Transient Receptor Potential Ankyrin Research Articles

Formaldehyde and the transient receptor potential ankyrin-1 contribute to electronic cigarette aerosol-induced endothelial dysfunction in mice.

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

Low temperature inhibits food intake via TRPA1 channel activation in Nile tilapia (Oreochromis niloticus)

Low temperatures significantly influence feeding behavior in ectothermic vertebrates, but the underlying mechanisms remain elusive. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in mediating the appetite-suppressing effects of low temperature in Nile tilapia. TRPA1 was found to be highly expressed in the hypothalamus and co-localized with neuropeptide Y (NPY) neurons. Exposure to low temperatures reduced feeding frequency and increased TRPA1 expression. In vitro experiments demonstrated that low temperature and TRPA1 agonists induced calcium influx, which was blocked by a TRPA1 inhibitor. TRPA1 expression exhibited post-prandial increases and was downregulated by fasting. TRPA1 activation dose-dependently inhibited food intake, while its inhibition restored feeding suppressed by low temperature. TRPA1 activation downregulated orexigenic factors and upregulated anorexigenic factors through Ca2+/calmodulin-dependent pathways. These findings suggest that TRPA1 plays a crucial role in sensing low temperatures and regulating feeding behavior in tilapia.

TRPA1 nanovesicle-conjugated receptonics for rapid biocide screening

Although biocides are important materials in modern society and help protect human health and the environment, increasing exposure to combined biocides can cause severe side effects in the human body, such as lung fibrosis. In this study, we developed a receptonics system to screen for biocides in combined household chemical products based on biocides. The system contains transient receptor potential ankyrin 1 (TRPA1) nanovesicles (NVs) to sense biocides based on pain receptors and a side-gated field-effect transistor (SGFET) using a single-layer graphene (SLG) micropattern channel. The binding affinities between the TRPA1 receptor and the various biocides were estimated by performing biosimulation and using a calcium ion (Ca2+) assay, and the sensitivity of the system was compared with that of TRPA1 NV receptonics systems. Based on the results of the TRPA1 NV receptonics system, the antagonistic and potentiation effects of combined biocides and household chemical products depended on the concentration. Finally, the TRPA1 NV receptonics system was applied to screen for biocides in real products, and its performance was successful. Based on these results, the TRPA1 NV receptonics system can be utilized to perform risk evaluations and identify biocides in a simple and rapid manner.

TRPA1, TRPV1, and Caffeine: Pain and Analgesia.

Caffeine (1,3,7-trimethylxanthine) is a naturally occurring methylxanthine that acts as a potent central nervous system stimulant found in more than 60 different plants and fruits. Although caffeinated beverages are widely and casually consumed, the application of caffeine beyond dietary levels as pharmacologic therapy has been recognized since the beginning of its recorded use. The analgesic and vasoactive properties of caffeine are well known, but the extent of their molecular basis remains an area of active research. There is existing evidence in the literature as to caffeine's effect on TRP channels, the role of caffeine in pain management and analgesia, as well as the role of TRP in pain and analgesia; however, there has yet to be a review focused on the interaction between caffeine and TRP channels. Although the influence of caffeine on TRP has been demonstrated in the lab and in animal models, there is a scarcity of data collected on a large scale as to the clinical utility of caffeine as a regulator of TRP. This review aims to prompt further molecular research to elucidate the specific ligand-host interaction between caffeine and TRP by validating caffeine as a regulator of transient receptor potential (TRP) channels-focusing on the transient receptor potential vanilloid 1 (TRPV1) receptor and transient receptor potential ankyrin 1 (TRPA1) receptor subtypes-and its application in areas of pain.

Examination of the Effect of Dimethyl Trisulfide in Acute Stress Mouse Model with the Potential Involvement of the TRPA1 Ion Channel.

