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Special Issue "TRPA1 Channel"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2021).

Special Issue Editors

Dr. Viktorie Vlachova

Guest Editor
Department of Cellular Neurophysiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic
Interests: thermosensitive TRP channels; membrane biophysics; electrophysiology; nociception; mathematical modeling
Prof. Peter M. Zygmunt

Guest Editor
Department of Clinical Sciences Malmö, Lund University, SE-214 28 Malmö, Sweden
Interests: TRP channel chemosensitivity; TRP channel thermosensitivity; TRP channel mechanosensitivity; TRP secretory cell signaling; TRP pharmacology; nociception; pain

Special Issue Information

Dear Colleagues,

The transient receptor potential ankyrin 1 receptor (TRPA1) is a cation channel expressed in dorsal root, trigeminal, and visceral primary sensory neurons, but also in various non-neuronal cells such as lung fibroblast and epithelial cells, smooth muscle cells, hair cells, keratinocytes, odontoblasts, astroglia, Schwann cells, and arterial vessels. There, TRPA1 acts as a multipurpose sensor of harmful signals, being activated by a wide range of chemical and physical stimuli. Accumulating evidence links the physiological functions of TRPA1 to nociception, inflammation, temperature perception, mechanosensation, insulin secretion, itching, respiratory functions, regulation of the cardiovascular system, and also the homeostatic balance between the immune and nociceptive systems. Given the wide expression pattern of TRPA1, a precise knowledge of the channel function is essential before it can be considered a potential target for the development of new, safe, and clinically relevant drugs.

Until very recently, information about the three-dimensional structure of TRPA1 has lagged behind information obtained from mutational and functional studies. At the break of 2019/2020, high-resolution structures of TRPA1 in different conformations have been published as a result of the recent “resolution revolution” in single-particle cryo-electron microscopy. Obviously, these new findings will further allow the rationalization of structure–activity studies, understanding the functional impact of TRPA1 genetic polymorphisms, and, perhaps more importantly, rational screening of novel modulators as potential selective therapeutic agents.

This Special Issue will provide a platform for original research papers and reviews describing the most recent findings in the TRPA1 field, covering any topics related to the biophysics, structure, pharmacology, physiological/pathophysiological roles, new molecular-based therapeutic strategies, and human genetic association studies.

Dr. Viktorie Vlachova
Prof. Peter M. Zygmunt
Guest Editors

Manuscript Submission Information

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Keywords

  • Transient receptor potential ankyrin subtype 1
  • Structure-function
  • Pain
  • Sensory neuron
  • Inflammation
  • Thermosensitive TRP channel
  • Mechanosensitive TRP channel

Published Papers (4 papers)

