NEW JOURNAL OF CHEMISTRY
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2022
·Vol. 46
·期 30
·14578-14585
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IF 3.925
Zhengji Yin,Junli Peng,Zhen Qiao,Yanru Zhang,Ningning Wei
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel, which is predominantly expressed in primary afferent neurons. TRPA1, as a chemical, mechanical and temperature sensor, is closely related to some inflammatory diseases and respiratory diseases. Fluorescent probes provide a useful tool to understand the function of ion channels because of their high selectivity, high sensitivity and excellent spatio-temporal resolution. In this study, a 4-Am agonist screened by an electrophysiological assay was used as a targeting group. We designed and synthesized a small molecule fluorescent probe named DPCC based on a molecular rotation mechanism. DPCC is applied to visualize the TRPA1 channel in living cells and screen TRPA1 channel regulators. Our data suggested that the DPCC probe has a high specificity and desired resolution, and may serve as an effective tool for understanding the TRPA1 channel.
研究领域:
药理学
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生物物理学
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细胞生物学
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神经科学
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DOI
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Junli Peng,Nan Yang,Zhen Qiao,Ningning Wei,KeWei Wang,Yanru Zhang
Background and Purpose As a polymodal biosensor, the TRPA1 ion channel undergoes rapid opening and closing, a dynamic process known as gating that defines the fundamental function and modulation of ion channels. TRPA1 gating is primarily regulated by chemical and mechanical stimuli. However, whether and how TRPA1 gating transduces the biological function of pain sensation is poorly understood. Experimental Approach A series of photoswitchable TRPA1 probes (PSTRAPs1–4) were designed and synthesized. Whole-cell patch clamp recordings of hTRPA1 channels expressed in CHO cells were performed to test whether PSTRAPs could optically switch TRPA1 channel function. Site-directed mutagenesis was conducted to identify the binding site of PSTRAPs on the extracellular surface of TRPA1. In a mouse model of cheek pain, intracutaneous injection of PSTRAPs elicited pain sensation in response to photoswitching. Key Results PSTRAP-2 and PSTRAP-4 reversibly modulate TRPA1 channel function with spatiotemporal resolution. These azobenzene photoswitches can activate and deactivate TRPA1 currents expressed in CHO cells upon switching between blue light and darkness. Structural-activity relationship (SAR) analysis of PSTRAPs1–4 combined with site-directed mutagenesis revealed a residue Y926 between the pore helix 1 and 2 critical for the interaction between the PSTRAPs and TRPA1. In a mouse cheek pain model, photochemical gating of TRPA1 by intracutaneous injections of photoswitchable PSTRAP-2 and PSTRAP-4 induced pain perception in response to photoswitching cycles. Conclusion and Implications Our identification of these photoswitches not only provides small molecule tools for probing and understanding TRPA1 channel gating but also holds developmental potential for pain modulation. Graphical
研究领域:
神经科学
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药理学
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生物化学
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DOI
PubMed
高影响因子
International Journal of Environmental Research and Public Health
·
2022
·Vol. 19
·期 13
·7985
·
IF 4.614
Xiaoning Wang,Yangyang Sun,Qian Wang,Fengying Liu,Weijie Yang,Xin Sui,Jun Yang,Minmin Zhang,Shuai Wang,Zhenyu Xiao,Yuan Luo,Yongan Wang,Tong Zhu
The “Multi-Threat Medical Countermeasure (MTMC)” strategy was proposed to develop a single drug with therapeutic efficacy against multiple pathologies or broad-spectrum protection against various toxins with common biochemical signals, molecular mediators, or cellular processes. This study demonstrated that cytotoxicity, expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) mRNA, and intracellular calcium influx were increased in A549 cells exposed to amide herbicides (AHs), in which the order of cytotoxicity was metolachlor > acetochlor > propisochlor > alachlor > butachlor > propanil > pretilachlor, based on IC50values of 430, 524, 564, 565, 619, 831, and 2333 μM, respectively. Inhibition/knockout of TRPA1 efficiently protected against cytotoxicity, decreased TRPA1 mRNA expression, and