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1
Bousquet, Jean, Wienczyslawa Czarlewski, Torsten Zuberbier, Joaquim Mullol, Hubert Blain, Jean-Paul Cristol, Rafael De La Torre, et al. "Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19." International Archives of Allergy and Immunology 182, no. 4 (2021): 324–38. http://dx.doi.org/10.1159/000514204.
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In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
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Zhang, Hongyu, Peter J. Wickley, Sayantani Sinha, Ian N. Bratz, and Derek S. Damron. "Propofol Restores Transient Receptor Potential Vanilloid Receptor Subtype-1 Sensitivity via Activation of Transient Receptor Potential Ankyrin Receptor Subtype-1 in Sensory Neurons." Anesthesiology 114, no. 5 (May 1, 2011): 1169–79. http://dx.doi.org/10.1097/aln.0b013e31820dee67.
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Background Cross talk between peripheral nociceptors belonging to the transient receptor potential vanilloid receptor subtype-1 (TRPV1) and ankyrin subtype-1 (TRPA1) family has been demonstrated recently. Moreover, the intravenous anesthetic propofol has directly activates TRPA1 receptors and indirectly restores sensitivity of TRPV1 receptors in dorsal root ganglion (DRG) sensory neurons. Our objective was to determine the extent to which TRPA1 activation is involved in mediating the propofol-induced restoration of TRPV1 sensitivity. Methods Mouse DRG neurons were isolated by enzymatic dissociation and grown for 24 h. F-11 cells were transfected with complementary DNA for both TRPV1 and TRPA1 or TRPV1 only. The intracellular Ca concentration was measured in individual cells via fluorescence microscopy. After TRPV1 desensitization with capsaicin (100 nM), cells were treated with propofol (1, 5, and 10 μM) alone or with propofol in the presence of the TRPA1 antagonist, HC-030031 (0.5 μM), or the TRPA1 agonist, allyl isothiocyanate (AITC; 100 μM); capsaicin was then reapplied. Results In DRG neurons that contain both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in DRG neurons containing only TRPV1 receptors, exposure to propofol or AITC after desensitization did not restore capsaicin-induced TRPV1 sensitivity. Similarly, in F-11 cells transfected with both TRPV1 and TRPA1, propofol and AITC restored TRPV1 sensitivity. However, in F-11 cells transfected with TRPV1 only, neither propofol nor AITC was capable of restoring TRPV1 sensitivity. Conclusions These data demonstrate that propofol restores TRPV1 sensitivity in primary DRG neurons and in cultured F-11 cells transfected with both the TRPV1 and TRPA1 receptors via a TRPA1-dependent process. Propofol's effects on sensory neurons may be clinically important and may contribute to peripheral sensitization to nociceptive stimuli in traumatized tissue.
3
Kiss, Fruzsina, Viktória Kormos, Éva Szőke, Angéla Kecskés, Norbert Tóth, Anita Steib, Árpád Szállási, et al. "Functional Transient Receptor Potential Ankyrin 1 and Vanilloid 1 Ion Channels Are Overexpressed in Human Oral Squamous Cell Carcinoma." International Journal of Molecular Sciences 23, no. 3 (February 8, 2022): 1921. http://dx.doi.org/10.3390/ijms23031921.
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Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis. Transient Receptor Potential Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) receptors are non-selective cation channels expressed on primary sensory neurons and epithelial and immune cells. TRPV1 mRNA and immunopositivity, as well as TRPA1-like immunoreactivity upregulation, were demonstrated in OSCC, but selectivity problems with the antibodies still raise questions and their functional relevance is unclear. Therefore, here, we investigated TRPA1 and TRPV1 expressions in OSCC and analyzed their functions. TRPA1 and TRPV1 mRNA were determined by RNAscope in situ hybridization and qPCR. Radioactive 45Ca2+ uptake and ATP-based luminescence indicating cell viability were measured in PE/CA-PJ41 cells in response to the TRPA1 agonist allyl-isothiocyanate (AITC) and TRPV1 agonist capsaicin to determine receptor function. Both TRPA1 and TRPV1 mRNA are expressed in the squamous epithelium of the human oral mucosa and in PE/CA-PJ41 cells, and their expressions are significantly upregulated in OSCC compared to healthy mucosa. TRPA1 and TRPV1 activation (100 µM AITC, 100 nM capsaicin) induced 45Ca2+-influx into PE/CA-PJ41 cells. Both AITC (10 nM–5 µM) and capsaicin (100 nM–45 µM) reduced cell viability, reaching significant decrease at 100 nM AITC and 45 µM capsaicin. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the OSCC and confirm the expression of TRPV1 channel. These channels are functionally active and might regulate cancer cell viability.
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Zhao, Huan, Leslie K. Sprunger, and Steven M. Simasko. "Expression of transient receptor potential channels and two-pore potassium channels in subtypes of vagal afferent neurons in rat." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 2 (February 2010): G212—G221. http://dx.doi.org/10.1152/ajpgi.00396.2009.
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Vagal afferent neurons relay important information regarding the control of the gastrointestinal system. However, the ionic mechanisms that underlie vagal activation induced by sensory inputs are not completely understood. We postulate that transient receptor potential (TRP) channels and/or two-pore potassium (K2p) channels are targets for activating vagal afferents. In this study we explored the distribution of these channels in vagal afferents by quantitative PCR after a capsaicin treatment to eliminate capsaicin-sensitive neurons, and by single-cell PCR measurements in vagal afferent neurons cultured after retrograde labeling from the stomach or duodenum. We found that TRPC1/3/5/6, TRPV1-4, TRPM8, TRPA1, TWIK2, TRAAK, TREK1, and TASK1/2 were all present in rat nodose ganglia. Both lesion results and single-cell PCR results suggested that TRPA1 and TRPC1 were preferentially expressed in neurons that were either capsaicin sensitive or TRPV1 positive. Expression of TRPM8 varied dynamically after various manipulations, which perhaps explains the disparate results obtained by different investigators. Last, we also examined ion channel distribution with the A-type CCK receptor (CCK-RA) and found there was a significant preference for neurons that express TRAAK to also express CCK-RA, especially in gut-innervating neurons. These findings, combined with findings from prior studies, demonstrated that background conductances such as TRPC1, TRPA1, and TRAAK are indeed differentially distributed in the nodose ganglia, and not only do they segregate with specific markers, but the degree of overlap is also dependent on the innervation target.
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Payrits, Maja, Ádám Horváth, Tünde Biró-Sütő, János Erostyák, Géza Makkai, Éva Sághy, Krisztina Pohóczky, et al. "Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification." International Journal of Molecular Sciences 21, no. 14 (July 16, 2020): 5019. http://dx.doi.org/10.3390/ijms21145019.
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Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.
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Wilzopolski, Jenny, Manfred Kietzmann, Santosh K. Mishra, Holger Stark, Wolfgang Bäumer, and Kristine Rossbach. "TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch." Biomolecules 11, no. 8 (August 6, 2021): 1166. http://dx.doi.org/10.3390/biom11081166.
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Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.
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Kunkler, Phillip Edward, LuJuan Zhang, Jessica Joan Pellman, Gerry Stephen Oxford, and Joyce Harts Hurley. "Sensitization of the trigeminovascular system following environmental irritant exposure." Cephalalgia 35, no. 13 (February 27, 2015): 1192–201. http://dx.doi.org/10.1177/0333102415574845.
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Background Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system. Methods Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels. Results Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18. Interpretation These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure.
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Li, Fengxian, Changxiong J. Guo, Cheng-Chiu Huang, Guang Yu, Sarah M. Brown, Shiyuan Xu, and Qin Liu. "Transient Receptor Potential A1 Activation Prolongs Isoflurane Induction Latency and Impairs Respiratory Function in Mice." Anesthesiology 122, no. 4 (April 1, 2015): 768–75. http://dx.doi.org/10.1097/aln.0000000000000607.
