Abstract 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.

Xiaoyi Mo

Qiang Liu

Luna Gao

Chang Xie

Xin Wei

Peiyuan Pang

Quan Tian

Yue Gao

Youjing Zhang

Yuanyuan Wang

Tianchen Xiong

Bo Zhong

Dongdong Li

Jing Yao

BMC Biology

BMC BIOLOGY 是一本涵盖生物学所有领域的广泛期刊。我们的内容包括研究文章、新方法和工具。 BMC BIOLOGY 还发布评论、问答和评论。

BMC Biology is a comprehensive journal that covers all areas of biology. We publish research articles, introductions to new methods and tools, as well as reviews, Q&A, and commentaries.

BMC Biology 是一本涵盖生物学各个领域的综合性期刊。我们提供研究文章、新方法和工具的介绍，同时也发布评论、问答和综述文章。

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

The results suggest TRPV1 is a co-receptor for 1,4-dioxane and that this accounts for its ability to dysregulate body nociceptive sensation.

Category	Quartile
生物学	1
生物学, 生物学	1

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

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