reduced calcium influx. The results suggested that the TRPA1 channel could be a key common target for AHs poisoning. The order of TRPA1 affinity for AHs was propanil > pretilachlor > metolachlor > (propiso/ala/aceto/butachlor), based on KDvalues of 16.2, 309, and 364 μM, respectively. The common molecular mechanisms of TRPA1-AHs interactions were clarified, including toxicity-effector groups (benzene ring, nitrogen/oxygen-containing functional groups, halogen) and residues involved in interactions (Lys787, Leu982). This work provides valuable information for the development of TRPA1 as a promising therapeutic target for broad-spectrum antitoxins.Keywords:amide herbicides;TRPA1 channel;cytotoxicity;computational simulation;common mechanisms
研究领域:
毒理学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
American Journal of Translational Research
·
2022
·
IF 3.94
Hai Zhu,Yi Wang,Yibo He,Weifeng Yu
Chronic pelvic pain (CPP) and infertility are the common characteristics of endometriosis. Macrophages and related inflammation play important roles in endometriosis pain. TRPV1 and TRPA1 form a heteromeric channel which is related to endometriosis pain. In the present study, the inflammation-mediated macrophage polarization along with TRPV1/TRPA1 heteromers in endometriosis was investigated in vivo and in vitro . Macrophage polarization and TRPV1/TRPA1 heteromers in endometriosis tissue of patients were assayed, and was further investigated in endometriosis mice by co-culturing macrophages derived from mice in different groups with human endometrium cells. Our results indicated that macrophage polarization, as CD86 and CD206 positive macrophages, were accompanied by TRPV1/TRPA1 heteromers in endometriosis tissues of patients with pain. Inflammatory factors in peritoneal lavage fluid and serum of mice were correlated with TRPV1/TRPA1 expression in endometriosis tissues of mice as well as macrophage polarization which tended to be consistent with TRPV1/TRPA1 heteromers in endometriosis tissue. Moreover, macrophage polarization in enterocoelia induced ectopic endometrial cells migration with the increase in TRPV1/TRPA1 heteromers. Our results suggest that endometriosis-induced celiac inflammation might mediate macrophage polarization along with the increase of TRPV1/TRPA1 heteromers, which may play a key role in endometriosis pain.
研究领域:
妇科学
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免疫学
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疼痛研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 5
·2119
·
IF 4.9
Chengwei Wang,Chunjie Wu,Linjiang Song
Saiga antelope horn (SAH), a rare traditional Chinese medicine, exhibits activities of anti-feverish convulsions and anti-inflammation, whereas its underlying mechanism and specific pharmacological components are still unclear. In the present study, transient receptor potential ankyrin 1 (TRPA1), a major transient receptor potential cation channel was used as a target protein to identified TRPA1 high-affinity peptides (THPs) from SAH digests. Firstly, the SAH was digested under in vitro gastrointestinal conditions. With the method of affinity ultrafiltration and liquid chromatography–mass spectrometry (AUF-LC/MS), about 200 peptides that have a high-affinity interaction with the TRPA1 protein were screened from SAH digests. Subsequently, bioactivity databases and molecular docking were further exploited to identified three THPs, including RCWPDCR, FGFDGDF, and WFCEGSF. Furthermore, RIN-14B cells, characterized by the high expression of TRPA1 on cell surfaces, were used as the cell model to investigate the biological effect of THPs. Immunofluorescence and ELISA were conducted and showed that THPs can increase the intracellular Ca2+concentration and serotonin (5-HT) secretion in RIN-14B cells by activating TRPA1, which is evidenced by impaired upregulation of intracellular Ca2+levels and 5-HT secretion after pretreatment with the TRPA1 inhibitor (HC-030031). Moreover, an analysis of Western blots displayed that THPs up-regulated the expression levels of the 5-HT synthesis rate-limiting enzyme (TPH1) and 5-hydroxytryptophan decarboxylase (Ddc), while serotonin reuptake transporter (SERT) levels were down-regulated, suggesting that THPs enhance 5-HT secretion by regulating the 5-HT synthesis pathway. In summary, our findings demonstrate that THPs, which were identified from SAH digest via TRPA1-targeted affinity panning, exhibited the activation of the TRPA1 channel and enhanced 5-HT release in RIN-14B cells.
