a different receptor system.

Once the sperm finds the egg, it undergoes the acrosome reaction. This makes it possible for the sperm - only one mind you - to enter the egg. A 2009 study indicated that anandamide and TRPV1 are crucial for the acrosome reaction as well.

From inside the male, to inside the female, to inside the egg, capsaicin receptors are crucial for making tiny humans. It doesn’t get more important than that. What I don’t know is if eating peppers affects any of this. Would a habanero make you more fertile or less?

The PSA test (prostate specific antigen) can be used

for monitoring treatment of prostate disease as well

as for diagnosis of prostate cancer in conjunction with

other tests. The tests measure s aprotein produced by

the prostate that is often elevated in those with prostate

cancer. PSA can be free or bound to a protein. You want

the free:bound ratio to be high, and low ratio is more

indicitive of cancer. However, there are noncancerous

reasons for an elevated PSA, so don’t go nuts if your

levels ar higher than normal (score of 4 ng/ml).

Cancer

In cancer we see the dual nature of TRPV1 again. In some cases it prevents or stops cancer, while in others, capsaicin might contribute to cancer.

Prostate cancer has been studied a lot with respect to TRPV1. Capsaicin, in particular, has an effect on prostatic cancer cells. It kills the cells and reduces tumor size in mice. However, in humans, little work as been done. One epidemiology study found that Nigerians that eat more peppers have a lower rate and later onset of prostate cancer.

In addition, a single study followed a man whose prostate cancer returned after several disease free years. His PSA value(prostate specific antigen, a sign of cancerous growth) started to double weekly, so he started taking 2 ml habanero sauce once or twice week. His PSA value increases slowed by half. He stopped and they sped up. He started daily habanero sauce and the PSA dropped. Sounds like a treatment to me.

The mechanisms of capsaicin action on prostate cancer cells has been determined in in vitro work. They are both TRPV1 dependent and TRPV1 independent. (studies) Capsaicin increases ROS, induces apoptosis, destabilizes membranes, throws off ion balances…basically everything capsaicin stopswhen used for protective hypothermia (from last week).

It isn’t just prostate cancer where capsaicin may help. In a mouse model of lung cancer, giving capsaicin prevent the lung tumors from forming by increasing apoptosis in the cancerous cells. Whether this is TRPV1 dependent or independent was not discussed.

But there is a darker side to capsaicin and TRPV1 in prostate cancer. The agonists have a small window of effectiveness. Low levels actually promote cancer growth, but higher levels cause cell cycle arrest and apoptosis. In one study, 10 µM capsaicin actually created prostate tumors in mice.

Where do you come down on the question of whether

peppers are good for you or not? Do they cause cancer

or prevent it? Do they cause pain or prevent it? I think

that as with most things, moderation is the key. Too

much of anything is bad for you, except maybe this blog.

One thing I do know; we have sharp canines for a reason -

we were meant to eat meat. This statement is why

she has that look on her face.

The bad news continues... maybe. Several studies have linked capsaicin to stomach, oral cavity, and gall bladder cancer. One epidemiologic study showed that US counties with higher Mexican American, Cajun, and Creole populations have higher rates of these cancers, and it just so happens that these are the folks that eat more chili peppers. Some skin cancers are also associated with capsaicin. This is a bit disconcerting considering the number of topical capsaicin pain creams on the market.

In squamous cell skin cancer, capsaicin can sometimes stunt the growth of tumors via apoptosis, but the mechanism seems to be TRPV1 independent, since a TRPV1 antagonist brings the same effect. The take home message is that TRPV1/capsaicin effects may be diet, individual, cancer specific. This will make it hard to develop therapeutics.

Next week - now its time to start talking about cool receptors. Like how the cigarette companies use "cool" to sell smokes.