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Abstract Background: Isoflurane is a potent volatile anesthetic; however, it evokes airway irritation and neurogenic constriction through transient receptor potential (TRP) A1 channels and sensitizes TRPV1 channels, which colocalizes with TRPA1 in most of the vagal C-fibers innervating the airway. However, little is known about the precise effects of these two channels on the respiratory function during isoflurane anesthesia. Methods: By using a rodent behavioral model and whole-body plethysmograph, the authors examined the response of Trpa1−/− and Trpv1−/− mice to isoflurane anesthesia and monitored their respiratory functions during anesthesia. Results: This study showed that Trpa1−/− mice (n = 9), but not Trpv1−/− mice (n = 11), displayed a shortened induction latency compared with wild-type mice (n = 10) during isoflurane anesthesia (33 ± 2.0 s in wild-type and 33 ± 3.8 s in Trpv1−/−vs. 17 ± 1.8 in Trpa1−/− at 2.2 minimum alveolar concentrations). By contrast, their response to the nonpungent volatile anesthetic sevoflurane is indistinguishable from wild-type mice (24 ± 3.6 s in wild-type vs. 26 ± 1.0 s in Trpa1−/− at 2.4 minimum alveolar concentrations). The authors discovered that Trpa1−/− mice inhaled more anesthetic but maintained better respiratory function. Further respiration pattern analysis revealed that isoflurane triggered nociceptive reflexes and led to prolonged resting time between breaths during isoflurane induction as well as decreased dynamic pulmonary compliance, an indicator of airway constriction, throughout isoflurane anesthesia in wild-type and Trpv1−/− mice, but not in Trpa1−/− mice. Conclusion: Activation of TRPA1 by isoflurane negatively affects anesthetic induction latency by altering respiratory patterns and impairing pulmonary compliance.
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Zhou, Fangyuan, Katharina Metzner, Patrick Engel, Annika Balzulat, Marco Sisignano, Peter Ruth, Robert Lukowski, Achim Schmidtko, and Ruirui Lu. "Slack Potassium Channels Modulate TRPA1-Mediated Nociception in Sensory Neurons." Cells 11, no. 10 (May 19, 2022): 1693. http://dx.doi.org/10.3390/cells11101693.
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The transient receptor potential (TRP) ankyrin type 1 (TRPA1) channel is highly expressed in a subset of sensory neurons where it acts as an essential detector of painful stimuli. However, the mechanisms that control the activity of sensory neurons upon TRPA1 activation remain poorly understood. Here, using in situ hybridization and immunostaining, we found TRPA1 to be extensively co-localized with the potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) in sensory neurons. Mice lacking Slack globally (Slack−/−) or conditionally in sensory neurons (SNS-Slack−/−) demonstrated increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. By contrast, pain behavior induced by the TRP vanilloid 1 (TRPV1) activator capsaicin was normal in Slack-deficient mice. Patch-clamp recordings in sensory neurons and in a HEK cell line transfected with TRPA1 and Slack revealed that Slack-dependent potassium currents (IKS) are modulated in a TRPA1-dependent manner. Taken together, our findings highlight Slack as a modulator of TRPA1-mediated, but not TRPV1-mediated, activation of sensory neurons.
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Hatano, Noriyuki, Hiroka Suzuki, Yukiko Muraki, and Katsuhiko Muraki. "Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin." American Journal of Physiology-Cell Physiology 304, no. 4 (February 15, 2013): C354—C361. http://dx.doi.org/10.1152/ajpcell.00096.2012.
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Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca2+-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca2+ and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1–4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1–4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.
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Rhyu, Mee-Ra, Yiseul Kim, and Vijay Lyall. "Interactions between Chemesthesis and Taste: Role of TRPA1 and TRPV1." International Journal of Molecular Sciences 22, no. 7 (March 25, 2021): 3360. http://dx.doi.org/10.3390/ijms22073360.
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In addition to the sense of taste and olfaction, chemesthesis, the sensation of irritation, pungency, cooling, warmth, or burning elicited by spices and herbs, plays a central role in food consumption. Many plant-derived molecules demonstrate their chemesthetic properties via the opening of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels. TRPA1 and TRPV1 are structurally related thermosensitive cation channels and are often co-expressed in sensory nerve endings. TRPA1 and TRPV1 can also indirectly influence some, but not all, primary taste qualities via the release of substance P and calcitonin gene-related peptide (CGRP) from trigeminal neurons and their subsequent effects on CGRP receptor expressed in Type III taste receptor cells. Here, we will review the effect of some chemesthetic agonists of TRPA1 and TRPV1 and their influence on bitter, sour, and salt taste qualities.
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Kameda, Takuya, Joel Zvick, Miriam Vuk, Aleksandra Sadowska, Wai Kit Tam, Victor Y. Leung, Kata Bölcskei, et al. "Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling." International Journal of Molecular Sciences 20, no. 7 (April 10, 2019): 1767. http://dx.doi.org/10.3390/ijms20071767.
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Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.
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Bai, Guang, Holly Ross, Youping Zhang, KiSeok Lee, and Jin Y. Ro. "The Role of DNA Methylation in Transcriptional Regulation of Pro-Nociceptive Genes in Rat Trigeminal Ganglia." Epigenetics Insights 13 (January 2020): 251686572093867. http://dx.doi.org/10.1177/2516865720938677.
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Epigenetic modulation by DNA methylation is associated with aberrant gene expression in sensory neurons, which consequently leads to pathological pain responses. In this study, we sought to investigate whether peripheral inflammation alters global DNA methylation in trigeminal ganglia (TG) and results in abnormal expression of pro-nociceptive genes. Our results show that peripheral inflammation remotely reduced the level of global DNA methylation in rat TG with a concurrent reduction in DNMT1 and DNMT3a expression. Using unbiased steps, we selected the following pro-nociceptive candidate genes that are potentially regulated by DNA methylation: TRPV1, TRPA1, P2X3, and PIEZO2. Inhibition of DNMT with 5-Aza-dC in dissociated TG cells produced dose-dependent upregulation of TRPV1, TRPA1, and P2X3. Systemic treatment of animals with 5-Aza-dC significantly increased the expression of TRPV1, TRPA1, and PIEZO2 in TG. Furthermore, the overexpression of DNMT3a, as delivered by a lentiviral vector, significantly downregulated TRPV1 and PIEZO2 expression and also reliably decreased TRPA1 and P2X3 transcripts. MeDIP revealed that this overexpression also significantly enhanced methylation of CGIs associated with TRPV1 and TRPA1. In addition, bisulfite sequencing data indicated that the CGI associated with TRPA1 was methylated in a pattern catalyzed by DNMT3a. Taken together, our results show that all 4 pro-nociceptive genes are subject to epigenetic modulation via DNA methylation, likely via DNMT3a under inflammatory conditions. These findings provide the first evidence for the functional importance of DNA methylation as an epigenetic factor in the transcription of pro-nociceptive genes in TG that are implicated in pathological orofacial pain responses.
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Xu, Mengmeng, Yanbei Zhang, Muyun Wang, Hai Zhang, Yuqing Chen, Ian M. Adcock, Kian Fan Chung, Jinhan Mo, Yinping Zhang, and Feng Li. "TRPV1 and TRPA1 in Lung Inflammation and Airway Hyperresponsiveness Induced by Fine Particulate Matter (PM2.5)." Oxidative Medicine and Cellular Longevity 2019 (June 2, 2019): 1–15. http://dx.doi.org/10.1155/2019/7450151.
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Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.
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Yu, Tian, Courtney E. Wilson, Jennifer M. Stratford, and Thomas E. Finger. "Genetic Deletion of TrpV1 and TrpA1 Does Not Alter Avoidance of or Patterns of Brainstem Activation to Citric Acid in Mice." Chemical Senses 45, no. 7 (June 23, 2020): 573–79. http://dx.doi.org/10.1093/chemse/bjaa043.
