That minty-fresh feeling? Scientists now know how our bodies feel cold
Scientists have finally pinned down the mechanism behind cold- and menthol-sensing proteins
Olga Yastremska/Getty Images
What do the feeling of an ice cube against your skin and the cool minty blast of toothpaste have in common? Both activate our body’s cold-sensing nerves. But until now, scientists hadn’t pinned down exactly how that happened at the level of individual proteins in our cells.
David Julius, a structural biologist at the University of California, San Francisco, shared the 2021 Nobel Prize in Physiology or Medicine for his discovery of a protein called TRPV1 that lets us feel the heat of chili peppers. Now, in a recent study published in Nature, he and his colleagues have taken a close look at a protein that let us feel the cool of menthol. Understanding this cold-sensing protein could one day lead to better therapies for cold hypersensitivity that often troubles people undergoing certain types of cancer chemotherapies. But the protein has been way trickier to handle than its heat-sensing cousin.
The protein in the new study is called TRPM8, and it acts as the body’s primary receptor for sensing both menthol and cold temperatures. It’s a channel embedded in cell membranes that opens when triggered by dropping temperatures or cooling agents. When opened, it lets in ions that trigger the nerves to send a “cold” signal to the brain. Scientists have known what TRPM8 does for years, but they didn’t understand how it worked, exactly.
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The TRP8 protein is much harder to study than TRPV1, the chili-pepper-heat-sensing channel, Julius explains. For starters, the cold-sensing protein loses its natural behavior when it is extracted from cell membranes using standard laboratory detergents. To figure out its mechanism, Julius’s team had to somehow extract it from cells without ruining the very properties the researchers were trying to understand.
Many kinds of receptors are triggered by molecules called ligands that fit into them like a key fitting into a lock: the key goes in the lock, the lock opens, and that’s it. Scientists can easily study these receptors by imaging the “lock” before and after the key goes in, and it’s easy to infer what happens in between the closed and open states. (The ligand latches and opens the channel.) The problem with temperature-activated receptors such as TRPM8 is that because the temperature acts on the entire protein, there is no such simple key. Taking before and after stills doesn’t tell you what, exactly, happened in between those two states. So to capture the TRPM8 in motion, the team had to shoot a movie.
The scientists used high frequency ultrasound pulses to extract the TRPM8 from human embryonic kidney cells without damaging the cells’ environment. Next, they mapped the protein’s structure using a method called cryogenic electron microscopy: they flash-froze the channel as it morphed from fully closed to fully open. To understand which parts of the TRPM8 were moving during those transitions, the scientists tracked it using a technique called hydrogen-deuterium exchange mass spectrometry (HDX-MS), which “tells you what parts of the protein are particularly dynamic,” Julius explains. By combining these two techniques, the team collected a series of still frames for a molecular movie and learned what exactly was in motion in between those frames.
“The key innovation was this combination of techniques,” says Rachelle Gaudet, a professor of molecular and cellular biology at Harvard University, who was not involved in the study. “Together these approaches yield the clearest picture yet of how TRPM8 reshapes itself in response to cold,” she adds.
The team could see that the protein forms a doughnutlike shape; the lining on the inside of the doughnut hole determines whether the hole is open or closed. When the temperature exceeds 26 degrees Celsius (79 degrees Fahrenheit), the TRPM8 ion permeation channel—the hole in the doughnut—is closed. As the temperature drops, the cold causes the protein to shift into a more stable state in which one of its key structural pillars bends sharply, breaks away from its neighbor and straightens out. Finally, this newly straightened pillar slides upward, like a mechanical latch, and pops the gate wide open so the receptor can send its cold-response signal. “This is something we have never seen before,” notes Yifan Cheng, a structural biologist at the University of California, San Francisco, and a co-author of the study.
To validate their findings, the researchers compared the mammalian TRPM8 with a version found in birds, which is mostly insensitive to cold despite its nearly identical appearance. They found that the mammalian channel, unlike the avian one, is highly dynamic. “Because the bird channel is already very stable, it does not respond to the cold temperature to be further stabilized,” Cheng says. It turned out the key to the cold-temperature sensitivity of the mammalian TRMP8 channel was its restlessness.
Julius and his colleagues also see how their findings can translate into better therapies for humans. “Cold hypersensitivity is a major issue for people who undergo cancer chemotherapy,” Julius says. Understanding the exact ways proteins like TRPM8 or TRPV1 work could help scientists develop specific blockers that would treat hypersensitivity without depriving people of normal temperature sensation. “I think it’s a good example for the community to say, ‘Maybe we can stretch our wings a little bit and start getting more sophisticated in how we look at protein structure,’” Julius says.
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