1.A.4.6.3
The nociceptive neuron TRPA1 (Trp-ankyrin 1) (also called the Wasabi Receptor) senses peripheral damage by transmitting pain signals (activated by cold temperatures, pungent compounds and environmental irritants). Noxious compounds also activate through covalent modification of cysteyl residues (Macpherson et al., 2007). TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal) (Chen et al., 2008). General anesthetics activate TRPA1 nociceptive ion channels to enhance pain and inflammation (Matta et al., 2008; Leffler et al., 2011). TMS5 is a critical molecular determinant of menthol sensitivity (Xiao et al., 2008) and a variety of inhibitors which are analgesics.  Another class of inhibitors are in the thiadiazole structural class of compounds, and they bind to the TRPA1 ankyrin repeat 6 (Tseng et al. 2018). Inhibitors are potential analgesics. The majority of TRPA1 inhibitors interact with the S5 transmembrane helices, forming part of the pore region of the channel. TRPA1 is a component of the nociceptive response to CO₂ (Wang et al., 2010). TRPA1 is a polyunsaturated fatty acid sensor in mammals but not in flies and fish (Motter and Ahern, 2012). It  is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012).  Mutations in TrpA1 cause alterred pain perception (Kremeyer et al. 2010). The hop compound, eudesmol, an oxygenated sesquiterpene, activates the channel (Ohara et al. 2015).  These channels regulate heat and cold perception, mechanosensitivity, hearing, inflammation, pain, circadian rhythms, chemoreception, and other processes (Laursen et al. 2014).  TRPA1 is a polymodal ion channel sensitive to temperature and chemical stimuli, but its resposes are species specific (Laursen et al. 2015). A probable binding site for general anesthetics has been identified (Ton et al. 2017), and specific residues involved in binding of the anesthetic, propofol, are known (Woll et al. 2017). TrpV1 and TrpA1 are inflammatory mediators causing cutaneous chronic itch in several diseases (Xie and Li 2018). TRPA1 is specifically activated by natural products including allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), allicin (garlic) and trans-anethole in Fennel Oil (FO) (Memon et al. 2019). Mutations in TRPA1 result in insensitivity to pain promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019). TRPA1 transduces noxious chemical stimuli into nociceptor electrical excitation and neuropeptide release, leading to pain and neurogenic inflammation. It is regulated by the membrane environment.  Startek et al. 2019 found that mouse TRPA1 localizes to cholesterol-rich domains, and that cholesterol depletion decreases channel sensitivity to chemical agonists. Two structural motifs in TMSs 2 and 4 are involved in cholesterol interactions that are necessary for normal agonist sensitivity and plasma membrane localization. TRPA1 is an irritant sensor and a therapeutic target for treating pain, itch, and respiratory diseases. It can be activated by electrophilic compounds such as allyl isothiocyanate (AITC). A class of piperidine carboxamides (PIPCs) are potent noncovalent agonists (Chernov-Rogan et al. 2019). Saikosaponins are channel antogonists (Lee et al. 2019). hTRPA1 is activated by electrophiles such as N-methyl maleimide (NMM). A conformational switch of the protein, possibly associated with activation or desensitization of the ion channel, involves covalent derivatization of several cysteyl and lysyl residues in the transmembrane domain and the proximal N-terminal region as targets for electrophilic activation (Moparthi et al. 2020). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). As a polymodal nocisensor, TRPA1 can be activated by thermal and mechanical stimuli as well as a wide range of chemically damaging molecules including small volatile environmental toxicants and endogenous algogenic lipids (Zsidó et al. 2021). After activation by such compounds, the ion channel opens up, allowing calcium influx into the cytosol, inducing signal transduction pathways. Then, calcium influx desensitizes irritant evoked responses and results in an inactive state of the ion channel. It was shown how reversible interactions with binding sites contribute to structural changes of TRPA1, leading to covalent bonding of agonists (Zsidó et al. 2021). The binding site(s) for antagonists have been determined for the TRPA1 ion channel (Gawalska et al. 2022). The hTRPA1 C-terminial domain (CTD) harbors cold and heat sensitive domains allosterically coupled to the S5-S6 pore region and the VSLD, respectively (Moparthi et al. 2022). TRPA1 is a sensor for inflammation and oxidative stress which contribute to the pathophysiology of major depressive disorder (MDD), and TRPA1 channels appear crucial to mediate behavioral impairment induced by chronic corticosterone administration (CCA) (Pereira et al. 2023). Neuronal and non-neuronal TRPA1 are therapeutic targets for pain and headache relief (Iannone et al. 2023). A TRPA1 mutant (R919*), identified in CRAMPT syndrome patients, confers hyperactivity when co-expressed with wild type TRPA1. The R919* mutant co-assembles with WT TRPA1 subunits into heteromeric channels at the plasma membrane. The R919* mutant hyperactivates channels by enhancing agonist sensitivity and calcium permeability, which could account for the observed neuronal hypersensitivity-hyperexcitability symptoms. Possibly, R919* TRPA1 subunits contribute to heteromeric channel sensitization by altering pore architecture and lowering energetic barriers to channel activation (Bali et al. 2023). Platycodonis Radix, a widely consumed herbal food produces a bioactive constituents, platycodins, alleviates LPS-induced lung inflammation through modulation of TRPA1 channels (Yang et al. 2023). The TRPA1 ion channel mediates oxidative stress-related migraine pathogenesis (Fila et al. 2024).