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Abstract Exposure of the oral cavity to acidic solutions evokes not only a sensation of sour, but also of sharp or tangy. Acidic substances potentially stimulate both taste buds and acid-sensitive mucosal free nerve endings. Mice lacking taste function (P2X2/P2X3 double-KO mice) refuse acidic solutions similar to wildtype (WT) mice and intraoral infusion of acidic solutions in these KO animals evokes substantial c-Fos activity within orosensory trigeminal nuclei as well as of the nucleus of the solitary tract (nTS) (Stratford, Thompson, et al. 2017). This residual acid-evoked, non-taste activity includes areas that receive inputs from trigeminal and glossopharyngeal peptidergic (CGRP-containing) nerve fibers that express TrpA1 and TrpV1 both of which are activated by low pH. We compared avoidance responses in WT and TrpA1/V1 double-KO (TRPA1/V1Dbl−/−) mice in brief-access behavioral assay (lickometer) to 1, 3, 10, and 30 mM citric acid, along with 100 µM SC45647 and H2O. Both WT and TRPA1/V1Dbl−/− show similar avoidance, including to higher concentrations of citric acid (10 and 30 mM; pH 2.62 and pH 2.36, respectively), indicating that neither TrpA1 nor TrpV1 is necessary for the acid-avoidance behavior in animals with an intact taste system. Similarly, induction of c-Fos in the nTS and dorsomedial spinal trigeminal nucleus was similar in the WT and TRPA1/V1Dbl−/− animals. Taken together these results suggest non-TrpV1 and non-TrpA1 receptors underlie the residual responses to acids in mice lacking taste function.
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Kumar, Vibhu, Vijay Kumar, Kirti Devi, Ajay Kumar, Rehan Khan, Ravindra Pal Singh, Sivasubramanian Rajarammohan, Kanthi Kiran Kondepudi, Kanwaljit Chopra, and Mahendra Bishnoi. "Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice." International Journal of Molecular Sciences 23, no. 17 (August 24, 2022): 9577. http://dx.doi.org/10.3390/ijms23179577.
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Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and luminal microbial community. The present study focuses on the effects’ intra rectal administration of capsazepine (modulator of TRPA1/TRPV1 expressing peptidergic sensory neurons) on colonic mucus production and gut health. We performed histological analysis, gut permeability alteration, gene expression changes, metabolite profiling, and gut microbial abundance in the ileum, colon, and cecum content of these animals. Intra rectal administration of capsazepine modulates TRPA1/TRPV1-positive nociceptors (behavioral pain assays) and resulted in damaged mucosal lining, increased gut permeability, and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. These results suggest that caution must be exercised before employing TRPA1/TRPV1 modulation as a therapeutic option to alleviate pain caused due to IBD.
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Blaha, Igor, María Elvira López-Oliva, María Pilar Martínez, Paz Recio, Ángel Agis-Torres, Ana Cristina Martínez, Sara Benedito, et al. "Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide." Oxidative Medicine and Cellular Longevity 2019 (August 20, 2019): 1–12. http://dx.doi.org/10.1155/2019/5641645.
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Purpose. This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H2S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR). Materials and Methods. Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H2S synthase cystathionine beta-synthase (CBS) and cysthathionine-γ-lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H2S production were also performed. Results. Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H2S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR. Conclusions. These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H2S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.
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Sun, Hui, Sonya Meeker, and Bradley J. Undem. "Role of TRP channels in Gq-coupled protease-activated receptor 1-mediated activation of mouse nodose pulmonary C-fibers." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 1 (January 1, 2020): L192—L199. http://dx.doi.org/10.1152/ajplung.00301.2019.
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We evaluated the mechanisms underlying protease-activated receptor 1 (PAR1)-mediated activation of nodose C-fibers in mouse lungs. The PAR1-induced action potential discharge at the terminals was strongly inhibited in phospholipase C-β3 (PLCβ3)-deficient animals. At the level of the cell soma, PAR1 activation led to an increase in cytosolic calcium that was largely inhibited by transient receptor potential (TRP) A1 antagonism. Patch-clamp recordings, however, revealed that neither TRPA1 nor TRPV1 or any other ruthenium red-sensitive ion channels are required for the PAR1-mediated inward current or membrane depolarization in isolated nodose neurons. Consistent with these findings, PAR1-mediated action potential discharge in mouse lung nodose C-fiber terminals was unaltered in Trpa1/ Trpv1 double-knockout animals and Trpc3/ Trpc6 double-knockout animals. The activation of the C-fibers was also not inhibited by ruthenium red at concentrations that blocked TRPV1- and TRPA1-dependent responses. The biophysical data show that PAR1/Gq-mediated activation of nodose C-fibers may involve multiple ion channels downstream from PLCβ3 activation. TRPA1 is an ion channel that participates in PAR1/Gq-mediated elevation in intracellular calcium. There is little evidence, however, that TRPA1, TRPV1, TRPC3, TRPC6, or other ruthenium red-sensitive TRP channels are required for PAR1/Gq-PLCβ3-mediated membrane depolarization and action potential discharge in bronchopulmonary nodose C-fibers in the mouse.
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Bessac, Bret F., and Sven-Eric Jordt. "Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control." Physiology 23, no. 6 (December 2008): 360–70. http://dx.doi.org/10.1152/physiol.00026.2008.
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New studies have revealed an essential role for TRPA1, a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species, and noxious constituents of smoke and smog, initiating irritation and airway reflex responses. Together with TRPV1, the capsaicin receptor, TRPA1 may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome.
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Csekő, Kata, Dániel Pécsi, Béla Kajtár, Ivett Hegedűs, Alexander Bollenbach, Dimitrios Tsikas, Imre László Szabó, Sándor Szabó, and Zsuzsanna Helyes. "Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target." International Journal of Molecular Sciences 21, no. 16 (August 5, 2020): 5591. http://dx.doi.org/10.3390/ijms21165591.
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Acute gastritis is often untreatable by acid secretion-inhibiting drugs. Understanding the protective mechanisms including the role of Transient Receptor Potential Ankyrin1 (TRPA1) and Vanilloid1 (TRPV1) channels localized on capsaicin-sensitive afferents and non-neuronal structures might identify novel therapeutic approaches. Therefore, we characterized a translational gastritis model using iodoacetamide (IAA) and investigated TRPA1/V1 expressions. Wistar rats and CD1, C57Bl/6J mice were exposed to IAA-containing (0.05, 0.1, 0.2, 0.3, 0.5%) drinking water for 7 or 14 days. Body weight and water consumption were recorded daily. Macroscopic lesions were scored, qualitative histopathologic investigation was performed, TRPA1/V1 immunopositivity and mRNA expressions were measured. IAA induced a concentration-dependent weight loss and reduced water intake in both species. Hyperemia, submucosal edema, inflammatory infiltration and hemorrhagic erosions developed after 7 days, while ulcers after 14 days in rats. Trpa1 mRNA/protein expressions were upregulated at both timepoints. Meanwhile, TRPV1 immunopositivity was upregulated in the gastric corpus after 0.05% IAA ingestion, but downregulated after 0.2%, whereas Trpv1 mRNA did not change. Interestingly, no macroscopic/microscopic changes were observed in mice. These are the first data for the concentration- and duration-dependent changes in the IAA-induced gastritis in rats accompanied by TRPA1 upregulation, therefore, its therapeutic potential in gastritis should further be investigated.
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Van Liefferinge, Elout, Maximiliano Müller, Noémie Van Noten, Jeroen Degroote, Shahram Niknafs, Eugeni Roura, and Joris Michiels. "Cinnamaldehyde Induces Release of Cholecystokinin and Glucagon-Like Peptide 1 by Interacting with Transient Receptor Potential Ankyrin 1 in a Porcine Ex-Vivo Intestinal Segment Model." Animals 11, no. 8 (July 30, 2021): 2262. http://dx.doi.org/10.3390/ani11082262.
