How Do We Sense Temperature and Pressure?
- Published2 Nov 2020
Throughout the day, we feel, taste, see, hear, and smell things, never thinking much about how these senses work. But that’s not the case for David Julius of the University of California, San Francisco, and Ardem Patapoutian of the Scripps Research Institute. These scientists have made it their mission to understand how our sensory systems build our experience of the world.
While scientists unraveled the neural basis of sight and smell decades ago, temperature and pressure remained a mystery. Using capsaicin, the chemical in chili peppers responsible for the sensation of heat, Julius uncovered an ion channel called TRPV1 in 1997 that is activated by high temperature. Thirteen years later, Patapoutian discovered a group of pressure-sensing ion channels called Piezos, which are not only responsible for pressure sensing in skin, but also in blood vessels, lungs, and more.
The work, which earned them the 2020 Kavli Prize in Neuroscience, has helped scientists understand how the body detects temperature and pressure, potentially driving efforts to develop future pain treatments.
How did you first get interested in the sensory systems?
Photo courtesy of UCSF
David Julius: I became interested in neurotransmitter receptors — not much was known about them at the time from a molecular point of view. Except for a few examples, there was little information about the structure or sequence of these receptors. Very few genes encoding such receptors had been isolated and so we knew relatively little about their identities, how many subtypes existed, or the genetic basis for such subtype diversity.
I became especially interested in understanding the genetics of serotonin receptors, which are targets for LSD and natural hallucinogens like ergots and psilocybin. That was the unifying interest that got me involved in using natural products to understand other systems.
Ardem Patapoutian: As a postdoc, I was studying how the sensory neurons develop. How do they become different than other types of neurons? How does a touch neuron decide to be a touch neuron? How does a pain neuron focus on pain? When I started my lab, it was a realization that these neurons do something pretty phenomenal. They convert these mechanical or thermal energies into electrical signals, and how they do this was still not known. I thought it was a major unanswered question with massive implications for pain.
David, in 1997 your lab identified the TRPV1 ion channel, which is activated by heat and capsaicin. What did this discovery mean for your lab?
DJ: The discovery of TRPV1 provided a molecular explanation for commonly experienced but enigmatic sensations: temperature and the “hotness” of chili peppers. It also revealed how we detect a physical stimulus. More generally, identification of TRPV1 catalyzed lots of excitement about understanding physiological roles for TRP channels in mammals since these proteins had previously been studied mostly in insects, where they play an important role in vision. Altogether, this moment set my lab on a course to delve deeper into ion channel physiology and pain biology — areas that continue to captivate us today.
Photo courtesy of Scripps Research
Ardem, you and Bertrand Coste discovered Piezo1 and 2 proteins in mouse cells in 2010. How did you find these proteins?
AP: There’s all this physiology that depends on pressure sensing, mechanical force sensing, and yet, the ion channel identity was not known. We asked: Can we find a cell line that electrophysiologically responds to pressure? To test this, we literally poked the cell while recording its electrical current. It was a very difficult project because we had to set up this screen to record cells and knock out each ion channel candidate at a time.
The first 72 candidates Coste tested were all negative, so it took a whole year of screening to finally find the one [ion channel] that, when it’s knocked out, this activity of touch sensitivity in the cell goes away. And that was Piezo1, which he named from the Greek word píesi, meaning pressure. And it just so happens that Piezo1 has a sister, a related protein — Piezo2 — and that ended up being the sensor for touch.
How might your research help scientists find new pain treatments?
DJ: TRPV1 and other “nociceptive” channels play important roles in not only acute pain, but also persistent pain mechanisms, especially in the context of tissue injury and inflammation. As such, they represent promising targets for new classes of analgesic drugs, which are designed to specifically relieve pain, that could be used to treat osteoarthritic pain (the most common type of arthritis), GI pain, or other persistent inflammatory pain syndromes.
AP: I really am fond of this new analogy I’m using — finding receptors is like identifying a doorknob that gets you into a room. And so, the room is something you want to understand and it’s mysterious to us, right? In this case, the room could be understanding pain, or it could be understanding touch, or it could be anything. So, the receptor is like the first entry point — it allows you to open the door and start investigating what's in this room.
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