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

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. 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. Our results suggest TRPV1 is a co-receptor for 1,4-dioxane and that this accounts for its ability to dysregulate body nociceptive sensation. © 2021. The Author(s).

Citation

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. The industrial solvent 1,4-dioxane causes hyperalgesia by targeting capsaicin receptor TRPV1. BMC biology. 2022 Jan 07;20(1):10

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PMID: 34996439

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