TY - JOUR
T1 - Umbellulone modulates TRP channels
AU - Zhong, Jian
AU - Minassi, Alberto
AU - Prenen, Jean
AU - Taglialatela-Scafati, Orazio
AU - Appendino, Giovanni
AU - Nilius, Bernd
N1 - Funding Information:
The work was supported by grants from the Belgian Federal Government (IUAP P6/28. BN), the Research Foundation-Flanders (F.W.O.) (G.0565.07 and G.0686.09, BN), and the Research Council of the KU Leuven (GOA 2009/07 and EF/95/010, BN). JZ was supported by grants from the Natural Science Foundation of China (no. 30900619) and the National Basic Research Program of China (no. 2012CB517806).
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Chemosensation
KW - Electrophiles
KW - Headache tree
KW - Menthol
KW - Mustard oil
KW - TRP channels
KW - TRPA1
KW - TRPM8
KW - Umbellulone
KW - Umbellulone derivatives
UR - http://www.scopus.com/inward/record.url?scp=83555165008&partnerID=8YFLogxK
U2 - 10.1007/s00424-011-1043-1
DO - 10.1007/s00424-011-1043-1
M3 - Article
SN - 0031-6768
VL - 462
SP - 861
EP - 870
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
IS - 6
ER -