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Cinnamaldehyde and capsaicin have been reported to exert effects on the gastric function, mediated by the interaction with transient receptor potential ankyrin channel 1 (TRPA1) and transient receptor potential vanilloid channel 1 (TRPV1), respectively. This study examined whether these compounds could trigger the release of cholecystokinin (CCK) and/or glucagon-like peptide 1 (GLP-1) in the pig’s gut in a porcine ex-vivo intestinal segment model. Furthermore, it was verified whether this response was mediated by TRPA1 or TRPV1 by using the channel’s antagonist. These gut peptides play a key role in the “intestinal brake”, a feedback mechanism that influences the function of proximal parts of the gut. Structural analogues of cinnamaldehyde were screened as well, to explore structure-dependent activation. Results showed a significant effect of capsaicin on GLP-1 release in the proximal small intestine, TRPV1 independent. TRPA1 showed to be strongly activated by cinnamaldehyde, both in proximal and distal small intestine, evidenced by the release of CCK and GLP-1, respectively. Out of all structural derivates, cinnamaldehyde showed the highest affinity for TRPA1, which elucidates the importance of the α,β-unsaturated aldehyde moiety. In conclusion, cinnamaldehyde as a TRPA1 agonist, is a promising candidate to modulate gastric function, by activating intestinal brake mechanisms.
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Kono, Toru, Atsushi Kaneko, Yuji Omiya, Katsuya Ohbuchi, Nagisa Ohno, and Masahiro Yamamoto. "Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 304, no. 4 (February 15, 2013): G428—G436. http://dx.doi.org/10.1152/ajpgi.00356.2012.
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The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161–170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.
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Hsu, Chun-Chun, and Lu-Yuan Lee. "Role of calcium ions in the positive interaction between TRPA1 and TRPV1 channels in bronchopulmonary sensory neurons." Journal of Applied Physiology 118, no. 12 (June 15, 2015): 1533–43. http://dx.doi.org/10.1152/japplphysiol.00043.2015.
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Both transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are abundantly expressed in bronchopulmonary C-fiber sensory nerves and can be activated by a number of endogenous inflammatory mediators. A recent study has reported a synergistic effect of simultaneous TRPA1 and TRPV1 activations in vagal pulmonary C-fiber afferents in anesthetized rats, but its underlying mechanism was not known. This study aimed to characterize a possible interaction between these two TRP channels and to investigate the potential role of Ca2+ as a mediator of this interaction in isolated rat vagal pulmonary sensory neurons. Using the perforated patch-clamp recording technique, our study demonstrated a distinct positive interaction occurring abruptly between TRPA1 and TRPV1 when they were activated simultaneously by their respective agonists, capsaicin (Cap) and allyl isothiocyanate (AITC), at near-threshold concentrations in these neurons. AITC at this low concentration evoked only minimal or undetectable responses, but it markedly amplified the Cap-evoked current in the same neurons. This potentiating effect was eliminated when either AITC or Cap was replaced by non-TRPA1 and non-TRPV1 chemical activators of these neurons, demonstrating the selectivity of the interaction between these two TRP channels. Furthermore, when Ca2+ was removed from the extracellular solution, the synergistic effect of Cap and AITC on pulmonary sensory neurons was completely abrogated, clearly indicating a critical role of Ca2+ in mediating the action. These results suggest that this TRPA1-TRPV1 interaction may play a part in regulating the sensitivity of pulmonary sensory neurons during airway inflammatory reaction.
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Mori, Noriyuki, Fuminori Kawabata, Shigenobu Matsumura, Hiroshi Hosokawa, Shigeo Kobayashi, Kazuo Inoue, and Tohru Fushiki. "Intragastric administration of allyl isothiocyanate increases carbohydrate oxidation via TRPV1 but not TRPA1 in mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 6 (June 2011): R1494—R1505. http://dx.doi.org/10.1152/ajpregu.00645.2009.
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The transient receptor potential (TRP) channel family is composed of a wide variety of cation-permeable channels activated polymodally by various stimuli and is implicated in a variety of cellular functions. Recent investigations have revealed that activation of TRP channels is involved not only in nociception and thermosensation but also in thermoregulation and energy metabolism. We investigated the effect of intragastric administration of TRP channel agonists on changes in energy substrate utilization of mice. Intragastric administration of allyl isothiocyanate (AITC; a typical TRPA1 agonist) markedly increased carbohydrate oxidation but did not affect oxygen consumption. To examine whether TRP channels mediate this increase in carbohydrate oxidation, we used TRPA1 and TRPV1 knockout (KO) mice. Intragastric administration of AITC increased carbohydrate oxidation in TRPA1 KO mice but not in TRPV1 KO mice. Furthermore, AITC dose-dependently increased intracellular calcium ion concentration in cells expressing TRPV1. These findings suggest that AITC might activate TRPV1 and that AITC increased carbohydrate oxidation via TRPV1.
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Krisztina, Pohóczky, Bohonyi Noémi, Maczkó Péter, Kajtár Béla, and Helyes Zsuzsanna. "Presence and upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) in translational rat endometriosis model." Bulletin of Medical Sciences 92, no. 1 (July 1, 2019): 15–26. http://dx.doi.org/10.2478/orvtudert-2019-0011.
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Abstract The Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are non-selective cation channels predominantly localized on capsaicin-sensitive sensory neurons; however both receptors have been described in non-neuronal tissues. It has been published that both receptors upregulated in peritoneal endometriosis in humans. Our research group demonstrated that TRPA1 and TRPV1 expression is elevated in human deep infiltrating endometriosis (DIE) lesions and the receptors have an estrogen-dependent expression pattern in rat endometrium. Here, we investigated the expression changes of TRPA1/V1 and the role of the capsaicin-sensitive sensory-nerve endings in a rat model of peritoneal endometriosis. Peritoneal endometriosis was surgically induced in 8-week-old female rats (n=7-7) for 2-weeks (acute condition) and 8-weeks (chronic condition). TRPA1/V1 mRNAs were quantified with quantitative polymerase chain reaction (qPCR). The expression levels were compared with the results obtained earlier from human DIE samples. The blockade of the TRPA1/V1 expressing capsaicin-sensitive nerve endings was induced with resiniferatoxin (RTX), followed by the measurement of the weight and size of the endometriosis lesions. We detected TRPV1 and TRPA1 mRNA in normal rat endometrium, their expression was not altered in sham-operated animals. In chronic, but not in acute endometriosis the expression was significantly elevated in the lesions, which results are consistent with our previous findings in human DIE. The elimination of capsaicin-sensitive nerve endings decreased the weight of the endometriosis lesions while the size of the ectopic tissue was not altered. Taken together, our results obtained from the rat endometriosis model are consistent with the previous human results, therefore this model is considered to have translational significance and it is suitable for functional analysis of the ion channels. The local, non-neuronal TRPA1 and TRPV1 might play a role in inflammation and sensory neuronal activation in endometriosis related pain, which is mediated by a broad range of pro-inflammatory molecules.
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Toschi, Andrea, Giorgia Galiazzo, Andrea Piva, Claudio Tagliavia, Gemma Mazzuoli-Weber, Roberto Chiocchetti, and Ester Grilli. "Cannabinoid and Cannabinoid-Related Receptors in the Myenteric Plexus of the Porcine Ileum." Animals 11, no. 2 (January 21, 2021): 263. http://dx.doi.org/10.3390/ani11020263.
