Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

Flynn, Rachel; Chapman, Kevin; Iftinca, Mircea; Aboushousha, Reem; Varela, Diego; Altier, Christophe

doi:10.1074/jbc.m114.558668

Cited by 33 publications

(32 citation statements)

References 43 publications

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“…This could explain, at least in part, the slight discrepancy in the results obtained from VMR to CRD and the LABORAS recordings in our model. Indeed, although changes in mobility and climbing activity observed in the recovery animals would normally be associated with allodynia (pain to innocuous stimuli), the VMR technique showed visceral hypersensitivity only upon noxious distension pressures (45-60 mmHg), rather that innocuous stimulation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). This may reflect the involvement of additional central mechanisms other than peripheral sensitization in our model.…”

Section: Discussionmentioning

confidence: 57%

“…The NK-1-pcDNA3.1ϩ expression vector was purchased from Missouri S&T cDNA Resource Center (Rolla, MO). Rat TRPV1 containing an extracellular HA epitope (TRPV1-HA) was made by introducing a ClaI restriction site into TRPV1-pcDNA5/FRT (A. Patapoutian) between residues H614 and K615, located in the S5-S6 linker upstream of the reentrant loop, then cloning in annealed sticky-ended oligonucleotides coding for the HA sequence (20). TRP ankyrin 1 (TRPA1)-pcDNA5/FRT (A. Patapoutian) was used as a PCR template to make TRPA1-yellow fluorescent protein (YFP) by introducing NheI and KpnI sites and cloning into pEYFP-N1 (Clontech, Mountain View, CA).…”

Section: Methodsmentioning

confidence: 99%

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TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis

Lapointe

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Iftinca

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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105

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Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild-type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1-deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation.

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Section: Discussionmentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis

Lapointe

Basso

Iftinca

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

105

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“…3C). The former three Cys residues are within or vicinal to an ankyrin repeat domain (ARD), and Cys-742 was previously predicted to interface the neighboring subunit (3,43). ARD and the C terminus were hypothesized to mediate subunit interactions based on the high resolution structure (3), where ARD interfaces the ARD-S1 (S1: the first transmembrane region) linker region and the C-terminal ␤-strands of the neighboring subunit (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional and Structural Divergence in Human TRPV1 Channel Subunits by Oxidative Cysteine Modification

Ogawa

Kurokawa

Fujiwara

et al. 2016

Journal of Biological Chemistry

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Transient receptor potential vanilloid 1 (TRPV1) channel is a tetrameric protein that acts as a sensor for noxious stimuli such as heat and for diverse inflammatory mediators such as oxidative stress to mediate nociception in a subset of sensory neurons. In TRPV1 oxidation sensing, cysteine (Cys) oxidation has been considered as the principle mechanism; however, its biochemical basis remains elusive. Here, we characterize the oxidative status of Cys residues in differential redox environments and propose a model of TRPV1 activation by oxidation. Through employing a combination of non-reducing SDS-PAGE, electrophysiology, and mass spectrometry we have identified the formation of subunit dimers carrying a stable intersubunit disulfide bond between Cys-258 and Cys-742 of human TRPV1 (hTRPV1). C258S and C742S hTRPV1 mutants have a decreased protein half-life, reflecting the role of the intersubunit disulfide bond in supporting channel stability. Interestingly, the C258S hTRPV1 mutant shows an abolished response to oxidants. Mass spectrometric analysis of Cys residues of hTRPV1 treated with hydrogen peroxide shows that Cys-258 is highly sensitive to oxidation. Our results suggest that Cys-258 residues are heterogeneously modified in the hTRPV1 tetrameric complex and comprise Cys-258 with free thiol for oxidation sensing and Cys-258, which is involved in the disulfide bond for assisting subunit dimerization. Thus, the hTRPV1 channel has a heterogeneous subunit composition in terms of both redox status and function.

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“…Although TRPV1 is activated by heat and mechanical stimulation (Flynn et al . ), a primary role of capsaicin‐sensitive nerves in natural swallowing of a food bolus, liquid and saliva is very doubtful because the nerves are believed to be noxious C‐ and A‐fibres (Valtschanoff et al . ).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the epithelial sodium channel in initiation of mechanically evoked swallows in anaesthetized rats

Tsujimura

Ueha

Yoshihara

et al. 2019

The Journal of Physiology

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Key points Afferents carried by the superior laryngeal nerve play a primary role in the initiation of laryngeal mechanically evoked swallows in anaesthetized rats. Amiloride and its analogues inhibit swallowing evoked by mechanical stimulation, but not swallowing evoked by chemical and electrical stimulation. The epithelial sodium channel is probably involved in the initiation of laryngeal mechanically evoked swallows. Abstract The swallowing reflex plays a critical role in airway protection. Because impaired laryngeal mechanosensation is associated with food bolus aspiration, it is important to know how the laryngeal sensory system regulates swallowing initiation. This study was performed to clarify the neuronal mechanism of mechanically evoked swallows. Urethane‐anaesthetized Sprague–Dawley male rats were used. A swallow was identified by activation of the suprahyoid and thyrohyoid muscles on electromyography. The swallowing threshold was measured by von Frey filament and electrical stimulation of the larynx. The number of swallows induced by upper airway distension and capsaicin application (0.03 nmol, 3 μl) to the vocal folds was counted. The effects of topical application (0.3–30 nmol, 3 μl) of the epithelial sodium channel (ENaC) blocker amiloride and its analogues (benzamil and dimethylamiloride), acid‐sensing ion channel (ASIC) inhibitors (mambalgine‐1 and diminazene) and gadolinium to the laryngeal mucosa on swallowing initiation were evaluated. A nerve transection study indicated that afferents carried by the superior laryngeal nerve play a primary role in the initiation of laryngeal mechanically evoked swallows. The mechanical threshold of swallowing was increased in a dose‐dependent manner by amiloride and its analogues and gadolinium, but not by ASIC inhibitors. The number of swallows by upper airway distension was significantly decreased by benzamil application. However, the initiation of swallows evoked by capsaicin and electrical stimulation was not affected by benzamil application. We speculate that the ENaC is involved in the initiation of laryngeal mechanically evoked swallows.

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Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

Cited by 33 publications

References 43 publications

TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis

TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis

Functional and Structural Divergence in Human TRPV1 Channel Subunits by Oxidative Cysteine Modification

Involvement of the epithelial sodium channel in initiation of mechanically evoked swallows in anaesthetized rats

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