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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

Chemical structures of TRPA1 modulators other than Cys-targeted activators. Major non-Cys-targeted modulators and syntheticinhibitors of TRPA1 are shown.
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Figure 3: Chemical structures of TRPA1 modulators other than Cys-targeted activators. Major non-Cys-targeted modulators and syntheticinhibitors of TRPA1 are shown.

Mentions: As discussed above, oxidative stress mediators and environmental electrophiles activate TRPA1, but it has also been demonstrated that various other activators and inhibitors modulate TRPA1 (Fig. 3 and Table 1).


Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels.

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

Chemical structures of TRPA1 modulators other than Cys-targeted activators. Major non-Cys-targeted modulators and syntheticinhibitors of TRPA1 are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Chemical structures of TRPA1 modulators other than Cys-targeted activators. Major non-Cys-targeted modulators and syntheticinhibitors of TRPA1 are shown.
Mentions: As discussed above, oxidative stress mediators and environmental electrophiles activate TRPA1, but it has also been demonstrated that various other activators and inhibitors modulate TRPA1 (Fig. 3 and Table 1).

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