Identification of Significant Amino Acids in Multiple Transmembrane Domains of Human Transient Receptor Potential Ankyrin 1 (TRPA1) for Activation by Eudesmol, an Oxygenized Sesquiterpene in Hop Essential Oil

Ohara, Kazuaki; Fukuda, Toshio; Okada, Hiroyuki; Kitao, Sayoko; Ishida, Yuko; Katō, K.; Takahashi, Chika; Katayama, Mikio; Uchida, Kunitoshi; Tominaga, Makoto

doi:10.1074/jbc.m114.600932

Cited by 27 publications

(23 citation statements)

References 32 publications

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“…It should be noted that ferutinin, a sesquiterpenic compound isolated from Ferula spp., has Ca 2+ ionophore properties [54] and can also induce Ca 2+ -dependent mitochondrial depolarization [55]. Another sesquiterpene, eudesmol, was recently reported as an activator of TRPA1 channels [56]. Thus, because the tested essential oils, with the exception of FEO Fr , contain eudesmane-type sesquiterpenes, we also cannot exclude roles of these sesquiterpenes in modulation of Ca 2+ flux in phagocytes by those essential oil extracts.…”

Section: Discussionmentioning

confidence: 97%

Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils

Özek

Schepetkin

Utegenova

et al. 2017

Journal of Leukocyte Biology

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Essential oil extracts from have been used traditionally in Kazakhstan for treatment of inflammation and other illnesses. Because little is known about the biologic activity of these essential oils that contributes to their therapeutic properties, we analyzed their chemical composition and evaluated their phagocyte immunomodulatory activity. The main components of the extracted essential oils were ()-propenyl -butyl disulfide (15.7-39.4%) and ()-propenyl -butyl disulfide (23.4-45.0%). essential oils stimulated [Ca] mobilization in human neutrophils and activated ROS production in human neutrophils and murine bone marrow phagocytes. Activation of human neutrophil [Ca] flux by essential oils was dose-dependently inhibited by capsazepine, a TRPV1 channel antagonist, indicating that TRPV1 channels mediate this response. Furthermore, essential oils stimulated Ca influx in TRPV1 channel-transfected HEK293 cells and desensitized the capsaicin-induced response in these cells. Additional molecular modeling with known TRPV1 channel agonists suggested that the active component is likely to be ()-propenyl -butyl disulfide. Our results provide a cellular and molecular basis to explain at least part of the beneficial therapeutic properties of FEOs.

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Section: Discussionmentioning

confidence: 97%

Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils

Özek

Schepetkin

Utegenova

et al. 2017

Journal of Leukocyte Biology

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“…The ARs form short helices assembled into an asymmetrical cylindrical tertiary structure possessing a surface available for protein interactions [22]. The influence of alterations within the individual ARs is relatively unexplored [23,24] compared with studies examining the transmembrane bundle [25][26][27][28][29] or C-terminal domain [30,31].…”

Section: Introductionmentioning

confidence: 99%

Genetic variants affecting human TRPA1 or TRPM8 structure can be classified in vitro as ‘well expressed’, ‘poorly expressed’ or ‘salvageable’

2015

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SynopsisMultiple mis-sense variants of TRPA1 (transient receptor potential A1) and TRPM8 (transient receptor potential M8) are recorded in the human genome single nt polymorphism (SNP) database, but their potential impact on channel signalling in patho-physiology is not fully explored. Variants, mostly quite rare in the general human population, alter sites in different structural domains of these homo-tetrameric ion channel proteins. The effects of individual SNPs affecting the large cytoplasmic N-terminal domain have not been completely documented for TRPM8 or TRPA1. We examined the Ca 2 + signalling properties of a short-list of eight variants affecting the N-terminal domain by individual expression in human embryonic kidney HEK293 or neuroblastoma (SH-SY5Y) cell lines (four SNP variants for TRPM8: G150R, K423N, R475C, R485W and four for TRPA1: Y69C, A366D, E477K, D573A). These were compared with TRPA1 SNP variants affecting intracellular loops located beyond the N-terminal domain and associated with gain of function (such as increased sensitivity to agonists: TRPA1 R797T and N855S). A substitution in TRPA1 (Y69C) exhibited high expression/sensitivity to agonists (high iCa 2 + max (maximum level of intracellular calcium ion), similar to R797T, but less sensitive than N855S), whereas each of the other non-conservative substitutions exhibited poor signalling response (low iCa 2 + max). Responses from these poorly expressed variants could be salvaged, to different extents, by pre-treating cells with the Src (Src protein) family inhibitor protein kinase inhibitor PP2 (PP2: 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo [3,4-d]pyrimidine, 4-Amino-5-(4-chlorophenyl)-7-(tbutyl)pyrazolo [3,4-d]pyrimidine), or with micromolar Zn 2 + . The TRPA1 variants and several experimental mutants (TRPA1 Y97F, Y226F and YY654-655FF) expressed poorly in SH-SY5Y compared with HEK293 cells. More in-depth studies are needed to identify SNP variants eliciting gain of function in these TRP (transient receptor potential) channels and to assess their roles in medical conditions.

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“…Electrophilic compounds are known to activate TRPA1 through covalent modification of cysteines and a lysine in the N-terminal region (12,13). In addition, the S5/S6 domain may serve as a target region for nonelectrophilic agonists, including menthol (14), eudesmol (15), and protons (16), or several antagonists (17,18), including the potent inhibitor A-967079 (14,(19)(20)(21). Furthermore, a recent electron cryo-microscopy (cryo-EM) study (22) has revealed the high-resolution structure of TRPA1 bound to an agonist or antagonists.…”

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confidence: 99%

Identification of a putative binding site critical for general anesthetic activation of TRPA1

Ton

Phan

Abramyan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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General anesthetics suppress CNS activity by modulating the function of membrane ion channels, in particular, by enhancing activity of GABA A receptors. In contrast, several volatile (isoflurane, desflurane) and i.v. (propofol) general anesthetics excite peripheral sensory nerves to cause pain and irritation upon administration. These noxious anesthetics activate transient receptor potential ankyrin repeat 1 (TRPA1), a major nociceptive ion channel, but the underlying mechanisms and site of action are unknown. Here we exploit the observation that pungent anesthetics activate mammalian but not Drosophila TRPA1. Analysis of chimeric Drosophila and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogenbond interactions with Ser-876, Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels.

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Identification of Significant Amino Acids in Multiple Transmembrane Domains of Human Transient Receptor Potential Ankyrin 1 (TRPA1) for Activation by Eudesmol, an Oxygenized Sesquiterpene in Hop Essential Oil

Cited by 27 publications

References 32 publications

Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils

Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils

Genetic variants affecting human TRPA1 or TRPM8 structure can be classified in vitro as ‘well expressed’, ‘poorly expressed’ or ‘salvageable’

Identification of a putative binding site critical for general anesthetic activation of TRPA1

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