研究领域:
药理学
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分子生物学
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传统中药
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biology-Basel
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2022
·Vol. 11
·期 4
·503
·
IF 5.168
Jingyun Ding,Huiyan Wang,Zequn Li,Jiangnan Sun,Peng Ding,Xiaomei Chi,Mingfang Yang,Yaqing Chang,Chong Zhao
Simple SummarySea urchins are key in the trophic cascades of benthic communities. They also possess physiological characteristics of low digestibility. Thus, we explored the relationship between the indicators (digestive enzymes activities and the gut emptying) and molecules (TRPA1 and 5-HT) related to digestive physiology in the sea urchinStrongylocentrotus intermedius. The results in the present study indicate that digestive enzyme activities and gut emptying are correlated with the TRPA1 and 5-HT in the gut ofS. intermedius.This novel finding not only is important for understanding the low food digestibility of sea urchins but provides an entry point to further investigate the molecular details of digestive physiology of sea urchins.AbstractThe energetic link in the benthic community is based on physiological characteristics of the low food absorption efficiency of sea urchins. Low food absorption efficiency of sea urchins is correlated with the activity of digestive enzymes and the duration of food in their gut. Thus, the digestive enzymes activities (pepsin and amylase enzyme activities) and gut emptying are important indicators in assessing nutrient digestion and absorption in sea urchins. In the present study, the relationship between these indicators and molecules related to digestive physiology were quantified in sea urchins. We found (1) an inter-regulatory relationship existed between Transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and serotonin (5-hydroxytryptamine; 5-HT) in the gut ofStrongylocentrotus intermedius; (2) digestive enzyme activities were negatively correlated with the TRPA1 and concentration of 5-HT in the gut ofS. intermedius; (3) gut emptying rate was positively correlated with TRPA1 and concentration of 5-HT in the gut ofS. intermedius. The present study revealed that the digestion and absorption of food are correlated with the TRPA1 and 5-HT in the gut ofS. intermedius, which provides valuable information about the digestive physiology of sea urchins. This novel finding is relevant to understanding the low food digestibility of sea urchins. It also provides valuable information to the digestive physiology of sea urchins, which are key to maintaining the stability of food webs in the marine ecosystem.Keywords:sea urchin;TRPA1;5-HT;digestive enzyme;gut emptying
研究领域:
海洋生物学
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生理学
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产品关联
DOI
PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
·
2015
·
IF 3.894
Qian Huang,Yuan Chen,Nian Gong,Yong-Xiang Wang
Objective Methylglyoxal is known to be associated with the development of nephropathy , retinopathy , and other complications in diabetes. The present study tested the hypothesis that endogenously increased levels of methylglyoxal in diabetes are causally associated with the induction of neuropathic pain . Materials and methods Streptozotocin- and methylglyoxal-induced pain models were established in rats, and the anti-nociceptive effects of the methylglyoxal scavenging agents, selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, and Nav1.8 antagonist were tested. Results Systemic injection of streptozotocin in rats induced a prolonged increase in plasma methylglyoxal by approximately 60%, which was correlated with the progressive development of mechanical allodynia and thermal hyperalgesia . Local subcutaneous injection of methylglyoxal into the hindpaw produced dose-dependent and biphasic flinching nociceptive responses, which resembled formaldehyde (formalin)-induced nociception . The local methylglyoxal nociception was significantly blocked by co-injection into the hindpaw of the selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, A967079, and the Nav1.8 antagonist, A803467. Co-incubation with the methylglyoxal scavengers, aminoguanidine , d -arginine, and metformin , reduced the level of free methylglyoxal by more than 90%, and injection of their incubation solutions into the hindpaw produced negligible (3–17%) nociception. Like the clinically effective anti-diabetic neuropathic pain drug gabapentin , systemic injection of aminoguanidine, d -arginine, and metformin at doses that effectively inhibit paw-injected methylglyoxal-induced nociception significantly blocked streptozotocin-induced mechanical allodynia. Conclusion Endogenously increased methylglyoxal may mediate diabetic neuropathic pain via activation of both TRPA1 and Nav1.8 expressed on primary afferent sensory neurons , and injection of methylglyoxal into the hindpaw may serve as a simple and robust model for testing the anti-diabetic pain drugs.
