Heat-sensing trigger: A team at Northwestern University has uncovered a new mechanism the human body uses to sense heat, identifying how a membrane protein called TRPM3 flips on to signal warmth, and, at higher levels, pain. When activated by environmental heat, TRPM3 opens a channel in the cell membrane that lets charged particles flow in, generating nerve signals the brain interprets as “heat” or “pain.”
Because TRPM3 is also implicated in pain, inflammation, and epilepsy, the discovery, published in Nature Structural & Molecular Biology, could pave the way for non-addictive treatments for chronic pain. “When TRPM3 becomes overactive, it can cause pain,” said senior author Wei Lü. “By learning how this sensor detects heat and how to control its activity, we may discover safer pain-relief strategies.”
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Using cryo-electron microscopy to capture near-atomic snapshots, researchers compared TRPM3 in an “on” state, triggered by a heat-mimicking chemical, with an “off” state bound to an epilepsy drug. The images show TRPM3 acts like a four-part molecular switch: when its inner regions lock together, the channel stays closed; heat or certain chemicals disrupt those connections, opening the channel. “Both heat and chemical activators push the same internal switch,” added co-lead author Juan Du. “In contrast, the epilepsy drug jams that switch, preventing it from changing shape.”
The findings help explain how the body distinguishes harmless warmth from damaging heat and point to new ways to dial TRPM3 activity up or down. That could inform therapies for chronic pain or neurological conditions without relying on addictive medications, an approach the team says merits rapid follow-up research.
