Cargando…
Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli
The tetrameric capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) in mammals has evolved the capability to integrate pain signal arising from harmful temperature and chemical irritants. The four repetitions of TRPV1 subunits result in an ion channel with excellent pain sensitivity,...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962233/ https://www.ncbi.nlm.nih.gov/pubmed/31998070 http://dx.doi.org/10.3389/fnmol.2019.00302 |
_version_ | 1783488123570749440 |
---|---|
author | Liu, Ting-Yi Chu, Ying Mei, Hao-Ruei Chang, Dennis Chuang, Huai-Hu |
author_facet | Liu, Ting-Yi Chu, Ying Mei, Hao-Ruei Chang, Dennis Chuang, Huai-Hu |
author_sort | Liu, Ting-Yi |
collection | PubMed |
description | The tetrameric capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) in mammals has evolved the capability to integrate pain signal arising from harmful temperature and chemical irritants. The four repetitions of TRPV1 subunits result in an ion channel with excellent pain sensitivity, allowing this ionotropic receptor to differentiate graded injuries. We manipulated the stoichiometry and relative steric coordination of capsaicin-bound structures at the molecular level to determine the rules by which the receptor codes pain across a broad range of intensities. By introducing capsaicin-insensitive S512F mutant subunits into the TRPV1 channel, we found that binding of the first ligand results in low but clear channel activation. Maximal agonist-induced activation is already apparent in tetramers harboring two or three wild-type TRPV1 subunits, which display comparable activity to wild-type tetramer. The non-vanilloid agonist 2-aminoethoxydiphenyl borate (2-APB) differs from that of capsaicin in the TRPV1 channel opening mechanism activating all S512F-mutated TRPV1 channels. Two or more wild-type TRPV1 subunits are also required for full anandamide-induced channel activation, a cannabinoid that shares overlapping binding-pocket to capsaicin. Our results demonstrate that the stoichiometry of TRPV1 activation is conserved for two types of agonists. |
format | Online Article Text |
id | pubmed-6962233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69622332020-01-29 Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli Liu, Ting-Yi Chu, Ying Mei, Hao-Ruei Chang, Dennis Chuang, Huai-Hu Front Mol Neurosci Neuroscience The tetrameric capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) in mammals has evolved the capability to integrate pain signal arising from harmful temperature and chemical irritants. The four repetitions of TRPV1 subunits result in an ion channel with excellent pain sensitivity, allowing this ionotropic receptor to differentiate graded injuries. We manipulated the stoichiometry and relative steric coordination of capsaicin-bound structures at the molecular level to determine the rules by which the receptor codes pain across a broad range of intensities. By introducing capsaicin-insensitive S512F mutant subunits into the TRPV1 channel, we found that binding of the first ligand results in low but clear channel activation. Maximal agonist-induced activation is already apparent in tetramers harboring two or three wild-type TRPV1 subunits, which display comparable activity to wild-type tetramer. The non-vanilloid agonist 2-aminoethoxydiphenyl borate (2-APB) differs from that of capsaicin in the TRPV1 channel opening mechanism activating all S512F-mutated TRPV1 channels. Two or more wild-type TRPV1 subunits are also required for full anandamide-induced channel activation, a cannabinoid that shares overlapping binding-pocket to capsaicin. Our results demonstrate that the stoichiometry of TRPV1 activation is conserved for two types of agonists. Frontiers Media S.A. 2020-01-09 /pmc/articles/PMC6962233/ /pubmed/31998070 http://dx.doi.org/10.3389/fnmol.2019.00302 Text en Copyright © 2020 Liu, Chu, Mei, Chang and Chuang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Liu, Ting-Yi Chu, Ying Mei, Hao-Ruei Chang, Dennis Chuang, Huai-Hu Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title | Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title_full | Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title_fullStr | Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title_full_unstemmed | Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title_short | Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli |
title_sort | two vanilloid ligand bindings per channel are required to transduce capsaicin-activating stimuli |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962233/ https://www.ncbi.nlm.nih.gov/pubmed/31998070 http://dx.doi.org/10.3389/fnmol.2019.00302 |
work_keys_str_mv | AT liutingyi twovanilloidligandbindingsperchannelarerequiredtotransducecapsaicinactivatingstimuli AT chuying twovanilloidligandbindingsperchannelarerequiredtotransducecapsaicinactivatingstimuli AT meihaoruei twovanilloidligandbindingsperchannelarerequiredtotransducecapsaicinactivatingstimuli AT changdennis twovanilloidligandbindingsperchannelarerequiredtotransducecapsaicinactivatingstimuli AT chuanghuaihu twovanilloidligandbindingsperchannelarerequiredtotransducecapsaicinactivatingstimuli |