scholarly journals Desensitization of TRPV1 Involved in the Antipruritic Effect of Osthole on Histamine-Induced Scratching Behavior in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Niuniu Yang ◽  
Ying Ju ◽  
Delun Huang ◽  
Kunhong Ling ◽  
Han Jin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Receptor Agonist ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Drg Neurons ◽  
Histamine H4 Receptor

Osthole has been isolated from the fruits of Cnidium monnieri (L.) Cusson, which has been used in Chinese traditional medicine to treat pruritic disorders for a long time. However, the antipruritic mechanism of osthole is not fully understood. In the present study, using calcium imaging, molecular docking, and animal scratching behavior, we analyzed the pharmacological effects of osthole on transient receptor potential vanilloid 1 (TRPV1). The results showed that osthole significantly induced calcium influx in a dose-dependent manner in dorsal root ganglion (DRG) neurons. Osthole-induced calcium influx was inhibited by AMG9810, an antagonist of TRPV1. Osthole and the TRPV1 agonist capsaicin-induced calcium influx were desensitized by pretreatment with osthole. Furthermore, molecular docking results showed that osthole could bind to TRPV1 with a hydrogen bond by anchoring to the amino acid residue ARG557 in the binding pocket of TRPV1. In addition, TRPV1 is a downstream ion channel for the histamine H1 and H4 receptors to transmit itch signals. Osthole attenuated scratching behavior induced by histamine, HTMT (histamine H1 receptor agonist), and VUF8430 (histamine H4 receptor agonist) in mice. These results suggest that osthole inhibition of histamine-dependent itch may be due to the activation and subsequent desensitization of TRPV1 in DRG neurons.

scholarly journals Binding Efficacy and Thermogenic Efficiency of Pungent and Nonpungent Analogs of Capsaicin

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3198 ◽  
Author(s):  
Padmamalini Baskaran ◽  
Kyle Covington ◽  
Jane Bennis ◽  
Adithya Mohandass ◽  
Teresa Lehmann ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Docking Studies ◽  
Transient Receptor Potential Vanilloid ◽  
Metabolic Dysfunction ◽  
High Fat

(1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor—transient receptor potential vanilloid subfamily 1 (TRPV1)—to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (± 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans.

scholarly journals Inhibitory Effect of Manassantin B Isolated from Saururus chinensis on Skin Heat Aging

Cosmetics ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 47
Author(s):  
Hwa Sun Ryu ◽  
Jeong-Yeon Choi ◽  
Kyeong-Sun Lee ◽  
Jung-No Lee ◽  
Chun Mong Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Skin Aging ◽  
Shock Treatment ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Heat Shock Treatment ◽  
Channel Inhibition ◽  
Saururus Chinensis

Heat shock treatment-induced skin aging causes a thickened epidermis, increased matrix metalloproteinase (MMP)-1 expression, collagen degradation, and deep wrinkles. In this study, we investigated the effect of manassantin B in preventing heat shock treatment-induced aging. We first separated manassantin B (MB) from the roots of Saururus chinensis, and the structure was identified using 1H- and 13C-NMR spectroscopy. RT-PCR and western blotting were applied to investigate the anti-aging effect of manassantin B. Manassantin B decreased MMP-1 expression through transient receptor potential vanilloid (TRPV) 1 channel inhibition and significantly increased procollagen expression. In addition, manassantin B suppressed MAPK phosphorylation in a dose-dependent manner. Our results suggest that manassantin B, the active ingredient in S. chinensis, can be effectively used to inhibit heat shock treatment-induced skin aging.

scholarly journals Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer-Related Pain by Using Network Pharmacology and Molecular Docking Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jinyuan Chang ◽  
Lixing Liu ◽  
Yaohan Wang ◽  
Yutong Sui ◽  
Hao Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Transient Receptor Potential Vanilloid ◽  
Mitogen Activated Protein ◽  
Transient Receptor

