Liu Yuxia, He Yuanyuan, Tong Jiahuan, Guo Shengyang, Zhang Xinyu, Luo Zichao, Sun Linlin, Chang Chao, Zhuang Bilin, Liu Xiaogang
Department of Chemistry, National University of Singapore, Singapore, Singapore.
The N.1 Institute for Health, National University of Singapore, Singapore, Singapore.
Nat Biomed Eng. 2024 Nov 21. doi: 10.1038/s41551-024-01288-2.
Activation of the ion channel transient receptor potential vanilloid 1 (TRPV1), which is integral to pain perception, leads to an expansion of channel width, facilitating the passage of cations and large organic molecules. However, the permeability of TRPV1 channels to water remains uncertain, owing to a lack of suitable tools to study water dynamics. Here, using upconversion nanophosphors to discriminate between HO and DO, by monitoring water permeability across activated TRPV1 at the single-cell and single-molecule levels, and by combining single-channel current measurements with molecular dynamics simulations, we show that water molecules flow through TRPV1 and reveal a direct connection between water migration, cation flow and TRPV1 functionality. We also show in mouse models of acute or chronic inflammatory pain that the administration of deuterated water suppresses TRPV1 activity, interrupts the transmission of pain signals and mitigates pain without impacting other neurological responses. Solvent-mediated analgesia may inspire alternative options for pain management.
离子通道瞬时受体电位香草酸亚型1（TRPV1）的激活对于痛觉至关重要，它会导致通道宽度增加，有利于阳离子和大型有机分子通过。然而，由于缺乏研究水动力学的合适工具，TRPV1通道对水的通透性仍不明确。在此，我们利用上转换纳米磷光体区分H₂O和D₂O，通过在单细胞和单分子水平监测激活的TRPV1的水通透性，并将单通道电流测量与分子动力学模拟相结合，我们发现水分子可通过TRPV1，并揭示了水迁移、阳离子流动与TRPV1功能之间的直接联系。我们还在急性或慢性炎性疼痛的小鼠模型中表明，给予重水可抑制TRPV1活性，中断疼痛信号的传递并减轻疼痛，而不影响其他神经反应。溶剂介导的镇痛作用可能为疼痛管理带来替代选择。
