Days after being recognized with the Nobel Prize in Medicine for his findings on the perception of heat and cold, Professor David julius explains the importance of studying all the components of “the inflammatory soup” that help to alert the body to wounds.
Julius, professor and head of the department of physiology at the University of California, in San Francisco, (UCSF), was announced as the winner last week along with his colleague from Scripps Research, Ardem Patapoutian, for his discoveries of receptors for temperature and touch.
In the late 1990s, Julius’ laboratory identified the TRPV1 protein, a member of what are known as TRP channels (transient potential receptors) responsible for detecting intense heat as in hot peppers or chili, and subsequently the TRPM8 protein, which does the same for the cold.
-Why are TRP channels important? What would have happened to humans if we didn’t have these receptors?
David Julius (DJ): It’s hard to say. It is a family of molecules very broad that perform functions ranging from absorbing the calcium for the cells until you feel the pain. There are people who have mutations in TRPV4, which is important for the development of bones, and therefore have defects in the skeleton or in the nervous system. What I can say is that if someone were missing all TRP channels, that person would be dead.
What if only TRPV1 and TRPM8 (the two identified by Julius and that perceive heat and cold) were missing?
DJ: So what I can say is that when we remove these receptors from laboratory mice, they don’t die. They have deficits, but they live, albeit in a very controlled environment. These receptors play a role in detecting temperature changes, so what would happen is that you would have trouble knowing what the ambient temperature is, but not the body temperature.
Q: Is that something that has been experimented with?
DJ: Yes. When a person is given drugs that block TRP channels, they have a hard time detecting something that is hot. This worries pharmaceutical companies, who do not want someone to burn themselves with, for example, a cup of coffee that is too hot because they no longer perceive it sensually.
Q: So we can live without pain?
DJ: There are people with mutations in other types of molecules that make them unable to perceive any pain stimulus. When they are little, you have to be very careful and watch over them, but if they get through that phase and learn what things to watch out for even if they don’t feel pain, they can live a pretty good life. When the molecules that we have studied are removed, only some components of pain are being removed, so it is not a dramatic deficit.
Q: And are these molecules present in all animals?
DJ: In general, yes.
Q: How are the molecules to perceive temperature (TRPV1 and TRPM8)?
DJ: We always describe them as a donut on the cell membrane. They are at the end of a sensory nerve in the skin or tongue, for example, and are shaped like a small donut. Under normal temperature circumstances, the donut hole is closed, but when they come in contact with something hot or cold, the TRP channel is activated and the hole widens.
Q: What then goes through that hole?
DJ: Calcium and sodium ions enter the cell through the hole, generating electrical currents that go to the neurons and that’s when we react and say: “I got burned!” or “How cold this is!”
Q: What good is that to us?
DJ: One of the main functions of pain is to indicate when we have hurt ourselves so that we can protect that area. Let’s imagine we go to the beach and burn our skin. Then the back becomes inflamed and becomes very sensitive to changes in temperature, so that when we shower with hot water, it gives us the feeling that we are burning. What that is telling us is that this part of the body is injured and that we must protect it until it heals.
Q: In addition to heat, TRPV1 also reacts to contact with acid. Why?
DJ: Heartburn is, like heat, another component of what we call “the inflammatory soup.” It is an agent that contributes to inflammation to increase the sensitivity of that part of the body when an injury has occurred. It is very important to study all the ingredients in this “soup” to be able to create drugs that are effective in reducing pain without blocking basic functions such as the perception of heat and thus prevent people from burning without noticing it.
Q: You started your investigations with the capsaicin chemical compound, found in hot peppers like chili. Why did you choose precisely that compound?
DJ: We chose capsaicin because we wanted to study pain in general. Chili is a product whose spices have been used as medicine for a long time, and we knew that capsaicin is a very powerful activator of nerve fibers that act on pain sensation.
P: And looking for pain, they found temperature …
DJ: Yes. It wasn’t until we identified the TRPV1 receiver that we understood that it was sensitive to heat.
Q: Are TRPV1 and TRPM8 responsible for different people having greater or lesser sensitivity to cold and heat?
DJ: Genetics has not yet answered this question, but there is a study that I think is very interesting according to which people who live in Nordic climates have differences in TRP channels compared to those who live in warmer climates.
Q: What are you currently working on?
DJ: We are still fascinated by these questions. Half of my lab is interested in delving deeper into these molecules and the biophysical infrastructure; and the other half, in understanding the molecular and cellular components of the different types of chronic pain.
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