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Research

Open AccessArticle
Renal Tubular Epithelial TRPA1 Acts as An Oxidative Stress Sensor to Mediate Ischemia-Reperfusion-Induced Kidney Injury through MAPKs/NF-κB Signaling
Int. J. Mol. Sci. 2021, 22(5), 2309; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052309 - 25 Feb 2021
Abstract
Oxidative stress and inflammation play important roles in the pathophysiology of acute kidney injury (AKI). Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable ion channel that is sensitive to reactive oxygen species (ROS). The role of TRPA1 in AKI remains unclear. In [...] Read more.
Oxidative stress and inflammation play important roles in the pathophysiology of acute kidney injury (AKI). Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable ion channel that is sensitive to reactive oxygen species (ROS). The role of TRPA1 in AKI remains unclear. In this study, we used human and animal studies to assess the role of renal TRPA1 in AKI and to explore the regulatory mechanism of renal TRPA1 in inflammation via in vitro experiments. TRPA1 expression increased in the renal tubular epithelia of patients with AKI. The severity of tubular injury correlated well with tubular TRPA1 or 8-hydroxy-2′-deoxyguanosine expression. In an animal model, renal ischemia-reperfusion injury (IR) increased tubular TRPA1 expression in wild-type (WT) mice. Trpa1/ mice displayed less IR-induced tubular injury, oxidative stress, inflammation, and dysfunction in kidneys compared with WT mice. In the in vitro model, TRPA1 expression increased in renal tubular cells under hypoxia-reoxygenation injury (H/R) conditions. We demonstrated that H/R evoked a ROS-dependent TRPA1 activation, which elevated intracellular Ca2+ level, increased NADPH oxidase activity, activated MAPK/NF-kB signaling, and increased IL-8. Renal tubular TRPA1 may serve as an oxidative stress sensor and a crucial regulator in the activation of signaling pathways and promote the subsequent transcriptional regulation of IL-8. These actions might be evident in mice with IR or patients with AKI. Full article
(This article belongs to the Special Issue TRPA1 Channel)
Open AccessArticle
Calmodulin Supports TRPA1 Channel Association with Opioid Receptors and Glutamate NMDA Receptors in the Nervous Tissue
Int. J. Mol. Sci. 2021, 22(1), 229; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010229 - 28 Dec 2020
Abstract
Transient receptor potential ankyrin member 1 (TRPA1) belongs to the family of thermo TRP cation channels that detect harmful temperatures, acids and numerous chemical pollutants. TRPA1 is expressed in nervous tissue, where it participates in the genesis of nociceptive signals in response to [...] Read more.
Transient receptor potential ankyrin member 1 (TRPA1) belongs to the family of thermo TRP cation channels that detect harmful temperatures, acids and numerous chemical pollutants. TRPA1 is expressed in nervous tissue, where it participates in the genesis of nociceptive signals in response to noxious stimuli and mediates mechanical hyperalgesia and allodynia associated with different neuropathies. The glutamate N-methyl-d-aspartate receptor (NMDAR), which plays a relevant role in allodynia to mechanical stimuli, is connected via histidine triad nucleotide-binding protein 1 (HINT1) and type 1 sigma receptor (σ1R) to mu-opioid receptors (MORs), which mediate the most potent pain relief. Notably, neuropathic pain causes a reduction in MOR antinociceptive efficacy, which can be reversed by blocking spinal NMDARs and TRPA1 channels. Thus, we studied whether TRPA1 channels form complexes with MORs and NMDARs that may be implicated in the aforementioned nociceptive signals. Our data suggest that TRPA1 channels functionally associate with MORs, delta opioid receptors and NMDARs in the dorsal root ganglia, the spinal cord and brain areas. These associations were altered in response to pharmacological interventions and the induction of inflammatory and also neuropathic pain. The MOR-TRPA1 and NMDAR-TRPA1 associations do not require HINT1 or σ1R but appear to be mediated by calcium-activated calmodulin. Thus, TRPA1 channels may associate with NMDARs to promote ascending acute and chronic pain signals and to control MOR antinociception. Full article
(This article belongs to the Special Issue TRPA1 Channel)
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Open AccessArticle
Phospho-Mimetic Mutation at Ser602 Inactivates Human TRPA1 Channel
Int. J. Mol. Sci. 2020, 21(21), 7995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217995 - 27 Oct 2020
Abstract
The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an integrative molecular sensor for detecting environmental irritant compounds, endogenous proalgesic and inflammatory agents, pressure, and temperature. Different post-translational modifications participate in the discrimination of the essential functions of TRPA1 in its physiological environment, [...] Read more.
The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an integrative molecular sensor for detecting environmental irritant compounds, endogenous proalgesic and inflammatory agents, pressure, and temperature. Different post-translational modifications participate in the discrimination of the essential functions of TRPA1 in its physiological environment, but the underlying structural bases are poorly understood. Here, we explored the role of the cytosolic N-terminal residue Ser602 located near a functionally important allosteric coupling domain as a potential target of phosphorylation. The phosphomimetic mutation S602D completely abrogated channel activation, whereas the phosphonull mutations S602G and S602N produced a fully functional channel. Using mutagenesis, electrophysiology, and molecular simulations, we investigated the possible structural impact of a modification (mutation or phosphorylation) of Ser602 and found that this residue represents an important regulatory site through which the intracellular signaling cascades may act to reversibly restrict or “dampen” the conformational space of the TRPA1 channel and promote its transitions to the closed state. Full article
(This article belongs to the Special Issue TRPA1 Channel)
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Open AccessArticle
Electrophile-Induced Conformational Switch of the Human TRPA1 Ion Channel Detected by Mass Spectrometry
Int. J. Mol. Sci. 2020, 21(18), 6667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186667 - 11 Sep 2020
Abstract
The human Transient Receptor Potential A1 (hTRPA1) ion channel, also known as the wasabi receptor, acts as a biosensor of various potentially harmful stimuli. It is activated by a wide range of chemicals, including the electrophilic compound N-methylmaleimide (NMM), but the mechanism of [...] Read more.
The human Transient Receptor Potential A1 (hTRPA1) ion channel, also known as the wasabi receptor, acts as a biosensor of various potentially harmful stimuli. It is activated by a wide range of chemicals, including the electrophilic compound N-methylmaleimide (NMM), but the mechanism of activation is not fully understood. Here, we used mass spectrometry to map and quantify the covalent labeling in hTRPA1 at three different concentrations of NMM. A functional truncated version of hTRPA1 (Δ1-688 hTRPA1), lacking the large N-terminal ankyrin repeat domain (ARD), was also assessed in the same way. In the full length hTRPA1, the labeling of different cysteines ranged from nil up to 95% already at the lowest concentration of NMM, suggesting large differences in reactivity of the thiols. Most important, the labeling of some cysteine residues increased while others decreased with the concentration of NMM, both in the full length and the truncated protein. These findings indicate a conformational switch of the proteins, possibly associated with activation or desensitization of the ion channel. In addition, several lysines in the transmembrane domain and the proximal N-terminal region were labeled by NMM, raising the possibility that lysines are also key targets for electrophilic activation of hTRPA1. Full article
(This article belongs to the Special Issue TRPA1 Channel)
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