Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Eberhardt, Mirjam; Filipovic, Milos R.; Leffler, Andreas; Kistner, Katrin; Fischer, Michael J.M.; Fleming, Thomas; Zimmermann, Katharina; Ivanović‐Burmazović, Ivana; Nawroth, Peter P.; Bierhaus, Angelika; Reeh, Peter W.; Sauer, Susanne K.

doi:10.1074/jbc.m111.328674

Cited by 176 publications

(191 citation statements)

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“…Therefore, to investigate whether TRPA1 can function in cardiac fibroblasts, the [Ca 2ϩ ] i measurement using fura-2 AM was applied. The effects of a dicarbonyl compound MG, an agent to activate TRPA1 (13,26,53) Figure 3B showed the concentration-dependent effects of MG on [Ca 2ϩ ] i . The increased value in F340/F380 measured at the peak level or 2 min after the application of MG with reference to F340/F380 at the resting state was plotted against each concentration of MG.…”

Section: Expression Of Trpa1 Protein In Human Cardiac Fibroblasts (Immentioning

confidence: 99%

“…In addition, it is very likely that MG stimulates TRPA1 through formation of reversible hemithioacetals with cysteine residues (26). To investigate this possibility, we examined the effect of the reducing agent, DTT (10 mM), on methylglyoxal-induced [Ca 2ϩ ] i .…”

Section: Expression Of Trpa1 Protein In Human Cardiac Fibroblasts (Immentioning

confidence: 99%

“…Diabetic neuropathy is one of diabetic complication. And it has been reported that a rise in serum MG density participates in diabetic neuropathy directly (9), and MG activates nociceptors through TRPA1 in diabetic neuropathy (26,53). Thus it is likely that MG may play a role in diabetic complication such as neuropathy.…”

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confidence: 99%

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Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels

Oguri

Nakajima

Yamamoto

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels. Am J Physiol Heart Circ Physiol 307: H1339 -H1352, 2014. First published August 29, 2014; doi:10.1152/ajpheart.01021.2013.-Cardiac fibroblasts contribute to the pathogenesis of cardiac remodeling. Methylglyoxal (MG) is an endogenous carbonyl compound produced under hyperglycemic conditions, which may play a role in the development of pathophysiological conditions including diabetic cardiomyopathy. However, the mechanism by which this occurs and the molecular targets of MG are unclear. We investigated the effects of MG on Ca 2ϩ signals, its underlying mechanism, and cell cycle progression/cell differentiation in human cardiac fibroblasts. The conventional and quantitative real-time RT-PCR, Western blot, immunocytochemical analysis, and intracellular Ca 2ϩ concentration [Ca 2ϩ ]i measurement were applied. Cell cycle progression was assessed using the fluorescence activated cell sorting. MG induced Ca 2ϩ entry concentration dependently. Ruthenium red (RR), a general cation channel blocker, and HC030031, a selective transient receptor potential ankyrin 1 (TRPA1) antagonist, inhibited MG-induced Ca 2ϩ entry. Treatment with aminoguanidine, a MG scavenger, also inhibited it. Allyl isothiocyanate, a selective TRPA1 agonist, increased Ca 2ϩ entry. The use of small interfering RNA to knock down TRPA1 reduced the MGinduced Ca 2ϩ entry as well as TRPA1 mRNA expression. The quantitative real-time RT-PCR analysis showed the prominent existence of TRPA1 mRNA. Expression of TRPA1 protein was confirmed by Western blotting and immunocytochemical analyses. MG promoted cell cycle progression from G0/G1 to S/G2/M, which was suppressed by HC030031 or RR. MG also enhanced ␣-smooth muscle actin expression. The present results suggest that methylglyoxal activates TRPA1 and promotes cell cycle progression and differentiation in human cardiac fibroblasts. MG might participate the development of pathophysiological conditions including diabetic cardiomyopathy via activation of TRPA1.human cardiac fibroblast; transient receptor potential ankyrin 1 channels; methylglyoxal CARDIAC FIBROBLASTS ARE THE predominant secretary cell types located within the extracellular matrix (ECM) (18), which account for 60ϳ70% of the cells in human hearts and play a key role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs with hypertension, heart failure, and myocardial infarction (12, 71). Many of the functional effects of cardiac fibroblasts are mediated through differentiation of cardiac fibroblasts to myofibroblasts phenotype that expresses contractile proteins such as ␣-smooth muscle actin (␣-SMA), and they consequently exhibit increased migratory and proliferative properties. Cardiac fibroblasts also take a part in the maintenance of myocardial function by producing the type I and type III collagens and by secreting growth factors (48), and a key source of components of the ECM that regulat...

