In 2021, David Julius, Ph.D. was co-winner of the Nobel Prize in Physiology or Medicine for identifying a receptor known as TRPV1 that detects the heat of chili peppers, capsaicin. Now, his team has revealed more about how a molecule called TRPM8 detects cold stimuli, like what we feel on a cool day or the effects of menthol. TRPM8 is found in neurons, and when cold is sensed, it opens up, sending the signal that cold has been detected to the brain. These findings, which were reported in Nature, could also open up new treatment options for pain caused by cold exposure.
"Everyone always wants to know how temperature sensing works, but it turns out to be a very technically challenging question to answer," said Julius, co-corresponding study author and Chair of Molecular Biology and Medicine, and of Physiology at the University of California San Franscisco, San Francisco (UCSF). "So, to finally have insight into this is really very exciting."
In this work, it was essential for the researchers to learn how TRPM8 moved while it was activated, by temperatures under roughly 79 degrees Fahrenheit. The receptor sits in the outer membrane of neurons, however, and has been too fragile to analyze as it changed shape. To overcome that challenge, the investigators observed TRPM8 while it was still embedded within cell membranes.
The researchers used both cryo-electron microscopy (cryo-EM) to take images of TRPM8 while frozen in different configurations. They also used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to see how TRPM8 moved as temperatures dropped. These efforts revealed the structures and forms of TRPM8 as it opened.
When exposed to cold, one part of TRPM8 seems to be stabilized, triggering another key portion to move. This action lets a lipid slip into that place, keeping the channel open and sending a continuous signal.
Birds are less sensitive to cold than many other animals. The researchers also compared the human and bird versions of TRPM8, and found specific parts that detect cold.
"The lessons we learned in studying this channel are actually very broadly useful," said co-corresponding study author Yifan Cheng, Ph.D., a professor of biochemistry and biophysics at UCSF and Howard Hughes Medical Institute (HHMI) investigator. "Dynamic behavior is critical for the function of many proteins, and you can't understand dynamic behavior from one snapshot of a protein's structure."