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An important piece of evidence has shown that molecules acting on cannabinoid receptors influence gastrointestinal motility and induce beneficial effects on gastrointestinal inflammation and visceral pain. The aim of this investigation was to immunohistochemically localize the distribution of canonical cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) and the cannabinoid-related receptors transient potential vanilloid receptor 1 (TRPV1), transient potential ankyrin receptor 1 (TRPA1), and serotonin receptor 5-HT1a (5-HT1aR) in the myenteric plexus (MP) of pig ileum. CB1R, TRPV1, TRPA1, and 5-HT1aR were expressed, with different intensities in the cytoplasm of MP neurons. For each receptor, the proportions of the immunoreactive neurons were evaluated using the anti-HuC/HuD antibody. These receptors were also localized on nerve fibers (CB1R, TRPA1), smooth muscle cells of tunica muscularis (CB1R, 5-HT1aR), and endothelial cells of blood vessels (TRPV1, TRPA1, 5-HT1aR). The nerve varicosities were also found to be immunoreactive for both TRPV1 and 5-HT1aR. No immunoreactivity was documented for CB2R. Cannabinoid and cannabinoid-related receptors herein investigated showed a wide distribution in the enteric neurons and nerve fibers of the pig MP. These results could provide an anatomical basis for additional research, supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders in porcine enteropathies.
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Raisinghani, Manish, Linlin Zhong, Joseph A. Jeffry, Mahendra Bishnoi, Reddy M. Pabbidi, Fátima Pimentel, De-Shou Cao, M. Steven Evans, and Louis S. Premkumar. "Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception." American Journal of Physiology-Cell Physiology 301, no. 3 (September 2011): C587—C600. http://dx.doi.org/10.1152/ajpcell.00465.2010.
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Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca2+-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca2+. The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin-induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced more pronounced and prolonged changes in nociceptive behavior than those induced by capsaicin. In conclusion, the characteristics of TRPA1 we have delineated suggest that it might play a unique role in nociception.
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Ceppa, Eugene, Fiore Cattaruzza, Victoria Lyo, Silvia Amadesi, Juan-Carlos Pelayo, Daniel P. Poole, Natalya Vaksman, et al. "Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 3 (September 2010): G556—G571. http://dx.doi.org/10.1152/ajpgi.00433.2009.
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The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. Immunoreactive TRPV4 and TRPA1 were detected in pancreatic nerve fibers and in dorsal root ganglia neurons innervating the pancreas, which were identified by retrograde tracing. Agonists of TRPV4 and TRPA1 increased intracellular Ca2+ concentration ([Ca2+]i) in these neurons in culture, and neurons also responded to the TRPV1 agonist capsaicin and are thus nociceptors. Intraductal injection of TRPV4 and TRPA1 agonists increased c-Fos expression in spinal neurons, indicative of nociceptor activation, and intraductal TRPA1 agonists also caused pancreatic inflammation. The effects of TRPV4 and TRPA1 agonists on [Ca2+]i, pain and inflammation were markedly diminished or abolished in trpv4 and trpa1 knockout mice. The secretagogue cerulein induced pancreatitis, c-Fos expression in spinal neurons, and pain behavior in wild-type mice. Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.
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Cheng, Li, Qing-Qing Luo, and Sheng-Liang Chen. "Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease." Gastroenterology Research and Practice 2022 (May 29, 2022): 1–7. http://dx.doi.org/10.1155/2022/7294775.
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Aim. Lots of researches have endeavored to elucidate the pathogenetic mechanism of visceral hypersensitivity in order to guide the therapy of diarrhea predominant-irritable bowel syndrome (IBS-D). Transient receptor potential (TRP) channels and their role in visceral nociception have been vastly investigated. We investigated the expression of TRP channels in IBS-D colonic biopsies and its correlation with the severity of the disease. Methods. Sigmoid biopsies were obtained from 34 IBS-D patients and 28 healthy controls (HCs). IBS-D was diagnosed according to Rome IV criteria. Their clinical parameters were assessed through questionnaires. Expression of TRPV1, TRPV4, TRPA1, TRPM2, and TRPM8 was evaluated with immunohistology staining. Results. Expression levels of TRPV1, TRPV4, and TRPA1 in the colonic mucosa of IBS-D patients were significantly higher than those in HCs ( p < 0.05 ), while there was no obvious difference of TRPM2 and TRPM8 expression between IBS-D patients and HCs. In addition, the expression levels of TRPV1 and TRPA1, but TRPV4, in the colonic mucosa correlated positively with the severity of diseases ( r = 0.6303 and 0.4506, respectively, p < 0.05 ). Conclusions. Expression of TRPV1, TRPA1, and TRPV4 in the colonic mucosa was enhanced in IBS-D patients compared with HCs with the former two correlated with the severity of the disease. TRP channels might be promising biomarkers in the diagnosis and estimate of the severity in IBS-D.
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Nilsson, Daniel, Eva Jennische, Nicola Cavallini, and Magnus Braide. "TRPA1 Mechanoreceptors Mediate the IL-6 Response to a Single PD Dwell in the Rat." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 37, no. 5 (September 2017): 509–15. http://dx.doi.org/10.3747/pdi.2016.00290.
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Background The development of modern, biocompatible peritoneal dialysis (PD) fluids has not entirely eliminated the local pro-inflammatory effects of PD fluid administration. The present study was performed in order to establish the importance of known signaling pathways connected to mechano-, osmo- and chemo-sensors of the transient receptor potential (TRP) family for the acute inflammatory response to PD. Methods Rats were exposed to a single 4-hour dwell of lactate-buffered, 2.5% glucose, filter-sterilized PD fluid through an implanted PD catheter. In some groups, the PD dwell was preceded by intravenous administration of blockers of TRPV1 (BCTC), TRPA1 (HC030031), or neurokinin 1 (NK1) (Spantide II) receptors. Cytokine messenger ribonucleic acid (mRNA) expressions were quantified in tissue biopsies (real-time polymerase chain reaction [qPCR]), and cytokine concentrations were quantified in dialysate samples by enzyme-linked immunosorbent assay (ELISA). Tissue expressions of TRPV1, TRPA1, and NK1 were evaluated immuno-histochemically. Results The PD dwell induced peritoneal synthesis of Il1b, Tnf, and Il6 and a secretion of interleukin-6 (IL-6) into the dialysate. The catheter implantation already induced the transcription of Il1b and Tnf but did not significantly affect Il6 transcription. The Il6 response to the PD dwell could be virtually eliminated by blocking TRPA1 but was not affected by TRPV1 blockade. Blocking the substance P receptor, NK1, produced an insignificant trend towards Il6 inhibition. TRPA1 and NK1 showed a stronger immuno-reactivity than TRPV1 on cells of the peritoneal tissue. Conclusion The results show that IL-6 synthesis and secretion were connected to acute PD fluid exposure, and this response was triggered by TRPA1 receptors, possibly located to non-neuronal cells.
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Tomsen, Noemí, Omar Ortega, Daniel Alvarez-Berdugo, Laia Rofes, and Pere Clavé. "A Comparative Study on the Effect of Acute Pharyngeal Stimulation with TRP Agonists on the Biomechanics and Neurophysiology of Swallow Response in Patients with Oropharyngeal Dysphagia." International Journal of Molecular Sciences 23, no. 18 (September 15, 2022): 10773. http://dx.doi.org/10.3390/ijms231810773.
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Fluid thickening is the main compensatory strategy for patients with oropharyngeal dysphagia (OD) associated with aging or neurological diseases, and there is still no pharmacological treatment. We aimed to compare the effects of increasing bolus viscosity with that of acute stimulation with TRPV1, TRPA1 or TRPM8 agonists on the biomechanics and neurophysiology of swallow response in patients with OD. We retrospectively analyzed seven studies from our laboratory on 329 patients with OD. The effect of increasing shear viscosity up to 3682 mPa·s was compared by videofluoroscopy and pharyngeal sensory evoked potentials (pSEP) with that of adding to the bolus: capsaicin (TRPV1, 150 μM/10 μM), piperine (TRPA1/V1, 1 mM/150 μM), menthol (TRPM8, 1 mM/10 mM), cinnamaldehyde-zinc (TRPA1, 100 ppm–70 mM), citral (TRPA1, 250 ppm) or citral-isopulegol (TRPA1-TRPM8, 250 ppm–200 ppm). Fluid thickening improved the safety of swallow by 80% (p < 0.0001) by delaying bolus velocity by 20.7 ± 7.0% and time to laryngeal vestibule closure (LVC) by 23.1 ± 3.7%. Capsaicin 150μM or piperine 1 mM significantly improved safety of swallow by 50% (p < 0.01) and 57.1% (p < 0.01) by speeding time to LVC by 27.6% (p < 0.001) and 19.5% (p < 0.01) and bolus velocity by 24.8% (p < 0.01) and 16.9% (p < 0.05), respectively. Cinnamaldehyde-zinc shortened the P2 latency of pSEPs by 11.0% (p < 0.01) and reduced N2-P2 amplitude by 35% (p < 0.01). In conclusion, TRPV1 and TRPV1/A1 agonists are optimal candidates to develop new pharmacological strategies to promote the recovery of brain and swallow function in patients with chronic OD.