Polysulfides are endogenously produced in mammals and generally associated with protective functions. Our aim was to investigate the effect of dimethyl trisulfide (DMTS) in a mouse model of acute stress. DMTS activates transient receptor potential ankyrin 1 (TRPA1) channels and leads to neuropeptide release, potentially that of substance P (SP). We hypothesize that DMTS might inhibit the degrading enzymes of endocannabinoids, so this system was also investigated as another possible pathway for mediating the effects of DMTS. Trpa1 gene wild-type (WT) and knockout (KO) mice were used to confirm the role of the TRPA1 ion channel in mediating the effects of DMTS. C57BL/6J, NK1 gene KO, and Tac1 gene KO mice were used to evaluate the effect of DMTS on the release and expression of SP. Some C57BL/6J animals were treated with AM251, an inhibitor of the cannabinoid CB1 receptor, to elucidate the role of the endocannabinoid system in these processes. Open field test (OFT) and forced swim test (FST) were performed in each mouse strain. A tail suspension test (TST) was performed in Trpa1 WT and KO animals. C-FOS immunohistochemistry was carried out on Trpa1 WT and KO animals. The DMTS treatment increased the number of highly active periods and decreased immobility time in the FST in WT animals, but had no effect on the Trpa1 KO mice. The DMTS administration induced neuronal activation in the Trpa1 WT mice in the stress-related brain areas, such as the locus coeruleus, dorsal raphe nucleus, lateral septum, paraventricular nucleus of the thalamus, and paraventricular nucleus of the hypothalamus. DMTS may have a potential role in the regulation of stress-related processes, and the TRPA1 ion channel may also be involved in mediating the effects of DMTS. DMTS can be an ideal candidate for further study as a potential remedy for stress-related disorders.

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets.

The transient receptor potential ankyrin 1 (TRPA1) channel plays a pivotal role in the respiratory and gastrointestinal tracts. Within the respiratory system, TRPA1 exhibits diverse distribution patterns across key cell types, including epithelial cells, sensory nerves, and immune cells. Its activation serves as a frontline sensor for inhaled irritants, triggering immediate protective responses, and influencing airway integrity. Furthermore, TRPA1 has been implicated in airway tissue injury, inflammation, and the transition of fibroblasts, thereby posing challenges in conditions, such as severe asthma and fibrosis. In sensory nerves, TRPA1 contributes to nociception, the cough reflex, and bronchoconstriction, highlighting its role in both immediate defense mechanisms and long-term respiratory reflex arcs. In immune cells, TRPA1 may modulate the release of pro-inflammatory mediators, shaping the overall inflammatory landscape. In the gastrointestinal tract, the dynamic expression of TRPA1 in enteric neurons, epithelial cells, and immune cells underscores its multifaceted involvement. It plays a crucial role in gut motility, visceral pain perception, and mucosal defense mechanisms. Dysregulation of TRPA1 in both tracts is associated with various disorders such as asthma, Chronic Obstructive Pulmonary Disease, Irritable Bowel Syndrome, and Inflammatory Bowel Disease. This review emphasizes the potential of TRPA1 as a therapeutic target and discusses the efficacy of TRPA1 antagonists in preclinical studies and their promise for addressing respiratory and gastrointestinal conditions. Understanding the intricate interactions and cross-talk of TRPA1 across different cell types provides insight into its versatile role in maintaining homeostasis in vital physiological systems, offering a foundation for targeted therapeutic interventions.

TRPA1 Inhibition Effects by 3-Phenylcoumarin Derivatives.

Transient receptor potential ankyrin 1 (TRPA1) protein plays an important role in the inflammatory response, and it has been associated with different pain conditions and pain-related diseases, making TRPA1 a valid target for painkillers. In this study, we identified potential TRPA1 inhibitors and located their binding sites utilizing computer-aided drug design (CADD) techniques. The designed 3-phenylcoumarin-based TRPA1 inhibitors were successfully synthesized using a microwave assisted synthetic strategy. 3-(3-Bromophenyl)-7-acetoxycoumarin (5), 7-hydroxy-3-(3-hydroxyphenyl)coumarin (12) and 3-(3-hydroxyphenyl)coumarin (23) all showed inhibitory activity toward TRPA1 in vitro. Compound 5 also decreased the size and formation of breast cancer cells. Hence, targeting TRPA1 may represent a promising alternative for the treatment of pain and inflammation.