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Section: Expression Of Trpa1 Protein In Human Cardiac Fibroblasts (Immentioning

confidence: 99%

Section: Expression Of Trpa1 Protein In Human Cardiac Fibroblasts (Immentioning

confidence: 99%

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Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels

Oguri

Nakajima

Yamamoto

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…The channel mediates, among others, the reaction to the pungent components of mustard, horseradish, and wasabi. TRPA1 is also activated by formaldehyde, bacterial endotoxins and proinflammatory mediators such as bradykinin, methylglyoxal, and prostaglandin E2 [71][72][73][74][75][76] . TRPA1 expression in sensory neuronal populations has little overlap with TRPM8 expression, but TRPA1 is highly co-expressed with TRPV1 and can form functional heteromultimers with TRPV1 77 , adding to the functional complexity of this channel.…”

Section: Trpa1mentioning

confidence: 99%

“…A monogenic TRPA1 gain-of-function mutation is also linked to a hereditary disease of episodic debilitating pain, which is triggered by cold 91 . Comparable mechanisms of TRPA1 sensitisation to cold may also apply for cold hypersensitivity in inflammatory conditions, as well as in diabetic neuropathy 71,72,79,92 .…”

Section: Trpa1mentioning

confidence: 99%

A pharmacological and transcriptomic approach to exploring novel pain targets

Yin¹

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Ever since the discovery that mutations in the voltage-gated sodium channel 1.7 protein are responsible for human congenital insensitivity to pain, the voltage-gated sodium channel (Na V ) family of ion channels has been the subject of intense research with the hope of discovering novel analgesics. We now know that Na V 1.7 deletion in select neuronal populations yield different phenotypes, with the deletion of Na V 1.7 in all sensory neurons being successful at abolishing mechanical and heat-induced pain. However, it is rapidly becoming apparent that a number of pain syndromes are not modulated by Na V 1.7 at all, such as oxaliplatin-mediated neuropathy. It is particularly interesting to note that the loss of Na V 1.7 function is also associated with the selective inhibition of pain mediated by specific stimuli, such as that observed in burn-induced pain where Na V 1.7 gene knockout abolished thermal allodynia but did not affect mechanical allodynia. Accordingly, significant interests exist in delineating the contribution of other Na V isoforms in modality-specific pain pathways. Two other isoforms, Na V 1.6 and Na V 1.8, are now specifically implicated in some Na V 1.7-independent conditions such as oxaliplatin-induced cold allodynia. Such selective contributions of specific ion channel isoforms to pain highlight the need to discover other putative protein targets involved in mediating nociception.The aim of my work is therefore to discover selective molecular inhibitors of Na V 1.6 and Na V 1.8, to find useful cell models for peripheral nociceptors, to investigate the roles of Na V 1.6 and Na V 1.8 in an animal model of burn-induced pain, and to screen for putative new targets for analgesia in burn-related pain.Chapter 2 of this thesis describes activity-guided discovery of novel Na V 1.6 and Na V 1.8-modulting peptides from crude spider venoms. Crude venom from Poecilotheria metallica successfully reduced Na V 1.8-mediated voltage changes in HEK293-expressing cells. A new Na V 1.8-inhibitory peptide was sequenced from the venom and named Pme1a. However, Pme1a exhibited TRPV1 agonist activity and induced nocifensive behaviours, such as paw licking, after injection into the hind paws of mice, indicating the peptide was not a selective Na V 1.8 modulator and was unsuitable as a tool for Na V 1.8 investigation.iii With the unsuccessful exploration of spider venoms for new specific inhibitors, I then investigated in vitro cell models as tools to research specific nociceptor subtypes that express Na V 1.6 or Na V 1.8. In Chapter 3, I provide the first complete transcriptome of three common in vitro neuronal cell lines (SH-SY5Y, F-11, and ND7/23) to examine whether they were appropriate for investigating the functions of Na V 1.6 and Na V 1.8, and to identify if the cell lines resemble in vivo dorsal root ganglion (DRG) neuronal subclasses. The three cell lines examined all expressed proteins belonging to similar pathways and of similar proportions to native DRG neurons. However, they did not express any ce...

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Transient receptor potential A1 channels regulate epithelial cell barriers formed by MDCK cells

et al. 2016

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Edited by Maurice MontalTransient receptor potential A1 channels are well-known as chemosensors in neuronal cells. However, recent studies also point to non-neuronal functions in epithelia. Here, we show that TRPA1 channels are expressed in epithelial MDCK II cells and contribute to Ca 2+ influx and whole-cell currents after stimulation with AITC. Stimulation of TRPA1 channels induced an immediate reduction of the transepithelial resistance of MDCK II cell layers that was blocked by the TRPA1 antagonist HC-030031. The present data provide strong evidence for a new role of TRPA1 channels in regulating the tightness of epithelial cell barriers.

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Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

Cited by 176 publications

References 93 publications

Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels

Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels

A pharmacological and transcriptomic approach to exploring novel pain targets

Transient receptor potential A1 channels regulate epithelial cell barriers formed by MDCK cells

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