Lee JH, Park C, Kim SJ, Kim HJ, Oh GS, Shen A, So HS, & Park R (2013). Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability. Experimental & molecular medicine, 45 PMID: 23470714

Amoako AA, Marczylo TH, Marczylo EL, Elson J, Willets JM, Taylor AH, & Konje JC (2013). Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Human reproduction (Oxford, England), 28 (8), 2058-66 PMID: 23697839

Gonzales CB, Kirma NB, De La Chapa JJ, Chen R, Henry MA, Luo S, & Hargreaves KM (2014). Vanilloids induce oral cancer apoptosis independent of TRPV1. Oral oncology PMID: 24434067

Anandakumar P, Kamaraj S, Jagan S, Ramakrishnan G, & Devaki T (2013). Capsaicin provokes apoptosis and restricts benzo(a)pyrene induced lung tumorigenesis in Swiss albino mice. International immunopharmacology, 17 (2), 254-9 PMID: 23747734

For more information or classroom activities, see:

Cochlear amplification –

http://www.slideshare.net/lynnroyer/hair-cell-function-and-purpose

https://www.bcm.edu/healthcare/care-centers/otolaryngology/patient-information/how-ear-works/inner-outer-hair-cells

http://neuroscience.uth.tmc.edu/s2/chapter12.html

http://www.d.umn.edu/~jfitzake/Lectures/UndergradPharmacy/SensoryPhysiology/Audition/OHCFunction.html

http://147.162.36.50/cochlea/cochleapages/theory/hcells/hcells.htm

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=5&ved=0CFQQFjAE&url=http%3A%2F%2Fwww.bcs.rochester.edu%2Fcourses%2Fcrsinf%2F221%2FARCHIVES%2FS11%2FCochlear_Amplifier.pdf&ei=YYoXU4X4NYS0ygHQ6oD4CA&usg=AFQjCNFHqR7wKBFlhBt1pSD9KRyFyt74Vg&sig2=G0wcwNIEzpSuSt5ZMkotlA&bvm=bv.62286460,d.aWc

http://medicalxpress.com/news/2012-12-cochlear-amplification-optical-technique.html

http://www.neurophys.wisc.edu/auditory/johc.html

http://science.howstuffworks.com/life/human-biology/hearing5.htm

Tinnitus –

http://www.dangerousdecibels.org/education/resources/dangerous-decibels-dvd/

http://www.ata.org/for-patients/student-zone

https://faculty.washington.edu/chudler/chhearing.html

http://faculty.washington.edu/chudler/hearing.html

http://www.ata.org/

http://www.webmd.com/a-to-z-guides/understanding-tinnitus-basics

http://www.mayoclinic.org/diseases-conditions/tinnitus/basics/definition/con-20021487

http://www.nlm.nih.gov/medlineplus/tinnitus.html

http://www.medicinenet.com/tinnitus_ringing_in_the_ears/article.htm

Sperm capacitation –

http://embryo.asu.edu/pages/sperm-capacitation

http://www.pbs.org/wgbh/nova/education/activities/2811_baby.html

http://www.keytoconceive.com/sperm-capacitation.php

http://www.glowm.com/section_view/heading/Sperm%20Transport%20and%20Capacitation/item/315

http://www.youtube.com/watch?v=rrFsTdfe2qw

http://www.wisegeek.org/what-is-sperm-capacitation.htm

http://www.youtube.com/watch?v=-J9deipbdSI

http://community.babycenter.com/post/a36676870/capacitation

Acrosome reaction –

http://education-portal.com/academy/lesson/acrosome-reaction-function-definition.html#lesson

http://www.youtube.com/watch?v=5-g8dLcERlM

http://www.youtube.com/watch?v=-jLyzWrSTOA

http://www.stanford.edu/group/Urchin/acrosome.htm

http://www.embryology.ch/anglais/dbefruchtung/akrosom02.html

http://worms.zoology.wisc.edu/urchins/SUfert_acrosome.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181525/

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/reprod/fert/fert.html

#zoology #TRPV1 #tinnitus #sperm motility #fertilization #exception #cochlear amplification #capsaicin #capacitation #cancer #apoptosis #animal #acrosome reaction

Chili Peppers Run Hot And Cold

Biology concepts – obesity, brown adipose tissue, agonist/antagonist, protective hypothermia, hyperthermia, reactive oxygen species, ischemia, hypoxia

When The Wizard of Oz was released in 1939, it just barely turned a profit. The '39 version was the third attempt at filming the children’s classic, and the first two efforts had not fared much better.

I don’t see how people didn’t take to the Wizard of Oz right away.

It had new technology for the movies, a good villain, and all those

little people. The tin man on the left was played by Jack Haley, but

originally it was supposed to Buddy Ebsen (Jed from the Beverly

Hillbillies). Unfortunately, the lead metal in the makeup almost

killed him during the makeup/costume tests. Glenda the good witch

(Billie Burke) had that squeaky voice. She only began acting

after her husband, Flo Ziegfeld, Jr. (son of the Ziegfeld Follies

creator), went belly up on Black Monday in 1929.

