Touch a hot frying pan and the searing message of pain sprints up to your brain and back down to your hand so fast that the impulse to withdraw your fingers seems instantaneous. That rapid-fire signal begins in a heat-sensing molecule called a TRPV1 channel. This specialized protein is abundant on the surface of sensory nerve cells in our fingers and elsewhere and is a shape-shifter that can take an open or closed configuration. Heat opens a central pore in the molecule, so do certain spider toxins and capsaicin—the substance that gives chili peppers their burn. Once the pore is open, charged ions of sodium and calcium flow into the nerve cell, triggering the pain signal. Ouch!
As neuroscientist-journalist Stephani Sutherland explains in “Pain that Won’t Quit,” in the December Scientific American, researchers have long been interested in finding ways to moderate the action of this channel—and other ion channels—in patients who suffer from chronic pain. Shutting down the TRPV1 channel completely, however, is not an option because it plays a vital role in regulating body temperature.
In two papers published in Nature in December 2013 investigators at the University of California, San Francisco, gave pain researchers a big leg up in understanding TRPV1. They revealed, in exquisite atomic detail, the structure of the channel molecule (from a rat) using an electron cryomicroscope, an instrument designed to explore the 3-D structure of molecules at very low temperatures. One of those investigators, Yifan Cheng, also created this colorful animation, showing how the molecule looks when the channel is open. (Scientific American is part of Nature Publishing Group.)
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The video reveals that the channel protein is composed of four helical subunits (depicted in pale shades yellow, blue, green and red). Cheng’s model shows the TRPV1 protein bound by a spider toxin (pink) and a deadly plant toxin (red spheres) that is similar to capsaicin. Both of these toxins open the channel. As the model rotates, it is easy to see the central gap through which ions pass—the step that sets pain signals in motion.