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The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1

BACKGROUND: The synthetic chemical 1,4-dioxane is used as industrial solvent, food, and care product additive. 1,4-Dioxane has been noted to influence the nervous system in long-term animal experiments and in humans, but the molecular mechanisms underlying its effects on animals were not previously...

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Autores principales: Mo, Xiaoyi, Liu, Qiang, Gao, Luna, Xie, Chang, Wei, Xin, Pang, Peiyuan, Tian, Quan, Gao, Yue, Zhang, Youjing, Wang, Yuanyuan, Xiong, Tianchen, Zhong, Bo, Li, Dongdong, Yao, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742357/
https://www.ncbi.nlm.nih.gov/pubmed/34996439
http://dx.doi.org/10.1186/s12915-021-01211-0
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author Mo, Xiaoyi
Liu, Qiang
Gao, Luna
Xie, Chang
Wei, Xin
Pang, Peiyuan
Tian, Quan
Gao, Yue
Zhang, Youjing
Wang, Yuanyuan
Xiong, Tianchen
Zhong, Bo
Li, Dongdong
Yao, Jing
author_facet Mo, Xiaoyi
Liu, Qiang
Gao, Luna
Xie, Chang
Wei, Xin
Pang, Peiyuan
Tian, Quan
Gao, Yue
Zhang, Youjing
Wang, Yuanyuan
Xiong, Tianchen
Zhong, Bo
Li, Dongdong
Yao, Jing
author_sort Mo, Xiaoyi
collection PubMed
description BACKGROUND: The synthetic chemical 1,4-dioxane is used as industrial solvent, food, and care product additive. 1,4-Dioxane has been noted to influence the nervous system in long-term animal experiments and in humans, but the molecular mechanisms underlying its effects on animals were not previously known. RESULTS: Here, we report that 1,4-dioxane potentiates the capsaicin-sensitive transient receptor potential (TRP) channel TRPV1, thereby causing hyperalgesia in mouse model. This effect was abolished by CRISPR/Cas9-mediated genetic deletion of TRPV1 in sensory neurons, but enhanced under inflammatory conditions. 1,4-Dioxane lowered the temperature threshold for TRPV1 thermal activation and potentiated the channel sensitivity to agonistic stimuli. 1,3-dioxane and tetrahydrofuran which are structurally related to 1,4-dioxane also potentiated TRPV1 activation. The residue M572 in the S4-S5 linker region of TRPV1 was found to be crucial for direct activation of the channel by 1,4-dioxane and its analogs. A single residue mutation M572V abrogated the 1,4-dioxane-evoked currents while largely preserving the capsaicin responses. Our results further demonstrate that this residue exerts a gating effect through hydrophobic interactions and support the existence of discrete domains for multimodal gating of TRPV1 channel. CONCLUSIONS: Our results suggest TRPV1 is a co-receptor for 1,4-dioxane and that this accounts for its ability to dysregulate body nociceptive sensation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01211-0.
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spelling pubmed-87423572022-01-10 The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1 Mo, Xiaoyi Liu, Qiang Gao, Luna Xie, Chang Wei, Xin Pang, Peiyuan Tian, Quan Gao, Yue Zhang, Youjing Wang, Yuanyuan Xiong, Tianchen Zhong, Bo Li, Dongdong Yao, Jing BMC Biol Research Article BACKGROUND: The synthetic chemical 1,4-dioxane is used as industrial solvent, food, and care product additive. 1,4-Dioxane has been noted to influence the nervous system in long-term animal experiments and in humans, but the molecular mechanisms underlying its effects on animals were not previously known. RESULTS: Here, we report that 1,4-dioxane potentiates the capsaicin-sensitive transient receptor potential (TRP) channel TRPV1, thereby causing hyperalgesia in mouse model. This effect was abolished by CRISPR/Cas9-mediated genetic deletion of TRPV1 in sensory neurons, but enhanced under inflammatory conditions. 1,4-Dioxane lowered the temperature threshold for TRPV1 thermal activation and potentiated the channel sensitivity to agonistic stimuli. 1,3-dioxane and tetrahydrofuran which are structurally related to 1,4-dioxane also potentiated TRPV1 activation. The residue M572 in the S4-S5 linker region of TRPV1 was found to be crucial for direct activation of the channel by 1,4-dioxane and its analogs. A single residue mutation M572V abrogated the 1,4-dioxane-evoked currents while largely preserving the capsaicin responses. Our results further demonstrate that this residue exerts a gating effect through hydrophobic interactions and support the existence of discrete domains for multimodal gating of TRPV1 channel. CONCLUSIONS: Our results suggest TRPV1 is a co-receptor for 1,4-dioxane and that this accounts for its ability to dysregulate body nociceptive sensation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01211-0. BioMed Central 2022-01-07 /pmc/articles/PMC8742357/ /pubmed/34996439 http://dx.doi.org/10.1186/s12915-021-01211-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Mo, Xiaoyi
Liu, Qiang
Gao, Luna
Xie, Chang
Wei, Xin
Pang, Peiyuan
Tian, Quan
Gao, Yue
Zhang, Youjing
Wang, Yuanyuan
Xiong, Tianchen
Zhong, Bo
Li, Dongdong
Yao, Jing
The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title_full The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title_fullStr The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title_full_unstemmed The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title_short The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1
title_sort industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor trpv1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742357/
https://www.ncbi.nlm.nih.gov/pubmed/34996439
http://dx.doi.org/10.1186/s12915-021-01211-0
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