trans-Anethole of Fennel Oil is a Selective and Nonelectrophilic Agonist of the TRPA1 Ion Channel

Mol Pharmacol. 2019 Apr;95(4):433-441. doi: 10.1124/mol.118.114561. Epub 2019 Jan 24.

Abstract

Transient receptor potential (TRP) cation channels are molecular targets of various natural products. TRPA1, a member of TRP channel family, is specifically activated by natural products such as allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), and allicin (garlic). In this study, we demonstrated that TRPA1 is also a target of trans-anethole in fennel oil (FO) and fennel seed extract. Similar to FO, trans-anethole selectively elicited calcium influx in TRPA1-expressing mouse sensory neurons of the dorsal root and trigeminal ganglia. These FO- and anethole-induced calcium responses were blocked by a selective TRPA1 channel antagonist, HC-030031. Moreover, both FO and trans-anethole induced calcium influx and transmembrane currents in HEK293 cells stably overexpressing human TRPA1 channels, but not in regular HEK293 cells. Mutation of the amino acids S873 and T874 binding site of human TRPA1 significantly attenuated channel activation by trans-anethole, whereas pretreating with glutathione, a nucleophile, did not. Conversely, activation of TRPA1 by the electrophile allyl isothiocyanate was abolished by glutathione, but was ostensibly unaffected by mutation of the ST binding site. Finally, it was found that trans-anethole was capable of desensitizing TRPA1, and unlike allyl isothiocyanate, it failed to induce nocifensive behaviors in mice. We conclude that trans-anethole is a selective, nonelectrophilic, and seemingly less-irritating agonist of TRPA1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anisoles / pharmacology*
  • Calcium Channels / metabolism
  • Foeniculum / chemistry
  • HEK293 Cells
  • Humans
  • Isothiocyanates / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Oils, Volatile / pharmacology*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Spinal Nerve Roots / drug effects
  • Spinal Nerve Roots / metabolism
  • TRPA1 Cation Channel / agonists*
  • Transient Receptor Potential Channels / metabolism
  • Trigeminal Ganglion / drug effects
  • Trigeminal Ganglion / metabolism

Substances

  • Anisoles
  • Calcium Channels
  • Isothiocyanates
  • Oils, Volatile
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • Transient Receptor Potential Channels
  • fennel oil, bitter
  • allyl isothiocyanate
  • anethole