When you reach into a bucket of ice, open your front door on a snowy day, or feel the tingle of menthol toothpaste, a protein in your nerve cells called TRPM8 springs into action, opening like a tiny gate to send a "cold" signal to your brain. Now, UC San Francisco researchers have discovered how TRPM8 changes its shape when exposed to cool temperatures. The work, published in Nature, could one day be used to help treat pain that is triggered by cold. It also answers a long-standing question about why birds—which also have TRPM8 in their nerve cells—are far less cold sensitive than mammals.

"Everyone always wants to know how temperature sensing works, but it turns out to be a very technically challenging question to answer," said co-senior author David Julius, Ph.D. "So, to finally have insight into this is really very exciting."

Julius is the Morris Herzstein Chair in Molecular Biology and Medicine, chair of Physiology, and recipient of the 2021 Nobel Prize in Physiology or Medicine. He won the prize for discovering TRPV1, which enables nerves to sense capsaicin, the spicy heat of chili peppers.

A key to the cold discovery was being able to see proteins in motion.

"For decades, structural biology has focused on capturing proteins in stable, frozen states. This work shows that to truly understand how a protein functions, you also have to understand how it moves," added Yifan Cheng, Ph.D., professor of biochemistry and biophysics and an investigator at the Howard Hughes Medical Institute (HHMI) who co-led the work.