Investigating the Structure‐Function Relationship Between TRPV1 Channels and Pain

Abstract

Transient receptor potential, or TRP, ion channels are a superfamily of non-selective cation transmembrane proteins expressed in many tissues. These channels play a key role in the sensory signaling of taste, thermosensation, mechanosensation, and nociception. Transient receptor potential vanilloid 1, or TRPV1, a member of the TRP family of ion channels, specifically responds to both heat and spice. The activation of this channel occurs when a ligand, such as capsaicin, binds to the ligand-binding site, replacing phosphatidylinositol lipids. Capsaicin is a chemical compound commonly found in chili peppers that transmits sensation of taste and pain when it binds to TRPV1. Neuropathic pain, inflammation, and reduced ability to detect stimuli are all symptoms associated with dysfunctional TRPV ion channels. The Summit Country Day School MSOE Center for Biomolecular Modeling MAPS Team used 3D modeling and printing technology to examine the structure-function relationship of the interaction between the TRPV1 ion channel and capsaicin. TRPV ion channels are homotetramers, and individual polypeptide chains contain a transmembrane domain composed of the pore region and vanilloid binding pocket. Capsaicin molecules have been shown to bind to the vanilloid binding pocket located above the S4-S5 linker of one monomer of the TRPV1 tetramer. Two main restriction points in the ion permeation channel were identified. A vanilloid agonist displaces phosphatidylinositide, facilitating the formation of a salt bridge between Arg557 and Glu570, which pulls the S4-S5 linker away from the central axis, opening the lower gate of the pore. The binding of capsaicin to the pocket leaves the selective permeability filter closed but the lower ion gate partially open. This channel is considered as a possible target for the creation of therapeutic treatments for chronic pain. TRPV1 antagonists, such as capsaicin, may play a key role in blocking chronic pain. Capsaicin is already used as a component in topical pain patches and natural and synthetic molecules related to capsaicin have been tested for their ability to decrease response to pain. In the recent movement to decrease the prescription of brain-based pain-blocking medication in response to the opioid epidemic, TRPV1 channels may play a significant role in the development of new therapeutic options in the treatment of pain.