Pflügers Archiv - European Journal of Physiology

, Volume 462, Issue 6, pp 861–870

Umbellulone modulates TRP channels

  • Jian Zhong
  • Alberto Minassi
  • Jean Prenen
  • Orazio Taglialatela-Scafati
  • Giovanni Appendino
  • Bernd Nilius
Ion Channels, Receptors and Transporters

Abstract

Inhalation of umbellulone (UMB), the offensive principle of the so-called “headache tree” (California bay laurel, Umbellularia californica Nutt.), causes a painful cold sensation. We therefore studied the action of UMB and some derivatives devoid of thiol-trapping properties on the “cold” transient receptor potential cation channels TRPA1 and TRPM8. UMB activated TRPA1 in a dose-dependent manner that was attenuated by cysteine-to-serine isosteric mutation in TRPA1 (C622S), while channel block was observed at higher concentration. However, although activation by mustard oil was completely prevented in these mutants, UMB still retained activating properties, indicating that it acts on TRPA1 only as a partial electrophilic agonist. UMB also activated TRPM8, but to a lower extent than TRPA1. Removing Michael acceptor properties of UMB (reduction or nucleophilic trapping) was detrimental for the activation of TRPA1, but increased the blocking potency. This was, however, attenuated by acetylation of the hydroxylated analogs. All UMB derivatives, except the acetylated derivatives, were also TRPM8 activators. They acted, however, in a bimodal manner, inhibiting the channel more potently than UMB, and with tetrahydro-UMB being the most potent TRPM8 activator. In conclusion, UMB is a bimodal activator of TRPA1 and a weak activator of TRPM8. Non-electrophilic derivatives of UMB are better TRPM8 activators than the natural product and also potent blockers of this channel as well as of TRPA1. The lack of effects of the acetylated UMB derivatives suggests that steric hindrance may prevent access to the recognition site for the bicyclic monoterpene pharmacophore on TRPA1 and TRPM8.

Keywords

TRP channels TRPA1 TRPM8 Headache tree Umbellulone Umbellulone derivatives Chemosensation Electrophiles Mustard oil Menthol 

Supplementary material

424_2011_1043_MOESM1_ESM.pdf (34 kb)
Figure supplementModulation of TRPM8 activation by malonildihydroumbellulone. (a) Representative time course of whole-cell currents through TRPM8 measured at membrane potential of −80 mV (black circles) and +80 mV (red circles) induced by malonildihydroumbellulone and menthol at indicated concentrations. Note accentuated off-response after washout of 300 μM malonildihydroumbellulone, and its 100% block of the 100 μM MO response. (b and c) I–V relations measured at the times indicated in (a) (PDF 34 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jian Zhong
    • 1
    • 2
  • Alberto Minassi
    • 3
  • Jean Prenen
    • 1
  • Orazio Taglialatela-Scafati
    • 4
  • Giovanni Appendino
    • 3
  • Bernd Nilius
    • 1
  1. 1.Department of Molecular Cell Biology, Laboratory Ion Channel Research, Campus GasthuisbergKatholieke Universiteit LeuvenLeuvenBelgium
  2. 2.Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping HospitalThird Military Medical University, Chongqing Institute of HypertensionChongqingChina
  3. 3.Dipartimento di Scienze ChimicheAlimentari, Farmaceutiche e FarmacologicheNovaraItaly
  4. 4.Dipartimento di Chimica delle Sostanze NaturaliUniversità di Napoli Federico IINaplesItaly

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