A Mechanism for the Treatment of Cardiovascular and Renal Disease: TRPV1 and TRPA1.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. CVD and kidney disease are closely related, with kidney injury increasing CVD mortality. The pathogenesis of cardiovascular and renal diseases involves complex and diverse interactions between multiple extracellular and intracellular signaling molecules, among which transient receptor potential vanilloid 1 (TRPV1)/transient receptor potential ankyrin 1 (TRPA1) channels have received increasing attention. TRPV1 belongs to the vanilloid receptor subtype family of transient receptor potential ion channels, and TRPA1 belongs to the transient receptor potential channel superfamily. TRPV1/TRPA1 are jointly involved in the management of cardiovascular and renal diseases and play important roles in regulating vascular tension, promoting angiogenesis, antifibrosis, anti-inflammation, and antioxidation. The mechanism of TRPV1/TRPA1 is mainly related to regulation of intracellular calcium influx and release of nitric oxide and calcitonin gene-related peptide. Therefore, this study takes the TRPV1/TRPA1 channel as the research object, analyzes and summarizes the process and mechanism of TRPV1/TRPA1 affecting cardiovascular and renal diseases, and lays a foundation for the treatment of cardiorenal diseases.

Pulpitis pain relief by modulating sodium channels in trigeminal ganglia

Objectives: The pulp is the center of the tooth containing nerves and blood vessels. The condition in which the pulp becomes inflamed due to caries or periodontitis is called pulpitis. Pulpitis is a difficult-to-treat disease and causes peripheral nerve tissue changes and severe pain; however, the relationship between neuronal activity and voltage-gated sodium channel 1.7 (Nav1.7) expression in the trigeminal ganglion (TG) during pulpitis has not been well studied. In this study, we found that experimentally induced pulpitis activates Nav1.7 expression in the periphery, leading to neuronal overexpression in the TG. Thus, we sought to identify ways to regulate this process. Methods: Acute pulpitis was induced in rat maxillary molars by treating the pulp with allyl isothiocyanate (AITC). Three days later, in vivo optical imaging was used to record and compare neural activities in the TG. Western blotting was used to identify molecular changes in terms of the expression of extracellular signal-regulated kinase (ERK), c-Fos, transient receptor potential ankyrin 1 (TRPA1), and collapsin response mediator protein-2 (CRMP2) in the brain stem. Results: The results confirmed the neurological changes in the TGs of the pulpitis model, and histological and molecular biological evidence confirmed that increased Nav1.7 expression induced by pulpitis leads to pain. Furthermore, selective inhibition of Nav1.7 resulted in changes in neural activity, suggesting that pulpitis induces increased Nav1.7 expression, and that effective control of Nav1.7 could potentially reduce pain. Conclusions: The inhibition of overexpressed Nav1.7 channels may modulate nociceptive signal processing in the brain and effectively control pain associated with pulpitis.

Skin- and airway-deliverable TRPA1 inhibitor

This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure–activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.

Aromatase inhibitors evoke periorbital allodynia in mice via calcitonin gene-related peptide and its receptors in Schwann cells