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Ghosh, Monica, Igor A. Schepetkin, Gulmira Özek, Temel Özek, Andrei I. Khlebnikov, Derek S. Damron, and Mark T. Quinn. "Essential Oils from Monarda fistulosa: Chemical Composition and Activation of Transient Receptor Potential A1 (TRPA1) Channels." Molecules 25, no. 21 (October 22, 2020): 4873. http://dx.doi.org/10.3390/molecules25214873.
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Little is known about the pharmacological activity of Monarda fistulosa L. essential oils. To address this issue, we isolated essential oils from the flowers and leaves of M. fistulosa and analyzed their chemical composition. We also analyzed the pharmacological effects of M. fistulosa essential oils on transient receptor potential (TRP) channel activity, as these channels are known targets of various essential oil constituents. Flower (MEOFl) and leaf (MEOLv) essential oils were comprised mainly of monoterpenes (43.1% and 21.1%) and oxygenated monoterpenes (54.8% and 77.7%), respectively, with a high abundance of monoterpene hydrocarbons, including p-cymene, γ-terpinene, α-terpinene, and α-thujene. Major oxygenated monoterpenes of MEOFl and MEOLv included carvacrol and thymol. Both MEOFl and MEOLv stimulated a transient increase in intracellular free Ca2+ concentration ([Ca2+]i) in TRPA1 but not in TRPV1 or TRPV4-transfected cells, with MEOLv being much more effective than MEOFl. Furthermore, the pure monoterpenes carvacrol, thymol, and β-myrcene activated TRPA1 but not the TRPV1 or TRPV4 channels, suggesting that these compounds represented the TRPA1-activating components of M. fistulosa essential oils. The transient increase in [Ca2+]i induced by MEOFl/MEOLv, carvacrol, β-myrcene, and thymol in TRPA1-transfected cells was blocked by a selective TRPA1 antagonist, HC-030031. Although carvacrol and thymol have been reported previously to activate the TRPA1 channels, this is the first report to show that β-myrcene is also a TRPA1 channel agonist. Finally, molecular modeling studies showed a substantial similarity between the docking poses of carvacrol, thymol, and β-myrcene in the binding site of human TRPA1. Thus, our results provide a cellular and molecular basis to explain at least part of the therapeutic properties of these essential oils, laying the foundation for prospective pharmacological studies involving TRP ion channels.
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Ibrahim, Dakik, Vandier, Chautard, Paintaud, Mazurier, Lecomte, Guéguinou, and Raoul. "Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer." Cancers 11, no. 4 (April 19, 2019): 561. http://dx.doi.org/10.3390/cancers11040561.
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Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca2+-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca2+ channels and Ca2+-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca2+ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca2+ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca2+ channels remodeling in CRC.
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Van Liefferinge, Elout, Noémie Van Noten, Jeroen Degroote, Gunther Vrolix, Mario Van Poucke, Luc Peelman, Chris Van Ginneken, Eugeni Roura, and Joris Michiels. "Expression of Transient Receptor Potential Ankyrin 1 and Transient Receptor Potential Vanilloid 1 in the Gut of the Peri-Weaning Pig Is Strongly Dependent on Age and Intestinal Site." Animals 10, no. 12 (December 17, 2020): 2417. http://dx.doi.org/10.3390/ani10122417.
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Transient receptor potential (TRP) channels contribute to sensory transduction in the body, agonized by a variety of stimuli, such as phytochemicals, and they are predominantly distributed in afferent neurons. Evidence indicates their expression in non-neuronal cells, demonstrating their ability to modulate gastrointestinal function. Targeting TRP channels could potentially be used to regulate gastrointestinal secretion and motility, yet their expression in the pig is unknown. This study investigated TRPA1 and TRPV1 expression in different gut locations of piglets of varying age. Colocalization with enteroendocrine cells was established by immunohistochemistry. Both channels were expressed in the gut mucosa. TRPV1 mRNA abundance increased gradually in the stomach and small intestine with age, most notably in the distal small intestine. In contrast, TRPA1 exhibited sustained expression across ages and locations, with the exception of higher expression in the pylorus at weaning. Immunohistochemistry confirmed the endocrine nature of both channels, showing the highest frequency of colocalization in enteroendocrine cells for TRPA1. Specific co-localization on GLP-1 immunoreactive cells indicated their possible role in GLP-1 release and the concomitant intestinal feedback mechanism. Our results indicate that TRPA1 and TRPV1 could play a role in gut enteroendocrine activity. Moreover, age and location in the gut significantly affected gene expression.
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Chen, Yu-Shan, Yu Zhi Lian, Wen-Chao Chen, Chun-Chao Chang, Alexey A. Tinkov, Anatoly V. Skalny, and Jane C. J. Chao. "Lycium barbarum Polysaccharides and Capsaicin Inhibit Oxidative Stress, Inflammatory Responses, and Pain Signaling in Rats with Dextran Sulfate Sodium-Induced Colitis." International Journal of Molecular Sciences 23, no. 5 (February 22, 2022): 2423. http://dx.doi.org/10.3390/ijms23052423.
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Ulcerative colitis (UC) is an inflammatory disease with chronic relapsing symptoms. This study investigated the effects of Lycium barbarum polysaccharides (LBP) and capsaicin (CAP) in dextran sulfate sodium (DSS)-induced UC rats. Rats were divided into normal, DSS-induced UC, and UC treated with 100 mg LBP/kg bw, 12 mg CAP/kg bw, or 50 mg LBP/kg bw and 6 mg CAP/kg bw. Rats were fed LBP or CAP orally by gavage for 4 weeks, and UC model was established by feeding 5% DSS in drinking water for 6 days during week 3. Oral CAP and mixture significantly reduced disease activity index. Oral LBP significantly decreased serum malondialdehyde, interleukin (IL)-6, colonic tumor necrosis factor (TNF)-α levels, and protein expression of transient receptor potential cation channel V1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), but increased serum catalase activity. Oral CAP significantly suppressed serum IL-6, colonic TRPV1 and TRPA1 protein expression, but elevated IL-10 levels, serum superoxide dismutase and catalase activities. The mixture of LBP and CAP significantly reduced serum IL-6, colonic TNF-α and TRPA1 protein. In conclusion, administration of LBP and/or CAP attenuate DSS-induced UC symptoms through inhibiting oxidative stress, proinflammatory cytokines, and protein expression of TRPV1 and TRPA1.
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Devos, Fien C., Brett Boonen, Yeranddy A. Alpizar, Tania Maes, Valérie Hox, Sven Seys, Lore Pollaris, et al. "Neuro-immune interactions in chemical-induced airway hyperreactivity." European Respiratory Journal 48, no. 2 (April 28, 2016): 380–92. http://dx.doi.org/10.1183/13993003.01778-2015.
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Asthma may be induced by chemical sensitisers,viamechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitrointracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using anin vivomodel, in which an airway challenge with TDI induces AHR in TDI-sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, inTrpa1andTrpv1knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficientKitWsh/Wshmice, and in wild-type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR.
