NPPB structure-specifically activates TRPA1 channels

Liu, Kun; Samuel, Manoj; Ho, Melisa W.Y.; Harrison, Richard K.; Paslay, Jeff W.

doi:10.1016/j.bcp.2010.03.005

Cited by 28 publications

(30 citation statements)

References 28 publications

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“…؊/؊ mice Because IL-6 sensitizes nociceptors to mechanical stimuli and its receptor gp130 is required for the maintenance of mechanical hypersensitivity in several rodent models of pathological pain (Brenn et al, 2007;Quarta et al, 2011), we hypothesized that gp130 may be an important switch for the function of mechanonociceptors. Therefore, we assessed the reflex withdrawal thresholds to mechanical stimuli of increasing strength of Ϫ/Ϫ mice were less sensitive to mechanical stimulation than control mice.…”

Section: Reduced Mechanonociception In Sns-gp130mentioning

confidence: 99%

“…All mice were maintained under specific pathogen free conditions. TRPA1 Ϫ/Ϫ mice were a generous gift from Dr. David Corey (Harvard Medical School, Boston) and used as controls where appropriate (Kwan et al, 2006). Unless otherwise stated, animals of either sex and older than 8 weeks were used in all experiments.…”

Section: Animals Sns-gp130mentioning

confidence: 99%

“…An in vitro skin nerve preparation was used to investigate the properties of unmyelinated afferent nerve fibers innervating the skin of the mouse dorsal hindpaw as previously reported Quarta et al, 2011). The saphenous nerve was dissected with the skin of the dorsal hindpaw attached and mounted in an organ bath "inside-up" to expose the corium side.…”

Section: Animals Sns-gp130mentioning

confidence: 99%

“…Furthermore, IL-6 sensitizes nociceptors to noxious mechanical stimuli, and SNS-gp130 Ϫ/Ϫ mice are largely protected and recover faster from mechanical hypersensitivity in models of inflammatory, neuropathic, and cancer pain (Brenn et al, 2007;Quarta et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

Malsch

Andratsch

Vogl

et al. 2014

Journal of Neuroscience

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Glycoprotein 130 (gp130) is the signal transducing receptor subunit for cytokines of the interleukin-6 (IL-6) family, and it is expressed in a multitude of cell types of the immune and nervous system. IL-6-like cytokines are not only key regulators of innate immunity and inflammation but are also essential factors for the differentiation and development of the somatosensory system. Mice with a null mutation of gp130 in primary nociceptive afferents (SNS-gp130 ؊/؊ ) are largely protected from hypersensitivity to mechanical stimuli in mouse models of pathological pain. Therefore, we set out to investigate how neuronal gp130 regulates mechanonociception. SNSgp130 ؊/؊ mice revealed reduced mechanosensitivity to high mechanical forces in the von Frey assay in vivo, and this was associated with a reduced sensitivity of nociceptive primary afferents in vitro. Together with these findings, transient receptor potential ankyrin 1 (TRPA1) mRNA expression was significantly reduced in DRG from SNS-gp130 ؊/؊ mice. This was also reflected by a reduced number of neurons responding with calcium transients to TRPA1 agonists in primary DRG cultures. Downregulation of Trpa1 expression was predominantly discovered in nonpeptidergic neurons, with the deficit becoming evident during stages of early postnatal development. Regulation of Trpa1 mRNA expression levels downstream of gp130 involved the classical Janus kinase family-signal transducer and activator of transcription pathway. Our results closely link proinflammatory cytokines to the expression of TRPA1, both of which have been shown to contribute to hypersensitive pain states. We suggest that gp130 has an essential role in mechanonociception and in the regulation of TRPA1 expression.