Background: Treatment with the currently recommended aromatase inhibitors (AIs) for adjuvant endocrine treatment of estrogen receptorpositive breast cancer is associated with debilitating musculoskeletal pain symptoms (AIMS) and headache. Recent evidence suggests that the proalgesic channel transient receptor potential ankyrin 1 (TRPA1) is implicated in AIMS. Here, we investigated the cellular and molecular mechanisms, including TRPA1, implicated in periorbital mechanical allodynia (PMA), a surrogate of headache-like pain, evoked by AIs in mice. Methods: C57BL6/J mice were treated with intragastric letrozole (0.05-0.5 mg/kg), exemestane (1-5 mg/kg) or anastrozole (0.02-0.2 mg/kg) and were evaluated by applying von Frey filaments to the periorbital region over the rostral portion of the eye. Some mice were pretreated (subcutaneous in the periorbital area) with receptor, channel, or enzyme inhibitors. PMA was also investigated in mice with selective silencing of Trpa1 and receptor activity modifying protein 1 [Ramp1, the component of calcitonin gene related peptide (CGRP) receptor required for its functioning] in Schwann cells (Plp-Cre+-Trpa1fl/fl and Plp-Cre+-Ramp1fl/fl mice, respectively) or trigeminal neurons (Adv-Cre+- Trpa1fl/fl and Adv- Cre+- Ramp1fl/fl mice, respectively). Results: Letrozole dose-dependently produced PMA that was attenuated by a TRPA1 antagonist (A967079) or a CGRP receptor antagonist (olcegepant), whereas indomethacin was ineffective. Selective silencing of Trpa1 in both Schwann cells and trigeminal neurons reduced letrozole- evoked PMA. Silencing of Ramp1 in Schwann cells, but not in trigeminal neurons, attenuated PMA. Inhibition of the intracellular pathway known to promote PMA by CGRP action in Schwann cells, including adenylyl cyclase (SQ-22536), nitric oxide synthase (L-NG-Nitro arginine methyl ester), and oxidative stress (N-tert-butyl-a-phenylnitrone) inhibitors reduced letrozole-evoked PMA. PMA evoked by exemestane (1, 5, 10 mg/kg i.g.) or anastrozole (0.02, 0.1, 0.2 mg/kg i.g.) Was also markedly reduced in mice with selective silencing of TRPA1 in Schwann cells and nociceptors. Conclusions: Data indicate that letrozole, targeting TRPA1 in peptidergic nerve terminals, releases CGRP that engages its receptor in adjacent Schwann cells to trigger a complex intracellular pathway that results in TRPA1 activation and the ensuing ROS release to sustain PMA. Should these mechanisms be present in patients, their inhibition may ameliorate cephalic mechanical allodynia associated with aromatase inhibitors-induced headaches.

Transient Receptor Potential Ankyrin 1 Channel Alters Transforming Growth Factor Beta 1/Smad Signaling in Rat Vocal Fold Fibroblasts.

Vocal fold scar remains a therapeutic challenge. Vocal fold fibroblasts (VFFs) secrete extracellular matrix (ECM), and transforming growth factor-beta 1 (TGF-β1)-mediated fibroblast to myofibroblast differentiation is central to the development of fibrosis. The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels, and activation of TRP ankyrin 1 (TRPA1) channel has been shown to have antifibrotic effects through TGF-β1/Smad signaling in various organs. This study aimed to elucidate expression of TRPA1 and the impact of TRPA1 activation on TGF-β1/Smad signaling in VFFs. Vocal folds were dissected from 10-week-old, male Sprague-Dawley rats and primary VFFs were established. TRPA1 was examined in VFFs and lamina propria via immunostaining. VFFs were treated with allyl isothiocyanate (AITC, TRP channel agonist, 10-5 M) ± TGF-β1 (10 ng/ml) ± A-967079 (selective TRPA1 channel antagonist, 5.0 × 10-7 M) for 4 or 24 h. Trpa1, Smad3, Smad7, Col1a1, Acta2, and Has1 mRNA expression were quantified via qPCR. TRPA1 was expressed in cultured VFFs and the lamina propria. TGF-β1 administration significantly increased Trpa1 compared to control. AITC alone did not alter Smad3, Smad7, Acta2, or ECM related genes. However, the combination of AITC and TGF-β1 significantly increased Smad3 and decreased Smad7 and Acta2 compared to TGF-β1 alone; A-967079 significantly reduced this response. VFFs expressed TRPA1, and the activation of TRPA1 regulated TGF-β1/Smad signaling in VFFs. These findings provide preliminary insights into potential anti-fibrotic mechanisms of TRPA1 activation through TGF-β1/Smad signaling in VFFs. NA Laryngoscope, 134:4593-4598, 2024.

