Modeling TRPV1, a Detector of Thermal and Chemical Stimuli, Producing Pain: No Capsaicin Sensation

Abstract

According to the Institute of Medicine, 100 million Americans suffer from chronic pain every year and the US spends over $500 billion trying to treat them. Pain begins as a stimulus that is detected by nociceptors, which are nerve fibers responsible for the detection of noxious mechanical, thermal, or chemical stimuli that give rise to pain sensations. These nociceptors transmit pain signals from the periphery to neurons in the spinal cord and brain. The Transient Receptor Potential Vanilloid 1 (TRPV1) is a nociceptive ion channel activated by capsaicin (the spicy component of hot peppers), heat, and endogenous pain molecules. Therefore, creating an inhibitor that partially blocks TRPV1 could treat chronic pain. The amino acids in the active site of TRPV1 are Y511, S512, M547, and T550. In addition, E600 controls the selectivity filter at the top gate of the channel and the hydrophobic seal mediated through I679 controls the lower gate. When capsaicin binds to the channel, a conformational change occurs that pulls the I679s on each subunit away from each other, opening up the lower gate. Understanding how activation of TRPV1 occurs may lead to the discovery of novel inhibitors of TRPV1 to help treat those suffering from chronic pain and reduce healthcare spending. The Divine Savior Holy Angels SMART (Students Modeling A Research Topic) Team modeled TRPV1 in a partially activated state using 3D printing technology. Program supported by a grant from NIH‐CTSA.