title: Ligustilide: a novel TRPA1 modulator.
abstract: 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.
authors: Department of Cell Biology, Laboratory of Ion Channel Research, Campus Gasthuisberg, KU Leuven, Herestraat 49, bus 802, 3000 Louvain, Belgium.
authors: Jian
authors: J
authors: Zhong
authors: Federica
authors: F
authors: Pollastro
authors: Jean
authors: J
authors: Prenen
authors: Zhiming
authors: Z
authors: Zhu
authors: Giovanni
authors: G
authors: Appendino
authors: Bernd
authors: B
authors: Nilius
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008519:Medicine, Traditional; D051379:Mice; D015394:Molecular Structure; D009149:Mustard Plant / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010938:Plant Oils / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C027820:ligustilide; D015107:4-Butyrolactone; C027793:mustard oil