Understand spiciness: mechanism of TRPV1 channel activation by capsaicin

Fan Yang, Jie Zheng, Fan Yang, Jie Zheng

Abstract

Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by "pull-and-contact" with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.

Keywords: TRPV1; capsaicin; computation; cryo-EM; ligand gating; spiciness.

Figures

Figure 1
Figure 1
Capsaicin and TRPV1. (A) Chemical structure of capsaicin. The vanillyl Head and hydrophobic Tail groups are shaded in orange and blue, respectively. The atoms forming hydrogen bonds with TRPV1 are highlighted in red. (B) Schematic diagram showing the topology of a TRPV1 subunit. Membrane is shaded in green. (C) High resolution structure of rat TRPV1 determined by cryo-EM (atomic model: 3J5R in PDB; electron density map, 5777 in EMD). It is clear that capsaicin (electron density boxed by solid line) binds to the transmembrane domains. Lipid membrane boundaries are indicated by cyan disks. (D) A zoom-in view of the capsaicin binding pocket. Residue important for capsaicin activation identified by mutagenesis and functional studies are colored in orange. The electron density of capsaicin is colored in red
Figure 2
Figure 2
Mechanism of TRPV1 activation by capsaicin. (A) Docking of capsaicin into its binding pocket on open-state TRPV1 structure (PDB ID: 3J5R). The Head, Neck and Tail of capsaicin are colored in red, blue and magenta, respectively. Two residues making hydrogen bonds with capsaicin are highlighted in orange. Note that the amino acid numbering for mouse TRPV1 differs from that for rat and human TRPV1 (Fig. 1) by one. (B) Diagram showing the principle of thermodynamic mutant cycle analysis. (C) Cartoon summarizing capsaicin binding and activation of TRPV1

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