Department of Cell Biology, Laboratory of Ion Channel Research, Campus Gasthuisberg, KU Leuven, Herestraat 49, bus 802, 3000 Louvain, Belgium.
Pflugers Arch. 2011 Dec;462(6):841-9. doi: 10.1007/s00424-011-1021-7. Epub 2011 Sep 6.
TRPA1 is activated by electrophilic compounds such as mustard oil (MO). Here, we demonstrate a bimodal sensitivity of TRPA1 to ligustilide (Lig), an electrophilic volatile dihydrophthalide of dietary and medicinal relevance. Lig is a potent TRPA1 activator and is also capable to induce a modest block of MO activated currents. Aromatization to dehydroligustilide (DH-Lig), as occurs during aging of its botanical sources, reversed this profile, enhancing TRPA1 inhibition and reducing activation. Mutation of the reactive cysteines in mouseTRPA1 (C622S, C642S, C666S) dramatically reduced activation by MO and significantly reduced that by Lig, but had an almost negligible effect on the action of DH-Lig, whose activation mechanism of TRPA1 is therefore largely independent from the alkylation of cysteine residues. Taken together, these observations show that the phthalide structural motif is a versatile platform to investigate the modulation of TRPA1 by small molecules, being tunable in terms of activation/inhibition profile and mechanism of interaction. Finally, the action of Lig on TRPA1 may contribute to the gustatory effects of celery, its major dietary source, and to the pharmacological action of important plants from the Chinese and native American traditional medicines.
TRPA1 可被芥子油（MO）等亲电化合物激活。在这里，我们证明了 TRPA1 对藁本内酯（Lig）具有双模态敏感性，藁本内酯是膳食和药用相关的亲电挥发性二氢苯酞。 Lig 是一种强效的 TRPA1 激活剂，也能够适度抑制 MO 激活的电流。其植物来源在老化过程中发生的芳构化作用，形成脱水藁本内酯（DH-Lig），改变了这种作用模式，增强了对 TRPA1 的抑制作用并降低了其激活作用。在小鼠 TRPA1 中突变反应性半胱氨酸（C622S、C642S、C666S）可显著降低 MO 和 Lig 对其的激活作用，但对 DH-Lig 的作用几乎没有影响，因此，DH-Lig 激活 TRPA1 的机制在很大程度上独立于半胱氨酸残基的烷基化。综上所述，这些观察结果表明，苯酞结构基序是研究小分子对 TRPA1 调制作用的多功能平台，可根据激活/抑制特性和相互作用机制进行调节。最后，藁本内酯对 TRPA1 的作用可能有助于芹菜的味觉作用，芹菜是其主要膳食来源，也可能有助于中美传统药物中重要植物的药理学作用。