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Xing, Jihong, and Jianhua Li. "TRPA1 Function in Skeletal Muscle Sensory Neurons Following Femoral Artery Occlusion." Cellular Physiology and Biochemistry 42, no. 6 (2017): 2307–17. http://dx.doi.org/10.1159/000480003.
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Background/Aims: Transient receptor potential channel A1 (TRPA1) is engaged in amplified autonomic responses evoked by stimulation of muscle afferent nerves in rats with experimental peripheral arterial disease. The purposes of this study were to characterize current responses induced by activation of TRPA1 in dorsal root ganglion (DRG) neurons of control limbs and limbs with femoral artery occlusion. Methods: DRG neurons from rats were labeled by injecting the fluorescence tracer DiI into the hindlimb muscles and whole-cell patch clamp experiments were performed to determine TRPA1 currents. Results: Data show that AITC (a TRPA1 agonist) from the concentrations of 50 µM to 200 µM produces a dose-dependent increase of amplitudes of inward current responses. Notably, the peak current amplitude induced by AITC is significantly larger in DRG neurons of ligated limbs than that in control limbs. AITC-induced current responses are observed in small and medium size DRG neurons, and there is no difference in size distribution of DRG neurons between control limbs and ligated limbs. However, femoral occlusion increases the percentage of the AITC-sensitive DRG neurons as compared to control. AITC-induced currents in DRG neurons are significantly attenuated by exposure to 10 µM of HC-030031, a potent and selective inhibitor of TRPA1, in both control and femoral occlusion groups. In addition, capsaicin (a TRPV1 agonist) evokes a greater increase in the amplitude of AITC-currents in DRG neurons of ligated limbs than that in control limbs. Conclusions: A greater current response with activation of TRPA1 is developed in muscle afferent nerves when hindlimb arterial blood supply is deficient under ischemic conditions; and TRPV1 is partly responsible for augmented TRPA1 responses induced by arterial occlusion.
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Blackshaw, L. Ashley, Stuart M. Brierley, Andrea M. Harrington, and Patrick A. Hughes. "TRP Channels in Visceral Pain." Open Pain Journal 6, no. 1 (March 8, 2013): 23–30. http://dx.doi.org/10.2174/1876386301306010023.
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Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.
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Suzuki, Hiroka, Noriyuki Hatano, Yukiko Muraki, Yuka Itoh, Satoko Kimura, Hidetoshi Hayashi, Kikuo Onozaki, Yoshiaki Ohi, Akira Haji, and Katsuhiko Muraki. "The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor." American Journal of Physiology-Cell Physiology 307, no. 4 (August 15, 2014): C384—C394. http://dx.doi.org/10.1152/ajpcell.00182.2013.
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Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable nonselective cation channel expressed in neuronal and nonneuronal cells and plays an important role in acute and inflammatory pain. Here, we show that an NADPH oxidase (NOX) inhibitor, diphenyleneiodonium (DPI), functions as a TRPA1 activator in human embryonic kidney cells expressing human TRPA1 (HEK-TRPA1) and in human fibroblast-like synoviocytes. Application of DPI at 0.03–10 μM induced a Ca2+ response in HEK-TRPA1 cells in a concentration-dependent manner. The Ca2+ response was effectively blocked by a selective TRPA1 antagonist, HC-030031 (HC). In contrast, DPI had no effect on HEK cells expressing TRPV1-V4 or TRPM8. Four other NOX inhibitors, apocynin (APO), VAS2870 (VAS), plumbagin, and 2-acetylphenothiazine, also induced a Ca2+ response in HEK-TRPA1 cells, which was inhibited by pretreatment with HC. In the presence of 5 mM glutathione, the Ca2+ response to DPI was effectively reduced. Moreover, mutation of cysteine 621 in TRPA1 substantially inhibited the DPI-induced Ca2+ response, while it did not inhibit the APO- and VAS-induced responses. The channel activity was induced by DPI in excised membrane patches with both outside-out and inside-out configurations. Internal application of neomycin significantly inhibited the DPI-induced inward currents. In inflammatory synoviocytes with TRPA1, DPI evoked a Ca2+ response that was sensitive to HC. In mice, intraplantar injection of DPI caused a pain-related response which was inhibited by preadministration with HC. Taken together, our findings demonstrate that DPI and other NOX inhibitors activate human TRPA1 without mediating NOX.
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Petrushenko, M. A., E. A. Petrushenko, and E. A. Lukyanetz. "STRUCTURE, PROPERTIES AND PHYSIOLOGICAL ROLE OF TRPA1 RECEPTORS." Fiziolohichnyĭ zhurnal 67, no. 1 (January 28, 2021): 44–56. http://dx.doi.org/10.15407/fz67.01.044.
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In mammals, the ankyrin ionotropic transient receptor potential type 1 (TRPA1) is the only member of the TRPA receptor gene subfamily. It is defined as a target for damaging and inflammatory effects in peripheral sensory neurons, which implies its functional role in the development of pain and neurogenic inflammation. Experimental studies indicate that calcium permeable non-selective ion receptor channel TRPA1 is activated by a number of exogenous irritant compounds, factors including low temperatures. This review describes the structure, properties, and physiological role of TRPA1 receptors.
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Marshall-Gradisnik, Sonya M., Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos, and Donald R. Staines. "Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients." Immunology and Immunogenetics Insights 7 (January 2015): III.S25147. http://dx.doi.org/10.4137/iii.s25147.
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Background The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments. OBJECTIVES The purpose of this study was to determine the role of TRPs in CFS. Methods The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes ( TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018). Conclusion The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.
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Stöckl, Stephanie K., Roberto de Col, Milos R. Filipovic, and Karl Messlinger. "Nitroxyl Delivered by Angeli’s Salt Causes Short-Lasting Activation Followed by Long-Lasting Deactivation of Meningeal Afferents in Models of Headache Generation." International Journal of Molecular Sciences 23, no. 4 (February 19, 2022): 2330. http://dx.doi.org/10.3390/ijms23042330.
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The role of TRPA1 receptor channels in meningeal nociception underlying the generation of headaches is still unclear. Activating as well as inhibitory effects of TRPA1 agonists have been reported in animal models of headache. The aim of the present study was to clarify the effect of the TRPA1 agonist nitroxyl (HNO) delivered by Angeli’s salt in two rodent models of meningeal nociception. Single fibre recordings were performed using half-skull preparations of mice (C57BL/6) in vitro. Angeli’s salt solution (AS, 300 µM) caused short-lasting vigorous increases in neuronal activity of primary meningeal afferents, followed by deactivation and desensitisation. These effects were similar in TRPA1 knockout and even more pronounced in TRPA1/TRPV1 double-knockout mice in comparison to wild-type mice. The activity of spinal trigeminal neurons with afferent input from the dura mater was recorded in vivo in anesthetised rats. AS (300 µM) or the TRPA1 agonist acrolein (100 and 300 µM) was applied to the exposed dura mater. AS caused no significant changes in spontaneous activity, while the mechanically evoked activity was reduced after acrolein application. These results do not confirm the assumption that activation of trigeminal TRPA1 receptor channels triggers the generation of headaches or contributes to its aggravation. Instead, there is evidence that TRPA1 activation may have an inhibitory function in the nociceptive trigeminal system.
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Balemans, D., J. Aguilera-Lizarraga, M. V. Florens, P. Jain, A. Denadai-Souza, M. F. Viola, Y. A. Alpizar, et al. "Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 3 (March 1, 2019): G338—G349. http://dx.doi.org/10.1152/ajpgi.00116.2018.
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Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.
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Salas, Margaux M., Kenneth M. Hargreaves, and Armen N. Akopian. "TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1." European Journal of Neuroscience 29, no. 8 (April 2009): 1568–78. http://dx.doi.org/10.1111/j.1460-9568.2009.06702.x.