Linalyl acetate exerts analgesic effects by inhibiting nociceptive TRPA1 in mice.

Clary sage essential oil (CSEO) is utilized in perfumery, aromatherapy, and skincare. Linalyl acetate (LA), a primary component of CSEO, possesses sedative, anxiolytic, and analgesic properties. However, the mechanism of its analgesic action is not clearly understood. Transient receptor potential ankyrin 1 (TRPA1) channel, a non-selective cation channel, is mainly expressed in sensory neurons and serves as a sensor of various irritants. In this study, we investigated the effects of LA on TRPA1 channel using heterologous expression system and isolated sensory neurons. To detect channel activity, we employed Ca2+ imaging and the whole-cell patch-clamp technique. The analgesic action of LA was measured in a pain-related behavioral mouse model. In cells that heterologously expressed TRPA1, LA diminished [Ca2+]i and current responses to allylisothiocyanate (AITC) and carvacrol: exogenous TRPA1 agonists, and the inhibitory effects were more pronounced for the former than for the latter. Moreover, LA suppressed [Ca2+] i and current responses to PGJ2: an endogenous TRPA1 agonist. Similar inhibitory actions were observed in native TRPA1 channels expressed in mouse sensory neurons. Furthermore, LA diminished PGJ2-induced nociceptive behaviors in mice. These findings suggest that analgesic effects of LA exert through inhibition of nociceptive TRPA1, making it a potential candidate for novel analgesic development.

The ion channel TRPA1 is a modulator of the cocaine reward circuit in the nucleus accumbens.

Drug addiction therapies commonly fail because continued drug use promotesthe release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential asa target for drug misuse therapies.

Dietary Cinnamaldehyde Activation of TRPA1 Antagonizes High-Salt-Induced Hypertension Through Restoring Renal Tubular Mitochondrial Dysfunction.

The renal proximal tubule (RPT) plays a pivotal role in regulating sodium reabsorption and thus blood pressure (BP). Transient receptor potential ankyrin 1 (TRPA1) has been reported to protect against renal injury by modulating mitochondrial function. We hypothesize that the activation of TRPA1 by its agonist cinnamaldehyde may mitigate high-salt intake-induced hypertension by inhibiting urinary sodium reabsorption through restoration of renal tubular epithelial mitochondrial function. Trpa1-deficient (Trpa1-/-) mice and wild-type (WT) mice were fed standard laboratory chow [normal diet (ND) group, 0.4% salt], standard laboratory chow with 8% salt [high-salt diet (HS) group], or standard laboratory chow with 8% salt plus 0.015% cinnamaldehyde [high-salt plus cinnamaldehyde diet (HSC) group] for 6 months. Urinary sodium excretion, reactive oxygen species (ROS) production, mitochondrial function, and the expression of sodium hydrogen exchanger isoform 3 (NHE3) and Na+/K+-ATPase of RPTs were determined. Chronic dietary cinnamaldehyde supplementation reduced tail systolic BP and 24-hour ambulatory arterial pressure in HS-fed WT mice. Compared with the mice fed HS, cinnamaldehyde supplementation significantly increased urinary sodium excretion, inhibited excess ROS production, and alleviated mitochondrial dysfunction of RPTs in WT mice. However, these effects of cinnamaldehyde were absent in Trpa1-/- mice. Furthermore, chronic dietary cinnamaldehyde supplementation blunted HS-induced upregulation of NHE3 and Na+/K+-ATPase in WT mice but not Trpa1-/- mice. The present study demonstrated that chronic activation of Trpa1 attenuates HS-induced hypertension by inhibiting urinary sodium reabsorption through restoring renal tubular epithelial mitochondrial function. Renal TRPA1 may be a potential target for the management of excessive dietary salt intake-associated hypertension.

TRPA1 Covalent Ligand JT010 Modifies T Lymphocyte Activation.

Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in sensitivity to a plethora of irritating agents and endogenous mediators of oxidative stress. TRPA1 influences neuroinflammation and macrophage and lymphocyte functions, but its role is controversial in immune cells. We reported earlier a detectable, but orders-of-magnitude-lower level of Trpa1 mRNA in monocytes and lymphocytes than in sensory neurons by qRT-PCR analyses of cells from lymphoid organs of mice. Our present goals were to (a) further elucidate the expression of Trpa1 mRNA in immune cells by RNAscope in situ hybridization (ISH) and (b) test the role of TRPA1 in lymphocyte activation. RNAscope ISH confirmed that Trpa1 transcripts were detectable in CD14+ and CD4+ cells from the peritoneal cavity of mice. A selective TRPA1 agonist JT010 elevated Ca2+ levels in these cells only at high concentrations. However, a concentration-dependent inhibitory effect of JT010 was observed on T-cell receptor (TcR)-induced Ca2+ signals in CD4+ T lymphocytes, while JT010 neither modified B cell activation nor ionomycin-stimulated Ca2+ level. Based on our present and past findings, TRPA1 activation negatively modulates T lymphocyte activation, but it does not appear to be a key regulator of TcR-stimulated calcium signaling.

Inhibition of TRPA1-like alleviated unfolded protein response and apoptosis by regulating cytoplasmic Ca2+ in Yesso scallop Patinopecten yessoensis under high temperature stress

Transient receptor potential ankyrin subtype 1 (TRPA1) is a nonselective cation channel protein typically forms ion channels that regulate intracellular calcium homeostasis, and can be induced by temperature and various chemicals. In the present study, the involvement of PyTRPA1-like in regulating unfolded protein response (UPR) and apoptosis in Yesso Scallop Patinopecten yessoensis under high temperature stress was investigated. The mRNA transcripts of PyTRPA1-like were detected in haemocytes and all the examined tissues with the highest expression level in mantle. After TRPA1 activator (allyl-isothiocyanate, AITC) and high temperature (25°C) treatment, the expression level of PyTRPA1-like mRNA and the Ca2+ content in haemocytes increased significantly (p < 0.05) at 3 h, and then recovered to the normal level at 12 h, and the expression level of PyGRP78, PyIRE1, PyATF6β, PyPERK and PyCaspase-3 mRNA in haemocytes, and Caspase-3 activity and apoptosis rate were also significantly upregulated (p < 0.05). After TRPA1 antagonist (HC-030031) and high temperature (25°C) treatment, the intracellular Ca2+ content, the transcripts of PyGRP78, PyIRE1 and PyCaspase-3 in haemocytes, as well as the Caspase-3 activity and apoptosis rate decreased significantly compared to the control group (p < 0.05), while the Ca2+ distribution in haemocytes showed no difference with that in control group. These results collectively suggest that PyTRPA1-like plays important roles in regulating UPR and apoptosis by mediating calcium influx under high temperature stress in scallop P. yessoensis.

Schwann cell TRPA1 elicits reserpine-induced fibromyalgia pain in mice.

Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known as both a pain sensor and an oxidative stress sensor, has been implicated in various painful conditions. The feed-forward mechanism that implicates reactive oxygen species (ROS) driven by TRPA1 was investigated in a reserpine-induced fibromyalgia model in C57BL/6J mice employing pharmacological interventions and genetic approaches. Reserpine-treated mice developed pain-like behaviours (mechanical/cold hypersensitivity) and early anxiety-depressive-like disorders, accompanied by increased levels of oxidative stress markers in the sciatic nerve tissues. These effects were not observed upon pharmacological blockade or global genetic deletion of the TRPA1 channel and macrophage depletion. Furthermore, we demonstrated that selective silencing of TRPA1 in Schwann cells reduced reserpine-induced neuroinflammation (NADPH oxidase 1-dependent ROS generation and macrophage increase in the sciatic nerve) and attenuated fibromyalgia-like behaviours. Activated Schwann cells expressing TRPA1 promote an intracellular pathway culminating in the release of ROS and recruitment of macrophages in the mouse sciatic nerve. These cellular and molecular events sustain mechanical and cold hypersensitivity in the reserpine-evoked fibromyalgia model. Targeting TRPA1 channels on Schwann cells could offer a novel therapeutic approach for managing fibromyalgia-related behaviours.

