Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel

Xingjuan Chen, Weiyang Sun, Nicholas G. Gianaris, Ashley M. Riley, Theodore R. Cummins, Jill C. Fehrenbacher, Alexander G. Obukhov

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Furanocoumarin imperatorin is the major active component of Angelica dahurica root extracts, widely used in traditional medicine to treat headache, toothache, and orbital eye pain. In this study, we investigated the mechanisms that may underlie the pain-relieving effects of the compound. We found that imperatorin significantly inhibited formalin-and capsaicin-induced nocifensive responses but did not alter baseline thermal withdrawal thresholds in the rat. We established that imperatorin is a weak agonist of TRPV1, a channel implicated in detecting several noxious stimuli, exhibiting a 50% effective concentration (EC50) of 12.6 ± 3.2 μM. A specific TRPV1 antagonist, JNJ-17203212 (0.5μM), potently inhibited imperatorin-induced TRPV1 activation. Site-directed mutagenesis studies revealed that imperatorin most likely acted via a site adjacent to or overlapping with the TRPV1 capsaicin-binding site. TRPV1 recovery from desensitization was delayed in the presence of imperatorin. Conversely, imperatorin sensitized TRPV1 to acid activation but did not affect the current amplitude and/or the activation-inactivation properties of Nav1.7, a channel important for transmission of nociceptive information. Thus, our data indicate that furanocoumarins represent a novel group of TRPV1 modulators that may become important lead compounds in the drug discovery process aimed at developing new treatments for pain management.

Original languageEnglish (US)
Pages (from-to)9600-9610
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number14
DOIs
StatePublished - Apr 4 2014

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Modulators
Capsaicin
Chemical activation
Eye Pain
Toothache
Angelica
Lead compounds
Mutagenesis
Traditional Medicine
Drug Discovery
Pain Management
Site-Directed Mutagenesis
imperatorin
Furocoumarins
vanilloid receptor subtype 1
Formaldehyde
Medicine
Headache
Rats
Hot Temperature

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. / Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G.; Riley, Ashley M.; Cummins, Theodore R.; Fehrenbacher, Jill C.; Obukhov, Alexander G.

In: Journal of Biological Chemistry, Vol. 289, No. 14, 04.04.2014, p. 9600-9610.

Research output: Contribution to journalArticle

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