2. Academic Validation
  3. Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin

Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin

  • J Biol Chem. 2021 Sep;297(3):101022. doi: 10.1016/j.jbc.2021.101022.
Yanxin Li 1,  Xiaoying Chen 2,  Yingying Nie 1,  Yuhua Tian 3,  Xian Xiao 4,  Fan Yang 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China.
  • 2 Department of Biophysics, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 3 Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China. Electronic address: yhtian05250@qdu.edu.cn.
  • 4 Institute for Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang Province, China. Electronic address: xiaoxian@westlake.edu.cn.
  • 5 Department of Biophysics, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. Electronic address: fanyanga@zju.edu.cn.
PMID: 34332978 DOI: 10.1016/j.jbc.2021.101022
Abstract

Transient receptor potential vanilloid 1 (TRPV1) ion channel serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH. This channel has also been shown to function as an ionotropic Cannabinoid Receptor. Despite the solving of high-resolution three-dimensional structures of TRPV1, how endocannabinoids such as anandamide and N-arachidonoyl dopamine bind to and activate this channel remains largely unknown. Here we employed a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking techniques to investigate how the endocannabinoids structurally bind to and open the TRPV1 ion channel. We found that these endocannabinoid ligands bind to the vanilloid-binding pocket of TRPV1 in the "tail-up, head-down" configuration, similar to capsaicin; however, there is a unique interaction with TRPV1 Y512 residue critical for endocannabinoid activation of TRPV1 channels. These data suggest that a differential structural mechanism is involved in TRPV1 activation by endocannabinoids compared with the classic agonist capsaicin.

Keywords

N-arachidonoyl dopamine; TRPV1; anandamide; endocannabinoids; ligand binding.

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