ArticleThe Journal of general physiology2016
The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1.
Article in The Journal of general physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 64 citations in OpenAlex.
- A Human TRPA1-Specific Pain Model.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Trial
- TRP channels and cancer modulation: a voyage beyond metabolic reprogramming, oxidative stress and the advent of nanotechnologies in targeted therapy.Journal of experimental & clinical cancer research : CR · 2025Review
- Article
- The Contact Allergen Methylisothiazolinone (MIT) is a Potent Activator of the TRPA1 Ion Channel.Pharmacology research & perspectives · 2025Article
- Insights into Molecular Interactions and Biological Effect of Natural Stilbenoids at the TRPA1 Ion Channel.ChemMedChem · 2025Article
- Desensitization of TRPA1 by dimethyl itaconate attenuates acute and chronic pain in mice.Frontiers in pharmacology · 2025Article
- Development of covalent chemogenetic KCell chemical biology · 2024Article
- TRPA1 Covalent Ligand JT010 Modifies T Lymphocyte Activation.Biomolecules · 2024Article
- Functions of TRPs in retinal tissue in physiological and pathological conditions.Frontiers in molecular neuroscience · 2024Review
- Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology.Sub-cellular biochemistry · 2024Review
- A Novel Flp Reporter Mouse Shows That TRPA1 Expression Is Largely Limited to Sensory Neuron Subsets.eNeuro · 2023Article
- Development of covalent chemogenetic KbioRxiv : the preprint server for biology · 2023Article
- Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as a Sensor of Oxidative Stress in Cancer Cells.Cells · 2023Review
- Bipartite Activation of Sensory Neurons by a TRPA1 Agonist Allyl Isothiocyanate Is Reflected by Complex CaInternational journal of molecular sciences · 2023Article
- Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms.Frontiers in molecular neuroscience · 2023Review
- TRPA1-dependent and -independent activation by commonly used preservatives.Frontiers in pharmacology · 2023Article
- Elucidation of the binding mode of organic polysulfides on the human TRPA1 receptor.Frontiers in physiology · 2023Article
- CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain.Acta pharmaceutica Sinica. B · 2023Article
- Potent Activation of Human but Not Mouse TRPA1 by JT010.International journal of molecular sciences · 2022Article
- The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain.Nature communications · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
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Abstract
Activation of the sensory nerve ion channel TRPA1 by electrophiles is the key mechanism that initiates nociceptive signaling, and leads to defensive reflexes and avoidance behaviors, during oxidative stress in mammals. TRPA1 is rapidly activated by subtoxic levels of electrophiles, but it is unclear how TRPA1 outcompetes cellular antioxidants that protect cytosolic proteins from electrophiles. Here, using physiologically relevant exposures, we demonstrate that electrophiles react with cysteine residues on mammalian TRPA1 at rates that exceed the reactivity of typical cysteines by 6,000-fold and that also exceed the reactivity of antioxidant enzymes. We show that TRPA1 possesses a complex reactive cysteine profile in which C621 is necessary for electrophile-induced binding and activation. Modeling of deprotonation energies suggests that K620 contributes to C621 reactivity and mutation of K620 alone greatly reduces the effect of electrophiles on TRPA1. Nevertheless, binding of electrophiles to C621 is not sufficient for activation, which also depends on the function of another reactive cysteine (C665). Together, our results demonstrate that TRPA1 acts as an effective electrophilic sensor because of the exceptionally high reactivity of C621.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.