研究领域:
药理学
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神经科学
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糖尿病研究
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疼痛管理
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2024
·
IF 4.2
Kaifang Yao,Zhihan Chen,Yanwei Li,Baomin Dou,Zhifang Xu,Yajing Ma,Simin Du,Jiangshan Wang,Jiangjiang Fu,Qi Liu,Zezhi Fan,Yangyang Liu,Xiaowei Lin,Yuan Xu,Yuxin Fang,Shenjun Wang,Yi Guo
Purpose Acupuncture (ACU) has been demonstrated to alleviate inflammatory pain. Mechanoreceptors are present in acupuncture points. When acupuncture exerts mechanical force, these ion channels open and convert the mechanical signals into biochemical signals. TRPA1 (T ransient receptor potential ankyrin 1) is capable of sensing various physical and chemical stimuli and serves as a sensor for inflammation and pain. This protein is expressed in immune cells and contributes to local defense mechanisms during early tissue damage and inflammation. In this study, we investigated the role of TRPA1 in acupuncture analgesia.Patients and Methods We injected complete Freund’s adjuvant (CFA) into the mouse plantars to establish a hyperalgesia model. Immunohistochemistry and immunofluorescence analyses were performed to determine the effect of acupuncture on the TRPA1 expression in the Zusanli (ST36). We used TRPA1−/− mouse and pharmacological methods to antagonize TRPA1 to observe the effect on acupuncture analgesia. On this basis, collagenase was used to destroy collagen fibers at ST36 to observe the effect on TRPA1.Results We found that the ACU group vs the CFA group, the number of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 increased significantly. In CFA- inflammatory pain models, the TRPA1−/− ACU vs TRPA1+/+ ACU groups, the paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) downregulated significantly. In the ACU + high-, ACU + medium-, ACU + low-dose HC-030031 vs ACU groups, the PWL and PWT were downregulated, and in carrageenan-induced inflammatory pain models were consistent with these results. We further found the ACU + collagenase vs ACU groups, the numbers of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 were downregulated.Conclusion These findings together imply that TRPA1 plays a significant role in the analgesic effects produced via acupuncture at the ST36. This provides new evidence for acupuncture treatment of painful diseases.
研究领域:
疼痛研究
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神经科学
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免疫学
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中医
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产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2021
·
IF 4.407
Yu-bo Sun,Mo Liu,Xin-sheng Fan,Li-ping Zhou,Meng-wen Li,Fang-yuan Hu,Qin-fei Yue,Yi-ming Zhang
The occurrence of asthma is closely related to environmental factors such as cigarette smoke (CS), one of the common risk factors. Environmental stimuli have the potential to activate transient receptor potential ankyrin 1 (TRPA1) and cause or aggravate asthma. The destruction of tight junctions (TJs) between airway epithelial cells by environmental stimuli in asthma has been researched. It is worth exploring whether CS can injury TJs and aggravate asthma by activating TRPA1. The objective of this study was to investigate the aggravation of CS on ovalbumin (OVA)-induced asthma related phenotypes and TJs expression in mice, and to explore the relationship between TRPA1 and the expression of TJs protein. Female wild type (WT) C57BL/6 mice, induced by OVA, CS and OVA plus CS (OVA + CS) respectively, were used to establish a 42-day asthma model, and mice with TRPA1 knockout (TRPA1 −/− ) were treated in the same way. This study detected the number of inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF), the levels of IL-4, IL-5, IL-13 in BALF, enhanced pause (Penh) of lung function, pathological changes and the gene and protein expressions of TRPA1 and TJs (including ZO-1, Occludin and Claudin-2) in lung tissues. Compared with normal saline (NS) group, WT mice in the OVA group and OVA + CS group were significantly higher in asthma related phenotypes. The WT-OVA + CS group also showed higher Penh value, levels of IL-5 and IL-13 in BALF and lung tissue injury scores when compared with the WT-OVA group and WT-CS group. However, WT-OVA + CS group mice had significantly larger number of neutrophils in BALF than the WT-OVA group, and had larger number of eosinophils in peripheral blood and higher levels of IL-4 in BALF than the WT-CS group. Meanwhile, compared with the WT-NS group, the expressions of TRPA1 and Claudin-2 in lung tissues increased in other three groups while their expressions of ZO-1 and Occludin decreased, among which, the WT-OVA + CS group showed more remarkable changes. Compared with the WT-OVA + CS group, mice in the TRPA1 −/− -OVA + CS showed a significant decrease in the number of inflammatory cells, levels of IL-4, IL-5 and IL-13 in BALF, Penh value and lung tissue injury score, and a downregulation of Claudin-2 expression while an upregulation of ZO-1 and Occludin expressions. In addition, the airway inflammation and injury, and the expressions of ZO-1, Occluding and Claudin-2 expressions were found with no statistic differences between TRPA1 −/− -OVA group and TRPA1 −/− -OVA + CS group. These results suggest that CS has aggravated the airway inflammation, pathological damage and destruction of TJs in airway epithelium of OVA-induced asthmatic mice, the processes of which are related to the increase of TRPA1 expression.
