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Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels.

Kozai D, Sakaguchi R, Ohwada T, Mori Y - Curr Neuropharmacol (2015)

Bottom Line: More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels.It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine.In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyoku, Kyoto 615-8510, Japan. mori@sbchem.kyoto-u.ac.jp.

ABSTRACT
The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

No MeSH data available.


Related in: MedlinePlus

Predicted structural features of TRPA1 with putative position of critical residues involved in human TRPA1 modulationby compounds. TRPA1 subunit, which has six transmembrane (TM) domains, a pore-forming region between TM5 and TM6, and many ankyrin repeats (indicated as ovals) in the cytoplasmic Nterminalregion [35], assembles into tetramers to form a cation channel. Collectively, indicated residues (filled circles) are reported to be important for TRPA1 activation or inhibition by severalcompounds [30-33, 76, 80, 91, 128, 130, 133].
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Figure 1: Predicted structural features of TRPA1 with putative position of critical residues involved in human TRPA1 modulationby compounds. TRPA1 subunit, which has six transmembrane (TM) domains, a pore-forming region between TM5 and TM6, and many ankyrin repeats (indicated as ovals) in the cytoplasmic Nterminalregion [35], assembles into tetramers to form a cation channel. Collectively, indicated residues (filled circles) are reported to be important for TRPA1 activation or inhibition by severalcompounds [30-33, 76, 80, 91, 128, 130, 133].

Mentions: TRPA1 proteins form a plasma membrane channel that contains many ankyrin repeats in its cytoplasmic N-terminal region [34, 35] and can form a tetrameric assembly [36] (Fig. 1). TRPA1 is expressed in a subset of nociceptive C-fiber neurons, including the dorsal root, trigeminal and nodose ganglion neurons [37-39]. It is targeted by environmental irritants, such as allyl isothiocyanate (AITC) from mustard oil and wasabi, cinnamaldehyde from cinnamon oil, allicin from garlic, and acrolein present in tear gas or vehicle exhaust [40-44]. These environmental irritants are electrophiles [30, 31], and further studies using Trpa1 knockout mice have shown that TRPA1 acts as a nociceptor for electrophilic environmental irritants to produce pain [42, 45-48]. ROS, RNS and lipid peroxidation products also activate TRPA1, and can induce a TRPA1-mediated pain sensation [49-53]. In terms of disorders, it is known that the activation of TRPA1 by oxidative stress byproducts is reported to mediate both diabetic and anti-cancer medicine-induced neuropathic pain [54-57]. TRPA1 is also involved in neurogenic inflammation, respiratory irritation and coughing elicited by electrophiles [49, 51, 58-62]. Therefore, oxidative stress-sensitive TRPA1 has been proposed as a potential drug target for the treatment of neurological diseases.


Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels.

Kozai D, Sakaguchi R, Ohwada T, Mori Y - Curr Neuropharmacol (2015)

Predicted structural features of TRPA1 with putative position of critical residues involved in human TRPA1 modulationby compounds. TRPA1 subunit, which has six transmembrane (TM) domains, a pore-forming region between TM5 and TM6, and many ankyrin repeats (indicated as ovals) in the cytoplasmic Nterminalregion [35], assembles into tetramers to form a cation channel. Collectively, indicated residues (filled circles) are reported to be important for TRPA1 activation or inhibition by severalcompounds [30-33, 76, 80, 91, 128, 130, 133].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4598439&req=5

Figure 1: Predicted structural features of TRPA1 with putative position of critical residues involved in human TRPA1 modulationby compounds. TRPA1 subunit, which has six transmembrane (TM) domains, a pore-forming region between TM5 and TM6, and many ankyrin repeats (indicated as ovals) in the cytoplasmic Nterminalregion [35], assembles into tetramers to form a cation channel. Collectively, indicated residues (filled circles) are reported to be important for TRPA1 activation or inhibition by severalcompounds [30-33, 76, 80, 91, 128, 130, 133].
Mentions: TRPA1 proteins form a plasma membrane channel that contains many ankyrin repeats in its cytoplasmic N-terminal region [34, 35] and can form a tetrameric assembly [36] (Fig. 1). TRPA1 is expressed in a subset of nociceptive C-fiber neurons, including the dorsal root, trigeminal and nodose ganglion neurons [37-39]. It is targeted by environmental irritants, such as allyl isothiocyanate (AITC) from mustard oil and wasabi, cinnamaldehyde from cinnamon oil, allicin from garlic, and acrolein present in tear gas or vehicle exhaust [40-44]. These environmental irritants are electrophiles [30, 31], and further studies using Trpa1 knockout mice have shown that TRPA1 acts as a nociceptor for electrophilic environmental irritants to produce pain [42, 45-48]. ROS, RNS and lipid peroxidation products also activate TRPA1, and can induce a TRPA1-mediated pain sensation [49-53]. In terms of disorders, it is known that the activation of TRPA1 by oxidative stress byproducts is reported to mediate both diabetic and anti-cancer medicine-induced neuropathic pain [54-57]. TRPA1 is also involved in neurogenic inflammation, respiratory irritation and coughing elicited by electrophiles [49, 51, 58-62]. Therefore, oxidative stress-sensitive TRPA1 has been proposed as a potential drug target for the treatment of neurological diseases.

Bottom Line: More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels.It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine.In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyoku, Kyoto 615-8510, Japan. mori@sbchem.kyoto-u.ac.jp.

ABSTRACT
The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

No MeSH data available.


Related in: MedlinePlus