Summary: For the first time, researchers have captured the dynamic molecular behavior of TRPM8 — the ion channel in sensory neurons that detects cold and mediates the cooling sensation of menthol. Using a combination of rapid freezing (cryo-EM) and real-time motion mapping (HDX-MS), the team reconstructed how this channel changes shape and how a lipid molecule locks its cold-sensing gate open.
The study shows that cooling stabilizes a specific region of TRPM8, allowing a nearby lipid to slide into a newly formed pocket and act like a deadbolt that preserves the open state. This mechanism explains why birds are less sensitive to cold than mammals and suggests new directions for treating cold-triggered pain conditions.
Key Facts
- Activation threshold (~79°F): TRPM8 begins its conformational change and opens when temperatures fall below about 26°C (79°F).
- Lipid locking: TRPM8 does not simply open on its own; a regulatory lipid must occupy a gap created by cooling to stabilize the open channel and sustain the cold signal.
- Birds vs. mammals: Comparing human and avian TRPM8 revealed the precise molecular hinges that make mammalian channels far more sensitive to cold than those of birds.
- Methodological advance: Researchers imaged TRPM8 in membranes taken directly from cells, preserving its native environment and capturing functional, temperature-evoked states that were previously elusive.
Source: UCSF
When you reach for ice, step outside on a snowy day, or feel menthol’s cool sting in toothpaste, TRPM8 in your sensory nerve endings opens like a tiny gate and sends a “cold” message to your brain.
Researchers at the University of California, San Francisco have now revealed how TRPM8 undergoes the structural changes that drive cold sensing.
Published in Nature on March 25, the work offers insights that could guide future therapies for pain driven by cold, and it solves a long-standing question about why birds with TRPM8 are comparatively insensitive to cold.
“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, PhD. “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 a Nobel laureate who previously discovered TRPV1, the channel that senses capsaicin.
A major advance in this study was the ability to observe TRPM8 as it moves, not only as a static structure.
“Structural biology has traditionally captured proteins in stable, frozen states,” said co-senior author Yifan Cheng, PhD. “To understand how a protein functions we must also track its motion. That is what this study accomplishes.”
A notoriously fragile protein
TRPM8 activates below roughly 79°F and is responsible both for natural cold sensation and for the cooling effect of menthol. However, isolating TRPM8 typically causes it to destabilize, and traditional imaging methods often require proteins to be locked in one conformation — preventing visualization of intermediate, functionally relevant states.
The teams led by Julius and Cheng overcame this by imaging TRPM8 while it remained embedded in membrane fragments taken directly from cells. Preserving the native membrane environment kept the channel intact and functionally responsive to cold and menthol.
“We realized the protein is particularly sensitive to handling. Keeping it in the native membrane finally let us see what it actually does,” said Kevin Choi, a UCSF graduate student and co-first author.
Capturing cold-driven changes
To map how TRPM8 opens, the researchers combined cryo-electron microscopy (cryo-EM) with hydrogen-deuterium exchange mass spectrometry (HDX-MS). Cryo-EM provided high-resolution snapshots of the channel arrested at different temperatures or in the presence of menthol, while HDX-MS measured which regions of the protein became more or less flexible as temperature changed.
Cryo-EM samples were flash-frozen under cold, menthol, or room-temperature conditions, preserving the channel’s instantaneous conformation. HDX-MS tracked dynamic changes in real time, revealing the portions of the molecule that gain rigidity or mobility as TRPM8 transitions between states. Together, these approaches allowed the team to reconstruct the conformational pathway leading to channel opening below 26°C.
The results show that cooling stabilizes the outer pore region, which triggers movement of a key transmembrane helix (S6). That movement creates space for a regulatory lipid to bind and lock the channel open, sustaining the cold signal to the nervous system.
Comparative analysis with avian TRPM8 — which responds to menthol but is largely insensitive to cold — pinpointed the structural features that specifically confer cold sensitivity in mammals.
Implications for structural biology and medicine
This strategy of imaging proteins in native membranes while combining static and dynamic methods opens the door to solving other challenging, motion-dependent structures. “Dynamic behavior is critical for many proteins, and a single snapshot can’t reveal that,” Cheng noted.
Julius and Cheng plan to apply the same approach to TRPV1, the heat-sensing channel, and to study how candidate drugs that block TRPM8 — some currently in clinical trials — alter channel structure. Understanding how the lipid lock and gating pathway work could help design targeted treatments for conditions such as cold allodynia, where mild cooling causes severe pain.
Key Questions Answered:
A: Menthol acts as a molecular mimic: it binds to TRPM8 and stabilizes the same channel conformation that cooling does. The channel opens and sends a cold signal to the brain even though the environment isn’t cold.
A: They combined cryo-EM, which produces many high-resolution frozen snapshots, with HDX-MS, which reports on dynamic flexibility. Together these methods provide a movie-like understanding of the channel’s motion.
A: Yes. By revealing how the TRPM8 gate becomes locked open, the study suggests ways to design drugs that prevent that lock from forming, which could reduce or eliminate pain in conditions like cold allodynia.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was added by editorial staff.
About this neuroscience research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image: Image credit: Neuroscience News
Original Research: Open access. “Structural energetics of cold sensitivity” by Kevin Y. Choi, Xiaoxuan Lin, Yifan Cheng & David Julius. Nature. DOI: 10.1038/s41586-026-10276-2
Abstract
Structural energetics of cold sensitivity
Thermosensitive transient receptor potential (TRP) ion channels allow somatosensory nerve fibers to detect temperature changes across a wide physiological range. In mammals, the menthol receptor TRPM8 activates at temperatures below roughly 26 °C and is essential for sensing cold and chemical cooling agents.
A central, unresolved goal has been to define the structural and thermodynamic mechanisms by which TRPM8 and other thermosensitive channels are gated by ambient temperature shifts. Prior cryo-EM studies faced challenges in visualizing intermediate, temperature-evoked conformational states and in assessing the energetic landscape that governs gating.
This study bridges that gap by combining cryo-EM with hydrogen–deuterium exchange mass spectrometry to reveal a mechanism for cold-evoked activation of TRPM8. Channels were visualized in cellular membranes, capturing bona fide menthol- and cold-evoked open states and revealing a ‘semi-swapped’ architecture in which subunit interdigitation rearranges after repositioning of the S6 transmembrane helix and elements of the pore region.
HDX-MS pinpointed the pore and TRP helices as regions undergoing the largest stimulus-evoked energetic changes that drive gating. Cold-evoked stabilization of the outer pore repositions the S6 helix and permits binding of a regulatory lipid that stabilizes the open channel. Structural mechanisms were validated by comparing the human channel to the menthol-sensitive but relatively cold-insensitive avian ortholog. The authors propose a free-energy landscape and conformational pathway by which cold and cooling agents activate this thermosensory receptor.