Over time, what was first considered bad has become a classic. In what many people consider the best year ever in film, The Wizard of Oz is now a favorite among favorites, more than Goodbye Mr. Chips, Mr. Smith Goes to Washington, Stagecoach, or even Gone With the Wind – all produced in 1939.

It’s smart to hang on to useless things and knowledge, something might change. For Oz – it was television. For some reason, this film translated better to TV than it did the big screen. The Library of Congress now rates it as the most viewed film ever. And it wasn’t even shown on TV until 1956. The weird part – very few people in 1956 owned a color television, so Dorothy’s entrance into the land of Oz was no big deal for most folks until the late 1960’s.

Why am I telling you this story? Because the same thing happens in biology and medicine. Problems can become assets if the right environment is created or the proper setting is found. We've been discussing the capsaicin receptor, TRPV1, for some weeks, and this is where I find a negative being turned into a positive.

As you know, the TRPV1 capsaicin receptor is primarily a heat sensing receptor for thermoregulation of the body. If activated by noxious (painful) high temperatures, it generates a pain signal and initiates a cooling program for the body, including sweating.

In an effort to block TRPV1 to create analgesia (no pain), the problem has been that blockers also stop thermoregulation and the patient overheats. This prevents most TRPV1 antagonists (substances that bind the receptor but don’t allow function) from being used as analgesics. But what about in other situations?

I was wondering if TRPV1 antagonists might be helpful in obesity, by helping burn off some fat through increased cooling activity. If they are indeed helpful, nobody knows about it yet. I couldn’t find even one paper that studied TRPV1 antagonists as a way to induce increased energy expenditure and weight loss. In fact, I learned just the opposite. Capsaicin and other TRPV1 agonists might help with weight loss.

On the left is brown fat and white fat. You can see that brown fat

actually looks browner because of all the mitochondria that it

contains. White fat contains a lot more lipid. The right cartoon

shows that a cold challenge initiates uncoupled fat metabolism in

brown fat, creating heat. But the cold also releases more fatty acids

from white fat, which can then be burned by the brown fat. The

involvement of bone comes from bone breakdown. Breakdown

releases a protein that stimulate white fat to release fatty acids,

this would provide energy for the brown fat.

We have discussed how TRPV1 activation by noxious heat helps to cool the body, but it turns out that noxious cold leads to TRPV1 activation as well, but in these cases, it brings an increase in heat production. So TRPV1 can cool you down or warm you up as needed. Pretty cool. You'll have to wait a few weeks to find out how a heat receptor senses noxious cold.

The heat induced by cold comes from increased activity of brown adipse tissue (BAT) – brown fat. We have talked about BAT before, how it is especially important for infants because they lose heat so easily. Brown fat has lots of mitochondria, but they don’t make ATP. They convert all the energy they burn into heat.

New research is showing that BAT can be important to adults as well. Those people that have more BAT tend to have less white fat, the kind that makes you bigger. What is more, a 2013 paper shows that cold temperature exposure can help create more BAT, and this effect is mimicked by capsaicin and other TRPV1 agonists.

If you expose adults to mildly cold temperatures for six hours a day, they start to make more BAT and this means they burn more energy for heat; therefore less energy is left to be stored as white fat. But the study also showed that giving the people capsaicin for weeks in a row generated the same increase in BAT and stopped white fat accumulation.

One mechanism involved is that TRPV1 agonists stimulate an increase in uncoupling protein (UCP) expression in BAT. This is the protein that permits the BAT mitochondria to produce lots of heat instead of lots of ATP and a little heat. The uncoupling protein activity in BAT uses excess calories to produce heat, so those calories are not available to make fat.

Here is how a stem cell becomes a fat cell (adipocyte).

The mesenchymal cell can go two directions, one

toward fat and one toward muscle. But notice you can

get to a brown fat cell through the pathway meant for

muscle cells. PG stands for prostaglandins; different

profiles of prostaglandins lead to a decision to become

a brown fat cell or a white fat cell. We know this picture

is incomplete now, because we have evidence that

TRPV1 agonists can drive the decision between

brown fat and white fat.

