Molecular snapshots reveal how the body knows it’s too hot

The ability to sense heat protects the body from burns and injury. But how the body actually feels temperature has remained an elusive mystery.

Now, Northwestern University researchers have captured a detailed look at one of the body’s major heat sensors, revealing how it turns on when temperatures rise. 

This sensor, called TRPM3, sits in the cell membrane, where it acts like a tiny gate. When TRPM3 detects heat, it allows charged particles, or ions, to flow into the cell. This triggers nerve signals, which the brain interprets as heat or pain. To their surprise, the scientists found that heat is sensed from within — by the part of the TRPM3 protein that lies inside the cell, not the section embedded within the membrane as previously assumed. 

The finding uncovers a new way that cells sense temperature and helps explain how the nervous system distinguishes harmless warmth from dangerous heat. Because TRPM3 also is involved in pain, inflammation and epilepsy, the discovery could lead to new types of non-addictive pain treatments.

The study will be published on Friday (Oct. 24) in Nature Structural & Molecular Biology.

“Temperature is an ever-present environmental factor that affects how we sense the world,” said Northwestern’s Juan Du, who co-led the study with Wei Lü. “It also affects how our bodies heal and how diseases progress. Understanding how temperature is detected at the molecular level can help us design better treatments for pain and inflammation.”

Du and Lü are professors of molecular biosciences at Northwestern’s Weinberg College of Arts and Sciences, professors of pharmacology at the Feinberg School of Medicine and members of Northwestern’s Chemistry of Life Processes Institute. Sushant Kumar, a postdoctoral fellow in the Du and Lü Labs, is the lead author of the study.

Visualizing the invisible

Because it can’t be seen or tracked directly, studying heat is notoriously difficult. Scientists often study drugs by watching them bind to proteins, but temperature has no physical shape or binding site.

To overcome this, Du and Lü’s teams used cryo-electron microscopy (cryo-EM) —a technique that takes thousands of pictures of flash-frozen proteins — to create 3D images of TRPM3 at near-atomic detail. They also used electrophysiology, which measures electrical currents through the protein, to watch how TRPM3 behaves in living cells.

Using a chemical that mimics heat, the researchers captured the “active” state of TRPM3. Then, using an epilepsy drug that binds to the protein, they captured the “inactive” state. Comparing these structures revealed which parts of the protein shift during activation. This provided the foundation for understanding how the sensor responds to heat. The team then imaged TRPM3 at low and high temperatures, finding that both heat and chemical activators trigger similar structural rearrangements inside the protein.

An inner switch

By combining imaging and electrical recordings, the team found that TRPM3 functions as a molecular switch made of four parts. When the inner regions of these parts hold tightly together, the sensor stays inactive. Heat or a chemical activator disrupts these connections, shifting the protein into its active state.

“Both heat and chemical activators push the same internal switch to activate the channel,” Du said. “In contrast, the epilepsy drug jams that same switch, preventing it from changing shape.”

Because TRPM3 is found in both the brain and sensory neurons in the skin, tuning its activity could help manage chronic pain or neurological disorders.

“When TRPM3 becomes overactive, it can cause pain,” Lü said. “By learning how this sensor detects heat and how to control its activity, we may discover new pain-relief strategies that are safer and less likely to cause addiction.”

The study, “Structural basis for agonist and heat activation of nociceptor TRPM3,” was supported by the National Institutes of Health (award numbers R01HL153219, R01NS112363, R01NS111031 and R01NS129804), a McKnight Scholar Award, Klingenstein-Simon Scholar Award, Sloan Research Fellowship and a Pew Scholar in the Biomedical Sciences award.

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