研究领域:
免疫学
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呼吸病学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2021
·Vol. 11
·期 1
·1-12
·
IF 4.38
Chen Chang,Huang Xiansheng,Zhu Wenqiang,Ding Chen,Huang Piaopiao,Li Rong
Hyperalgesia has become a major problem restricting the clinical application of tooth bleaching. We hypothesized that transient receptor potential ankyrin 1 (TRPA1), a pain conduction tunnel, plays a role in tooth hyperalgesia and inflammation after bleaching. Dental pulp stem cells were seeded on the dentin side of the disc, which was cut from the premolar buccal tissue, with 15% (90 min) or 40% (3 × 15 min) bleaching gel applied on the enamel side, and treated with or without a TRPA1 inhibitor. The bleaching gel stimulated intracellular reactive oxygen species, Ca 2+ , ATP, and extracellular ATP in a dose-dependent manner, and increased the mRNA and protein levels of hyperalgesia (TRPA1 and PANX1) and inflammation (TNFα and IL6) factors. This increment was adversely affected by TRPA1 inhibitor. In animal study, the protein levels of TRPA1 ( P = 0.0006 ), PANX1 ( P < 0.0001 ), and proliferation factors [PCNA ( P < 0.0001 ) and Caspase 3 ( P = 0.0066 )] increased significantly after treated rat incisors with 15% and 40% bleaching gels as detected by immunohistochemistry. These results show that TRPA1 plays a critical role in sensitivity and inflammation after tooth bleaching, providing a solid foundation for further research on reducing the complications of tooth bleaching.
研究领域:
牙科
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 7.446
Zhen Qiao,Jiajie Luo,Yi-Quan Tang,Qiqi Zhou,Hang Qi,Zhengji Yin,Xiaowen Tang,Wei Zhu,Yanru Zhang,Ningning Wei,KeWei Wang
Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4′-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.
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DOI
PubMed
高影响因子
Redox Biology
·
2026
·
IF 16.2
Yunshen Chen,Gaogao He,Wei Zhang,Jiajie Li,Xiaoxi Li,Sijun Dong,Qinglian Liu,Lei Zhou
By responding to stimuli of diverse physics and chemical nature, transient receptor potential (TRP) channels fulfill important physiological functions in both excitable and non-excitable cells. Capsaicin (CAP) from chili peppers and allyl isothiocyanate (AITC) from mustard are natural and potent agonists for TRPV1 and TRPA1, respectively. Upon exposure to hydrogen peroxide (H 2 O 2 ), the central molecule in redox signaling pathways, TRPA1 shows robust activation and much higher sensitivity than TRPV1. Singlet oxygen ( 1 O 2 ), the molecular oxygen in electrically excited states, is the least studied reactive oxygen species (ROS). Here we report that both TRPV1 and TRPA1 are sensitive to the modification by 1 O 2 , but they exhibit drastically different responses. 1 O 2 generated by excited photosensitizers enhances the function of TRPV1 by accelerating its opening kinetics, increasing the current amplitude, and left-shifting the voltage-dependent activation curve towards physiological membrane potentials. A histidine residue located in the N-terminal ankyrin repeat domain of TRPV1 is identified to be important in 1 O 2 modification process. In contrast, as reported by imaging of cytosolic calcium, 1 O 2 modification of TRPA1 leads to a transient increase and then permanent inhibition of channel activity, and eventually obliterates TRPA1's response to AITC but not carvacrol – electrophilic and non-electrophilic agonists for TRPA1, respectively. Conversely, hTRPA1 is much more sensitive to H 2 O 2 , with the EC50 for channel activation about five times lower than that of hTRPV1, and the responses by two channels to H 2 O 2 mainly involves intracellular cysteine residues. The physiological significance of the distinct responses of TRPV1 and TRPA1 to two representative ROS, 1 O 2 and H 2 O 2 , warrants further investigation.
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PubMed
高影响因子
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