But there may also be another mechanism at work. A 2014 study in laboratory petri dishes shows that cells destined to become white fat cells can be stopped from changing by capsaicin. In cells called preadipocytes, capsaicin stopped their proliferation (dividing to become more cells) and their differentiation (changing) to become full-fledged adipocytes (fat cells). Another study (2012) showed that in liver, capsaicin could prevent the accumulation of white fat build up (called fatty liver) and could actually induce UCP protein expression in some fat cells, turning them into liver BAT. Amazing.

This all sounds fine, but the proof is in the pudding, so to speak. Capsaicin and other TRPV1 agonists have been shown to reduce white fat and total body mass in rabbits fed a high-fat/1% capsaicin diet, in mice fed a high sucrose diet, and in human patients kept cold or fed hot. Tomorrow I’m going to start eating hot peppers in a cold house – I’ll shrink away before your eyes.

What about on the other end of the thermometer? People freeze to death when they get too cold, and TRPV1 agonists will cool you off when too warm. No TRPV1 activity causes a reactive hyperthermia, and too much TRPV1 activity will induce a reactive hypothermia. But is there a time when inducing cold in a body with capsaicin would be a good thing?

Would we be talking about it if there weren’t an exception? It's called protective hypothermia, and it has become a very important treatment adjunct during stroke and some over conditions.

Ischemia (left) is often associated with coronary (heart) arteries.

Ischemia means a reduction in blood flow to a tissue or the whole

body. With less blood flow comes less oxygen, so tissue cells suffer.

Several mechanisms can lead to a lessening of blood flow. On the

right is hypoxia, which is often used when referring to the brain or

specific organs. Hypoxia is a reduction in oxygen to the tissues,

whether it comes from a reduction in blood flow or some other

reason, like fewer red blood cells, lower oxygen in the air, etc.

Protective hypothermia is an induced cold that is used to protect tissues from post-ischemic injury. When there is a reduction in blood (ischemia) or oxygen (hypoxia) to a tissue or organ, the cells are starved for oxygen and then become starved for ATP (you need oxygen to make ATP). With lower oxygen over time, either from low oxygen or reduced blood flow, the tissues get used to having lower oxygen levels.

Getting used to it would include down-regulating the systems that would normally combat the damage that could be caused by reactive oxygen species(ROS). Whenever oxygen is being used in tissues, ROS are an unfortunate by-product. Their name tells you that they’re reactive, which means they can react with many molecules in the cell and they will do significant damage.

When normal blood flow or oxygen perfusion is re-established, the sudden increase in O2 causes a spike in ROS (reperfusion injury) – until the cell can ramp up its antioxidant capabilities again. What medicine needs to do is find a way to increase the O2 without increasing the ROS damage.

Cold seems to do the trick. Reducing the temperature of the body reduces cell death and ROS after cardiac arrest, stroke, neonatal encephalopathy, or traumatic spinal/brain injury. Why? There have been a few ideas why.

The old hypothesis was that the lower temperature would reduce cellular metabolism, so that there is less need for O2. This would imply that the lower the temperature, the better. But very low temperatures might lead to injury or damage on their own. Also, extended cold could bring pneumonia or promote sepsis. Maybe colder isn’t always better.

There are many ways to get a perfusion injury when

oxygenation of the tissues is reestablished after hypoxia.

We talked about the free radicals (ROS) in the post. The

other injuries are a bit less obvious. We mentioned the

problems with membranes and the increase in apoptosis.

The other two are related to spasm of the muscle cells in

the vessels which would again reduce oxygen levels, and

a nonspecific activation of coagulation and cell killing that

would lead to damage as well.

Now scientists think protective hypothermia works in a couple of different ways. Colder temperatures bring a neuroprotective effect by preventing apoptosis (programmed cell death). Less O2means less ATP being made, and a decrease in ATP usually means that the mechanisms for maintaining proper ion movements in and out of the cell are hampered. Increased ion flux triggers apoptosis. So lower temperature brings less ion flux, less damage, and less cellular suicide.

Even a small decrease in temperature can stabilize the cell membrane independent of ATP levels. This makes sense; membranes are mostly lipid, and lower temperatures make fats stiffer – like cold butter. This will decrease ion movement across the membrane and reduce cell damage.

