Reactivity Recognition by TRPA1 Channels

Cebi, Menekse; Koert, Ulrich

doi:10.1002/cbic.200700113

Cited by 12 publications

(7 citation statements)

References 15 publications

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“…It is similar to other electrophilic agonists including AITC and NMM, which activate TRPA1 by covalently modifying free thiol groups in cysteine side chains (Dennehy et al, 2006;Cebi and Koert, 2007). The human TRPA1 channel contains 28 cysteine residues.…”

Section: Discussionmentioning

confidence: 94%

“…The activation of TRPA1 occurs via two described mechanisms: First, electrophilic molecules (including AITC, cinnamaldehyde, allicin and N-methylmaleimide) react with free sulfhydryl groups on cysteine and the primary amine of lysine residues in the amino terminus, which leads to channel opening (Hinman et al, 2006;Cebi and Koert, 2007;Macpherson et al, 2007a). Mutagenesis studies show that residues Cys422, Cys621, Cys641, Cys665, and Lys710 (Hinman et al, 2006;Macpherson et al, 2007a) are crucial for activation by electrophiles.…”

Section: Introductionmentioning

confidence: 99%

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Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1

Ibarra

Blair

2013

Mol Pharmacol

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The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serinesubstituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium) ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1

Ibarra

Blair

2013

Mol Pharmacol

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“…enones), disulfides form protein cystein–disulfide products, or alkylation (e.g. iodoacetamides) (Cebi & Koert, 2007). It is still unknown whether different modifications have different effects on channel gating.…”

Section: Trpa1 Gating By Covalent Cystein Modificationmentioning

confidence: 99%

Irritating channels: the case of TRPA1

Nilius

Prenen

Owsianik

2011

The Journal of Physiology

123

117

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Transient receptor potential (TRP) channels have been extensively studied over the past years. Yet, in most cases, the gating mechanisms of these polymodal cation channels still remain a puzzle. Using the nociceptive channel TRPA1 as an example, we discuss the role of dynamic regulation of the pore size (pore dilatation) on channel gating. Additionally, we critically revise current knowledge of the role of intracellular domains, such as ankyrin repeats and EF hand motifs, in channel activation and function. Finally, we assess some problems inherent to activation of TRPA1 by the reaction of electrophilic compounds with the nucleophilic thiol sink of N-terminal reactive cysteines.

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“…Hydrogen peroxide (H 2 O 2 ) and ␣,␤-unsaturated aldehydes acutely activate TRPA1 (12)(13)(14)(15). The reactive compound allicin from garlic and nitric oxide activate TRPA1 and TRPV1 via covalent modification (16)(17)(18)(19)(20)(21)(22), providing examples for oxidative stress-related pain or hyperalgesia. H 2 O 2 was discovered to mediate thermal hyperalgesia through TRPV1-dependent and -independent mechanisms; TRPV1 is required for long sustenance of thermal hypersensitivity after strong oxidative challenge (23).…”

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confidence: 99%

Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification

Chuang

Lin

2009

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

167

119

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The capsaicin receptor TRPV1, one of the major transduction channels in the pain pathway, integrates information from extracellular milieu to control excitability of primary nociceptive neurons. Sensitization of TRPV1 heightens pain sensation to moderately noxious or even innocuous stimuli. We report here that oxidative stress markedly sensitizes TRPV1 in multiple species' orthologs. The sensitization can be recapitulated in excised insideout membrane patches, reversed by strong reducing agents, and blocked by pretreatment with maleimide that alkylates cysteines. We identify multiple cysteines required for full modulation of TRPV1 by oxidative challenges. Robust oxidative modulation recovers the agonist sensitivity of receptors desensitized by prolonged exposure to capsaicin. Moreover, oxidative modulation operates synergistically with kinase or proton modulations. Thus, oxidative modulation is a robust mechanism tuning TRPV1 activity via covalent modification of evolutionarily conserved cysteines and may play a role in pain sensing processes during inflammation, infection, or tissue injury.covalent modification ͉ pain

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Reactivity Recognition by TRPA1 Channels

Cited by 12 publications

References 15 publications

Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1

Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1

Irritating channels: the case of TRPA1

Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification

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