Visual analysis of global research on the transient receptor potential ankyrin 1 channel: A literature review from 2002 to 2022

Background and aimsThe transient receptor potential ankyrin 1 (TRPA1) channel has become a focus in pain research. However, there are no bibliometric studies that systematically analyze the existing research in this area. This study aimed to provide a systematic review of the existing literature on TRPA1 using a bibliometric analysis. MethodsPublished literature in the field of TRPA1 was collected from the Web of Science Core Collection database. Quantitative and qualitative analyses of publications, countries, institutions, authors, journals, and other entries were conducted using Excel, VOSview, and Citespace software to provide insight into global research hotspots and trends in the TRPA1 field. ResultsThis study included 1189 scientific products published in 398 journals from 52 countries. The United States of America (n = 367) had the most publications, ahead of Japan (n = 212) and China (n = 199). The University of Florence (n = 55) was the most productive institution and Pierangelo Geppetti (n = 46) was the most productive author. PLoS One (n = 40) published the most articles on TRPA1. Pain, cold, inflammation, covalent modification, hyperalgesia, and oxidative stress were the most common keywords used in the studies. ConclusionThis study provides the first bibliometric analysis of TRPA1 publications. The physiological functions of TRPA1, TRPA1, and neuropathic pain, TRPA1 as a therapeutic target, and agonists of TRPA1 are trending in TRPA1 research. Neuropathic pain, apoptosis, and sensitization could be focus areas of future research. This study provides important insight in the field of TRPA1 research.

Modulation of TNF Release by the Innate Fear Odorant 2-Methylthiazoline Requires TRPA1-Mediated Signaling

The innate fear odorant 2-Methylthiazoline (2-MT) elicits highly robust innate fear and defensive behaviors, such as freezing, hypothermia and bradycardia via activation of transient receptor potential ankyrin 1 (TRPA1) channels. Activation of TRPA1-expressing vagus nerve fibers also regulates IL-1β induced hypothermia and reflex anti-inflammatory responses. However, it is unclear whether 2-MT can trigger an anti-inflammatory response via TRPA1 activation. Here, we demonstrate that 2-MT attenuates endotoxin-induced tumor necrosis factor (TNF) production in wild-type mice in TRPA1-dependent manner. Exposure to 2-MT induces a significant reduction in serum TNF in wild-type mice injected with endotoxin as compared to vehicle control mice (vehicle control vs. 2-MT; 1,123 ± 32.3 pg/mL vs. 714.1 ± 58.2 pg/mL; * p=0.02). However, 2-MT exposure fails to suppress endotoxin-induced TNF-release in TrpA1-knock out mice (vehicle control vs. 2-MT; 1,123 ± 32.3 vs. 948.7 ± 99.2 pg/mL; ns p=0.89). A single exposure to 2-MT during endotoxin injection also protects animals from lethal endotoxemia and significantly improves survival as compared to vehicle-exposed endotoxemic controls (vehicle control vs. single 2-MT Odor; 26.7% vs. 66.7% survival 120 hours post LPS injection). In addition, significant improvement in disease activity is observed in mice exposed to 2-MT odorant (vehicle control vs. single 2-MT Odor; disease activity: 0.5 ± 0.2 a.u. vs. 0.3 ± 0.1 a.u., * p=0.01). Collectively, these data characterize the anti-inflammatory effcacy of 2-MT and demonstrate that the modulation of TNF release by 2-MT requires TRPA1-mediated signaling. This work is supported in part by grants from NIH, NIGMS, 1R35 GM118182 to KJT and 1R01AR083159-01 to SSC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.