The ability to sense heat protects the body from burns and injury. But how the body actually feels temperature has remained an elusive mystery.<\/p>\n
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.\u00a0<\/p>\n
This sensor, called\u00a0TRPM3, 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.\u00a0<\/p>\n
The finding uncovers a new way that cells sense temperature and helps explain how the nervous system<\/a> distinguishes harmless warmth from dangerous heat. Because TRPM3 also is involved in pain, inflammation<\/a> and epilepsy, the discovery could lead to new types of non-addictive pain treatments.<\/p>\n The study will be published on Friday (Oct. 24) in Nature Structural & Molecular Biology.<\/p>\n “Temperature is an ever-present environmental factor that affects how we sense the world,” said Northwestern’s\u00a0Juan Du, who co-led the study with\u00a0Wei L\u00fc. “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.”<\/p>\n Du and L\u00fc are professors of molecular biosciences at Northwestern’s\u00a0Weinberg College of Arts and Sciences, professors of pharmacology at the\u00a0Feinberg School of Medicine\u00a0and members of Northwestern’s\u00a0Chemistry of Life Processes Institute. Sushant Kumar, a postdoctoral fellow in the\u00a0Du and L\u00fc Labs, is the lead author of the study.<\/p>\n Visualizing the invisible<\/p>\n 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.<\/p>\n To overcome this, Du and L\u00fc’s teams used\u00a0cryo-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\u00a0electrophysiology, which measures electrical currents through the protein, to watch how TRPM3 behaves in living cells.<\/p>\n 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.<\/p>\n An inner switch<\/p>\n By combining imaging and electrical recordings, the team found that TRPM3 functions as a\u00a0molecular 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.<\/p>\n “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.”<\/p>\n