Lastly, decreased body temperature brings less reperfusion injury. In this case, maybe the old hypothesis was correct. Colder tissues metabolize less, so less oxygen will be needed and less ROS will be produced.

So cold is helpful, but how do you do it? You can lower the body temperature by using cooled IV fluid, cold mist in the nose, or even wrapping specific body parts in cooled blankets. But perhaps TRPV1 agonists could help cool the body from the inside.

As of early 2014, the evidence for TRPV1 agonists is only in mouse models, but it’s looking good. A study in 2011 showed the an injection of capsaicin into the abdominal cavity three hours before inducing hypoxia reduced the volume of dead tissue and the amount of apoptosis in the brains of the mice.

This is the fruit of the Evodia rutaecarpa Bentham plant. It has been

used in Chinese herbal medicine for hundreds of years. We are

starting to learn why it does what it does. It has been shown to be

an anti-cancer, anti-obesity, anti-vomiting, anti-hypertension

anti-ulcer, anti-pain drug. Five thousand years of

culture leads to good drugs like this.

Two 2013 studies added strength to the 2012 study. One experiment used a Chinese herbal medicine that contained a chemical called evodiamine. It had been known that evodiamine helped in stroke victims, but we didn’t know why. Evodiamine was shown to be a TRPV1 agonist in 2012, and the 2013 study showed that after a stroke, the agonist increased cell survival mechanisms and reduced apoptosis.

The other study from 2013 showed that capsaicin also helps in reperfusion injury. Mice were given strokes by blocking an artery in the brain and then unblocking it to replenish the blood and oxygen. Injecting capsaicin within 90 minutes of the re-establishment of blood flow produced a mild hypothermia, reduced the volume of dead tissue in the brain, and increased neural function. This didn’t occur in mice without TRPV1, so we know the capsaicin receptor was responsible. Sounds like emergency rooms are going to start stocking hot peppers.

Today we discussed interesting uses for capsaicin and its receptor in temperature-related functions. Next week, some weird functions for TRPV1 that have little or nothing to do with temperature.

Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, & Saito M (2013). Recruited brown adipose tissue as an antiobesity agent in humans. The Journal of clinical investigation, 123 (8), 3404-8 PMID: 23867622

Feng Z, Hai-Ning Y, Xiao-Man C, Zun-Chen W, Sheng-Rong S, & Das UN (2014). Effect of yellow capsicum extract on proliferation and differentiation of 3T3-L1 preadipocytes. Nutrition (Burbank, Los Angeles County, Calif.), 30 (3), 319-25 PMID: 24296036

Yoneshiro T, & Saito M (2013). Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Current opinion in clinical nutrition and metabolic care, 16 (6), 625-31 PMID: 24100669

Muzzi M, Felici R, Cavone L, Gerace E, Minassi A, Appendino G, Moroni F, & Chiarugi A (2012). Ischemic neuroprotection by TRPV1 receptor-induced hypothermia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32 (6), 978-82 PMID: 22434066

Cao Z, Balasubramanian A, & Marrelli SP (2014). Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion. American journal of physiology. Regulatory, integrative and comparative physiology, 306 (2) PMID: 24305062

For more information or classroom activities, see:

Brown adipose tissue –

https://exploreb2b.com/articles/how-does-brown-fat-help-to-reduce-obesity

http://www.medicalnewstoday.com/articles/240989.php

http://www.webmd.com/diet/features/the-truth-about-fat

http://www.landesbioscience.com/curie/chapter/623/

http://diabetes.diabetesjournals.org/content/58/7/1482.full

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/misc_topics/brownfat.html

http://www.marksdailyapple.com/a-primal-primer-brown-adipose-tissue/

http://wholehealthsource.blogspot.com/2013/07/brown-fat-its-big-deal.html

Protective hypothermia -

https://www.google.com/#q=protective+hypothermia

http://www.qscience.com/doi/full/10.5339/qmj.2012.2.19

http://ccforum.com/content/16/S2/A2

http://www.ctnow.com/health/ctn-woman-dead-revived-with-cpr-hypothermia-web,0,3890140.htmlstory

https://www.med.upenn.edu/resuscitation/hypothermia/

http://emedicine.medscape.com/article/812407-overview

#zoology #TRPV1 #taste #protective hypothermia #obesity #lipid #ischemia #hypoxia #hyperthermia #exception #capsaicin #brown adipose tissue #animal