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Curcumin ((E,E)‐1,7‐bis(4‐Hydroxy‐3‐methoxyphenyl)‐1,6‐heptadiene‐3,5‐dione) activates and desensitizes the nociceptor ion channel TRPA1
Author(s) -
Ghatta Srinivas,
Leamy Andrew W,
Mcalexander M Allen,
Carr Michael J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb687
Subject(s) - chemistry , trpv1 , transient receptor potential channel , trpv , biophysics , patch clamp , ruthenium red , ion channel , hek 293 cells , curcumin , capsaicin , biochemistry , calcium , receptor , biology , organic chemistry
Many TRPA1 ion channel activators are reactive electrophiles that form Michael adducts with cysteine and lysine residues in TRPA1’s intracellular N‐terminus. Curcumin (CUR), the active principle of turmeric root ( Curcuma longa ), can form Michael adducts. To test the hypothesis that the electrophilic CUR activates TRPA1 and desensitizes in presence of physiological levels of calcium, we have performed whole‐cell voltage‐clamp analysis on both human TRPA1 heterologously expressed in HEK293 cells (hTRPA1) and native mouse vagal neurons. In nominally calcium‐free solutions to minimize calcium‐dependent indirect activation of TRPA1, CUR increased TRPA1 currents in hTRPA1 cells in a concentration‐dependent manner (1 – 30 μM) but did not activate recombinant TRPM8, TRPV1, or TRPV4 channels. In 7/11 vagal neurons from wild type mice, CUR (30 μM) produced inward currents (11.6 ± 5.4 pA/pF) that were largely reversed by the non‐specific ion channel blocker, ruthenium red (10 μM) or the selective blockers, AP‐18 (20 μM) and HC‐030031 (20 μM). By contrast, 6 capsaicin‐sensitive neurons from TRPA1‐deficient mice did not respond to CUR. CUR‐dependent currents in hTRPA1‐HEK cells desensitized completely and exhibited marked tachyphylaxis. The data demonstrate that CUR causes activation and subsequent desensitization of native and recombinant TRPA1 ion channels of multiple mammalian species.