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Section: Reduced Mechanonociception In Sns-gp130mentioning

confidence: 99%

Section: Animals Sns-gp130mentioning

confidence: 99%

Section: Animals Sns-gp130mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

Malsch

Andratsch

Vogl

et al. 2014

Journal of Neuroscience

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“…NH-ABBH, NCHO-ABBH, and NMe-ABBH did induce [Ca 21 ] i increases in TRPA1-expressing HEK 293 cells, but only at higher concentrations. It has been shown that some nonelectrophilic compounds can activate TRPA1 by noncovalent ligand-receptor interaction (Karashima et al, 2007;Maher et al, 2008;Xiao et al, 2008;Hu et al, 2010;Liu et al, 2010;Nagatomo et al, 2010;Zhong et al, 2011a,b). However, the precise molecular mechanism by which noncovalent binding compounds activate TRPA1 remains controversial.…”

Section: Trpa1 Subtype Selectivity Of Nitrosaminesmentioning

confidence: 99%

Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

et al. 2013

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S-Nitrosylation, the addition of a nitrosyl group to cysteine thiols, regulates various protein functions to mediate nitric oxide (NO) bioactivity. Recent studies have demonstrated that selectivity in protein S-nitrosylation signaling pathways is conferred through transnitrosylation, a transfer of the NO group, between proteins via interaction. We previously demonstrated that sensitivity to activation by synthetic NO-releasing agents via S-nitrosylation is a common feature of members of the transient receptor potential (TRP) family of Ca 21 -permeable cation channels. However, strategies to confer subtype selectivity to nitrosylating agents targeted to TRP channels are yet to be developed. Here, we show selective activation of TRPA1 channels by novel NO donors derived from the ABBH (7-azabenzobicyclo[2.2.1]heptane) N-nitrosamines, which exhibit transnitrosylation reactivity to thiols without releasing NO. The NNO-ABBH1 (N-nitroso-2-exo,3-exo-ditrifluoromethyl-7-azabenzobicyclo[2.2.1]heptane) elicits S-nitrosylation of TRPA1 proteins, and dose-dependently induces robust Ca 21 influx via both recombinant and native TRPA1 channels, but not via other NO-activated TRP channels. TRPA1 activation by NNO-ABBH1 is suppressed by specific cysteine mutations but not by NO scavenging, suggesting that cysteine transnitrosylation underlies the activation of TRPA1 by NNO-ABBH1. This is supported by the correlation of N-NO bond reactivity and TRPA1-activating potency in a congeneric series of ABBH N-nitrosamines. Interestingly, nonelectrophilic derivatives of ABBH also activate TRPA1 selectively, but less potently, compared with NNO-ABBH1. Thus, ABBH N-nitrosamines confer subtype selectivity on S-nitrosylation in TRP channels through synergetic effects of two chemical processes: cysteine transnitrosylation and molecular recognition of the nonelectrophilic moiety.

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Trpa1

Zygmunt

Högestätt

2014

Handbook of Experimental Pharmacology

203

201

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The transient receptor potential ankyrin subtype 1 protein (TRPA1) is a nonselective cation channel permeable to Ca(2+), Na(+), and K(+). TRPA1 is a promiscuous chemical nocisensor that is also involved in noxious cold and mechanical sensation. It is present in a subpopulation of Aδ- and C-fiber nociceptive sensory neurons as well as in other sensory cells including epithelial cells. In primary sensory neurons, Ca(2+) and Na(+) flowing through TRPA1 into the cell cause membrane depolarization, action potential discharge, and neurotransmitter release both at peripheral and central neural projections. In addition to being activated by cysteine and lysine reactive electrophiles and oxidants, TRPA1 is indirectly activated by pro-inflammatory agents via the phospholipase C signaling pathway, in which cytosolic Ca(2+) is an important regulator of channel gating. The finding that non-electrophilic compounds, including menthol and cannabinoids, activate TRPA1 may provide templates for the design of non-tissue damaging activators to fine-tune the activity of TRPA1 and raises the possibility that endogenous ligands sharing binding sites with such non-electrophiles exist and regulate TRPA1 channel activity. TRPA1 is promising as a drug target for novel treatments of pain, itch, and sensory hyperreactivity in visceral organs including the airways, bladder, and gastrointestinal tract.

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NPPB structure-specifically activates TRPA1 channels

Cited by 28 publications

References 28 publications

Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

Trpa1

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