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Pohóczky, Krisztina, József Kun, Bálint Szalontai, Éva Szőke, Éva Sághy, Maja Payrits, Béla Kajtár, et al. "Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium." Journal of Molecular Endocrinology 56, no. 2 (December 7, 2015): 135–49. http://dx.doi.org/10.1530/jme-15-0184.
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Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen- and progesterone-dependent alterations in the rat endometrium in comparison with the estrogen-regulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non-selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca2+]imeasurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults,Trpa1andTrpv1mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulatedTrpa1,Trpv1andMifmRNA levels in endometrial cell cultures, but 17β-oestradiol having ERα-selective potency increased only the expression ofTrpv1. We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF.
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Stueber, Thomas, Mirjam J. Eberhardt, Christoph Hadamitzky, Annette Jangra, Stefan Schenk, Felicia Dick, Carsten Stoetzer, et al. "Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity." Anesthesiology 124, no. 5 (May 1, 2016): 1153–65. http://dx.doi.org/10.1097/aln.0000000000001050.
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Abstract Background The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity. Methods Human embryonic kidney 293 (HEK-293) cells expressing wild-type or mutant human (h) TRPV1 or TRPA1 constructs as well as the sodium channel Nav1.7 were investigated by means of patch clamp and ratiometric calcium imaging. Cytotoxicity was examined by flow cytometry. Results Activation of hTRPA1 by carvacrol and hTRPV1 by capsaicin produced a QX-314–independent reduction of sodium current amplitudes. However, permeation of QX-314 through hTRPV1 or hTRPA1 was evident by a concentration-dependent, use-dependent inhibition of Nav1.7 activated at 10 Hz. Five and 30 mM QX-314 activated hTRPV1 via mechanisms involving the intracellular vanilloid-binding domain and hTRPA1 via unknown mechanisms independent of intracellular cysteins. Expression of hTRPV1, but not hTRPA1, was associated with a QX-314–induced cytotoxicity (viable cells 48 ± 5% after 30 mM QX-314) that was ameliorated by the TRPV1 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide (viable cells 81 ± 5%). Conclusions The study data demonstrate that QX-314 directly activates and permeates the human isoforms of TRPV1 and TRPA1 to induce inhibition of sodium channels, but also a TRPV1-dependent cytotoxicity. These results warrant further validation of this approach in more intact preparations and may be valuable for the development of this concept into clinical practice.
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Miyano, Kanako, Seiji Shiraishi, Koichiro Minami, Yuka Sudo, Masami Suzuki, Toru Yokoyama, Kiyoshi Terawaki, et al. "Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways." International Journal of Molecular Sciences 20, no. 13 (July 3, 2019): 3271. http://dx.doi.org/10.3390/ijms20133271.
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Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.
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Marguerite, Nicole T., Jate Bernard, Douglas A. Harrison, David Harris, and Robin L. Cooper. "Effect of Temperature on Heart Rate for Phaenicia sericata and Drosophila melanogaster with Altered Expression of the TrpA1 Receptors." Insects 12, no. 1 (January 6, 2021): 38. http://dx.doi.org/10.3390/insects12010038.
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The transient receptor potential (TrpA—ankyrin) receptor has been linked to pathological conditions in cardiac function in mammals. To better understand the function of the TrpA1 in regulation of the heart, a Drosophila melanogaster model was used to express TrpA1 in heart and body wall muscles. Heartbeat of in intact larvae as well as hearts in situ, devoid of hormonal and neural input, indicate that strong over-expression of TrpA1 in larvae at 30 or 37 °C stopped the heart from beating, but in a diastolic state. Cardiac function recovered upon cooling after short exposure to high temperature. Parental control larvae (UAS-TrpA1) increased heart rate transiently at 30 and 37 °C but slowed at 37 °C within 3 min for in-situ preparations, while in-vivo larvae maintained a constant heart rate. The in-situ preparations maintained an elevated rate at 30 °C. The heartbeat in the TrpA1-expressing strains could not be revived at 37 °C with serotonin. Thus, TrpA1 activation may have allowed enough Ca2+ influx to activate K(Ca) channels into a form of diastolic stasis. TrpA1 activation in body wall muscle confirmed a depolarization of membrane. In contrast, blowfly Phaenicia sericata larvae increased heartbeat at 30 and 37 °C, demonstrating greater cardiac thermotolerance.
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Jeske, Nathaniel A., Amol M. Patwardhan, Nikita Gamper, Theodore J. Price, Armen N. Akopian, and Kenneth M. Hargreaves. "Cannabinoid WIN 55,212-2 Regulates TRPV1 Phosphorylation in Sensory Neurons." Journal of Biological Chemistry 281, no. 43 (September 5, 2006): 32879–90. http://dx.doi.org/10.1074/jbc.m603220200.
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Cannabinoids are known to have multiple sites of action in the nociceptive system, leading to reduced pain sensation. However, the peripheral mechanism(s) by which this phenomenon occurs remains an issue that has yet to be resolved. Because phosphorylation of TRPV1 (transient receptor potential subtype V1) plays a key role in the induction of thermal hyperalgesia in inflammatory pain models, we evaluated whether the cannabinoid agonist WIN 55,212-2 (WIN) regulates the phosphorylation state of TRPV1. Here, we show that treatment of primary rat trigeminal ganglion cultures with WIN led to dephosphorylation of TRPV1, specifically at threonine residues. Utilizing Chinese hamster ovary cell lines, we demonstrate that Thr144 and Thr370 were dephosphorylated, leading to desensitization of the TRPV1 receptor. This post-translational modification occurred through activation of the phosphatase calcineurin (protein phosphatase 2B) following WIN treatment. Furthermore, knockdown of TRPA1 (transient receptor potential subtype A1) expression in sensory neurons by specific small interfering RNA abolished the WIN effect on TRPV1 dephosphorylation, suggesting that WIN acts through TRPA1. We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels. These results imply that the cannabinoid WIN modulates the sensitivity of sensory neurons to TRPV1 activation by altering receptor phosphorylation. In addition, our data could serve as a useful strategy in determining the potential use of certain cannabinoids as peripheral analgesics.
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Pecze, László, Péter Pelsőczi, Miklós Kecskés, Zoltán Winter, András Papp, Krisztián Kaszás, Tamás Letoha, Csaba Vizler, and Zoltán Oláh. "Resiniferatoxin Mediated Ablation of TRPV1+ Neurons Removes TRPA1 as Well." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 36, no. 2 (March 2009): 234–41. http://dx.doi.org/10.1017/s0317167100006600.
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Objectives:Resiniferatoxin, the most potent agonist of inflammatory pain/vanilloid receptor/cation channel (TRPV1) can be used for neuron subtype specific ablation of pain generating cells at the level of the peripheral nervous system by Ca2+-excytotoxicity. Molecular neurosurgery is an emerging technology either to alleviate severe pain in cancer or treat/prevent different local neuropathies. Our aim was determining sensory modalities that may be lost after resiniferatoxin treatment.Methods:Newborn or adult mice were treated with resiniferatoxin, then changes in chemical and heat sensitivity were correlated with alterations of the cell composition of sensory ganglions.Results:Only mice treated at adult age became less sensitive to heat stimuli, while both treatment groups lost sensitivity to specific vanilloid agonists of TRPV1 and, interestingly, to allyl-isothiocyanate, a selective agonist of TRPA1. Our in vivo and post mortem analytical results confirmed that TRPV1 and TRPA1 function together and resiniferatoxin-mediated neurosurgery removes both sensor moleculesDiscussion:In adult mice resiniferatoxin causes: i) desensitization to heat and ii) sensitization to cold. Cold hyperalgesia, an imbalance in thermosensation, might be conferred by a prominent cold receptor that is expressed in surviving resiniferatoxin-resistant sensory neurons and compensates for pain signals lost with TRPA1 and TRPV1 double positive cells in the peripheral nervous system.