Scientists at Northwestern University have provided new insights into how the body senses heat by capturing detailed images of a major heat sensor protein, TRPM3, in both its resting and activated states. The findings were published in Nature Structural & Molecular Biology on October 24.
TRPM3 is located in the cell membrane and acts as a gate that allows ions to flow into the cell when it detects heat. This process triggers nerve signals that the brain interprets as heat or pain. Contrary to previous assumptions, researchers discovered that the part of TRPM3 responsible for sensing heat is located inside the cell rather than within the membrane itself.
“Temperature is an ever-present environmental factor that affects how we sense the world,” said 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 at Northwestern’s Weinberg College of Arts and Sciences and Feinberg School of Medicine, as well as members of the Chemistry of Life Processes Institute. Sushant Kumar, a postdoctoral fellow in their labs, served as lead author.
The research team used cryo-electron microscopy (cryo-EM) to create three-dimensional images of TRPM3 with near-atomic detail. They also applied electrophysiology techniques to measure electrical currents through the protein in living cells. By using a chemical mimic of heat, they observed TRPM3 in its active state, while an epilepsy drug allowed them to capture its inactive state. Comparing these states revealed structural changes that occur during activation.
The study found that both heat and chemical activators trigger similar internal rearrangements in TRPM3, functioning like a molecular switch made up of four parts. When these inner regions are tightly connected, the sensor remains inactive; exposure to heat or chemical activators disrupts these connections and activates the protein.
“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.”
TRPM3 is present in both brain tissue and sensory neurons in skin. Its activity has been linked not only to pain but also to conditions such as inflammation and epilepsy. Adjusting its function could help develop non-addictive treatments for 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 research was supported by grants from the National Institutes of Health along with several scholarly awards.