Graduate School.
Faculty of Life and Environmental Sciences.
J Biochem. 2020 Oct 1;168(4):407-415. doi: 10.1093/jb/mvaa057.
Activation of the transient receptor potential A1 channel (TRPA1) by electrophilic agonists was reported to induce the opening of tight junctions (TJs). Because compounds that increase TJ permeability can be paracellular permeability enhancers, we investigated the effect of non-electrophilic TRPA1 activators, including food ingredients (menthol and carvacrol) and medication (clotrimazole), on epithelial permeability. We show that all three compounds induced increase of the permeability of fluorescein isothiocyanate-conjugated dextran (4 kDa) and decrease of transepithelial electrical resistance, accompanied by Ca2+ influx and cofilin activation in epithelial MDCK II monolayers. These phenotypes were attenuated by pretreatment of a TRPA1 antagonist, suggesting TRPA1-mediated opening of TJs. These results suggest that non-electrophilic TRPA1 activators with established safety can be utilized to regulate epithelial barriers.
已报道，瞬时受体电位 A1 通道（TRPA1）的激活可诱导紧密连接（TJ）开放。由于增加 TJ 通透性的化合物可以作为细胞旁通透性增强剂，因此我们研究了非亲电子 TRPA1 激活剂（包括食物成分（薄荷醇和香芹酚）和药物（克霉唑））对上皮通透性的影响。我们发现这三种化合物均诱导荧光素异硫氰酸酯-结合葡聚糖（4 kDa）的通透性增加和跨上皮电阻降低，同时在 MDCK II 上皮细胞单层中伴有 Ca2+内流和丝切蛋白激活。用 TRPA1 拮抗剂预处理可减弱这些表型，表明 TRPA1 介导 TJ 开放。这些结果表明，具有既定安全性的非亲电子 TRPA1 激活剂可用于调节上皮屏障。
