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      TRPA1-dependent calcium transients and CGRP release in DRG neurons require extracellular calcium

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          Abstract

          Refutation of TRPA1-mediated lysosomal calcium release in sensory neurons, emphasizing the requirement and influx of extracellular calcium through TRPA1 for activation.

          Abstract

          Shang et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201603081) reported that activation of lysosomal TRPA1 channels led to intracellular calcium transients and CGRP release from DRG neurons. We argue that both findings are more likely due to influx of insufficiently buffered extracellular calcium rather than lysosomal release.

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          Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.

          Michael Bandell, Gina M Story, Sun Wook Hwang … (2004)
          Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.
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            The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions.

            David D. McKemy, Clarice Waters, Emily R. Liman … (2008)
            The transient receptor potential A1 (TRPA1) channel is the molecular target for environmental irritants and pungent chemicals, such as cinnamaldehyde and mustard oil. Extracellular Ca(2+) is a key regulator of TRPA1 activity, both potentiating and subsequently inactivating it. In this report, we provide evidence that the effect of extracellular Ca(2+) on these processes is indirect and can be entirely attributed to entry through TRPA1 and subsequent elevation of intracellular calcium. Specifically, we found that in a pore mutant of TRPA1, D918A, in which Ca(2+) permeability was greatly reduced, extracellular Ca(2+) produced neither potentiation nor inactivation. Both processes were restored by reducing intracellular Ca(2+) buffering, which allowed intracellular Ca(2+) levels to become elevated upon entry through D918A channels. Application of Ca(2+) to the cytosolic face of excised patches was sufficient to produce both potentiation and inactivation of TRPA1 channels. Moreover, in whole cell recordings, elevation of intracellular Ca(2+) by UV uncaging of 1-(4,5-dimethoxy-2-nitrophenyl)-EDTA-potentiated TRPA1 currents. In addition, our data show that potentiation and inactivation are independent processes. TRPA1 currents could be inactivated by Mg(2+), Ba(2+), and Ca(2+) but potentiated only by Ba(2+) and Ca(2+). Saturating activation by cinnamaldehyde or mustard oil occluded potentiation but did not interfere with inactivation. Last, neither process was affected by mutation of a putative intracellular Ca(2+)-binding EF-hand motif. In conclusion, we have further clarified the mechanisms of potentiation and inactivation of TRPA1 using the D918A pore mutant, an important tool for investigating the contribution of Ca(2+) influx through TRPA1 to nociceptive signaling.
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              Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies.

              K Kistner, Susanne Sauer, Jeanne de la Roche … (2012)
              Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of the severity of the disorder. The electrophilic structure of this cytotoxic ketoaldehyde suggests TRPA1, a receptor channel deeply involved in inflammatory and neuropathic pain, as a molecular target. We demonstrate that extracellularly applied MG accesses specific intracellular binding sites of TRPA1, activating inward currents and calcium influx in transfected cells and sensory neurons, slowing conduction velocity in unmyelinated peripheral nerve fibers, and stimulating release of proinflammatory neuropeptides from and action potential firing in cutaneous nociceptors. Using a model peptide of the N terminus of human TRPA1, we demonstrate the formation of disulfide bonds based on MG-induced modification of cysteines as a novel mechanism. In conclusion, MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and thus is a promising target for medicinal chemistry.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Journal ID (iso-abbrev): J. Cell Biol
                Journal ID (publisher-id): jcb
                Title: The Journal of Cell Biology
                Publisher: Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date Collection: 01 June 2020
                Publication date (Electronic): 20 May 2020
                Volume: 219
                Issue: 6
                Electronic Location Identifier: e201702151
                Affiliations
                [1 ]Institute of Physiology & Pathophysiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
                [2 ]Center of Physiology & Pharmacology, Medical University, Vienna, Austria
                Author notes
                Correspondence to Peter W. Reeh: peter.reeh@ 123456fau.de
                [*]

                L. Gebhardt and T.I. Kichko contributed equally to this paper.

                Author information
                https://orcid.org/0000-0003-1383-5747
                https://orcid.org/0000-0003-1330-0849
                https://orcid.org/0000-0002-3811-7066
                https://orcid.org/0000-0002-4367-094X
                Article
                Publisher ID: jcb.201702151
                DOI: 10.1083/jcb.201702151
                PMC ID: 7265312
                PubMed ID: 32434221
                SO-VID: 1c618d46-c17d-4f16-b7e1-e477b4c9a0b3
                Copyright © © 2020 Gebhardt et al.
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                Date received : 12 June 2017
                Date revision received : 14 June 2018
                Date accepted : 20 August 2019
                Related
                Page count
                Pages: 6
                Funding
                Funded by: Deutsche Forschungsgemeinschaft, DOI http://doi.org/10.13039/501100001659;
                Award ID: Project E 27
                Award ID: DFG 704/3-1
                Categories
                Subject: Letter
                Subject: Physiology
                Subject: Organelles
                Subject: Neuroscience
                Subject: Cell Signaling

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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