Gu-tong formula (GTF) has achieved good curative effects in the treatment of cancer-related pain. However, its potential mechanisms have not been explored. We used network pharmacology and molecular docking to investigate the molecular mechanism and the effective compounds of the prescription. Through the analysis and research in this paper, we obtained 74 effective compounds and 125 drug-disease intersection targets to construct a network, indicating that quercetin, kaempferol, and β-sitosterol were possibly the most important compounds in GTF. The key targets of GTF for cancer-related pain were Jun proto-oncogene (JUN), mitogen-activated protein kinase 1 (MAPK1), and RELA proto-oncogene (RELA). 2204 GO entries and 148 pathways were obtained by GO and KEGG enrichment, respectively, which proved that chemokine, MAPK, and transient receptor potential (TRP) channels can be regulated by GTF. The results of molecular docking showed that stigmasterol had strong binding activity with arginine vasopressin receptor 2 (AVPR2) and C-X3-C motif chemokine ligand 1 (CX3CL1) and cholesterol was more stable with p38 MAPK, prostaglandin-endoperoxide synthase 2 (PTGS2), and transient receptor potential vanilloid-1 (TRPV1). In conclusion, the therapeutic effect of GTF on cancer-related pain is based on the comprehensive pharmacological effect of multicomponent, multitarget, and multichannel pathways. This study provides a theoretical basis for further experimental research in the future.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

scholarly journals Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Xingchen Li ◽  
Yuan Cheng ◽  
Zhiqi Wang ◽  
Jingyi Zhou ◽  
Yuanyuan Jia ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Significance ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanistic Investigation

AbstractTransient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

scholarly journals Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 775
Author(s):  
Xingjuan Chen ◽  
Yaqian Duan ◽  
Ashley Riley ◽  
Megan Welch ◽  
Fletcher White ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dorsal Root Ganglion ◽  
Patch Clamp ◽  
Dorsal Root ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dorsal Root Ganglion Neurons ◽  
Transient Receptor Potential Vanilloid ◽  
Drg Neurons ◽  
Ganglion Neurons

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

scholarly journals TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus

2015 ◽  
Vol 308 (6) ◽  
pp. G489-G496 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Fei Ru ◽  
Marian Kollarik ◽  
Bradley J. Undem ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Ex Vivo ◽  
Receptor Potential ◽  
Sensory Transduction ◽  
Dependent Manner ◽  
Preferential Expression ◽  
C Fibers ◽  
C Fiber ◽  
Transient Receptor

Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

TRPV1 activation mitigates hypoxic injury in mouse cardiomyocytes by inducing autophagy through the AMPK signaling pathway

2020 ◽  
Vol 318 (5) ◽  
pp. C1018-C1029
Author(s):  
Jinyu Wei ◽  
Jiezhi Lin ◽  
Junhui Zhang ◽  
Di Tang ◽  
Fei Xiang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Cell Counting ◽  
Transient Receptor Potential Vanilloid ◽  
Hypoxic Stress ◽  
Autophagy Flux ◽  
Ampk Signaling ◽  
Hypoxic Injury

Autophagy is a highly conserved self-protection mechanism that plays a crucial role in cardiovascular diseases. Cardiomyocyte hypoxic injury promotes oxidative stress and pathological alterations in the heart, although the interplay between these effects remains elusive. The transient receptor potential vanilloid 1 (TRPV1) ion channel is a nonselective cation channel that is activated in response to a variety of exogenous and endogenous physical and chemical stimuli. Here, we investigated the effects and mechanisms of action of TRPV1 on autophagy in hypoxic cardiomyocytes. In this study, primary cardiomyocytes isolated from C57 mice were subjected to hypoxic stress, and their expression of TRPV1 and adenosine 5′-monophosphate-activated protein kinase (AMPK) was regulated. The autophagy flux was assessed by Western blotting and immunofluorescence staining, and the cell viability was determined through Cell counting kit-8 assay and Lactate dehydrogenase assays. In addition, the calcium influx after the upregulation of TRPV1 expression in cardiomyocytes was examined. The results showed that the number of autophagosomes in cardiomyocytes was higher under hypoxic stress and that the blockade of autophagy flux aggravated hypoxic damage to cardiomyocytes. Moreover, the expression of TRPV1 was induced under hypoxic stress, and its upregulation by capsaicin improved the autophagy flux and protected cardiomyocytes from hypoxic damage, whereas the silencing of TRPV1 significantly attenuated autophagy. Our observations also revealed that AMPK signaling was activated and involved in TRPV1-induced autophagy in cardiomyocytes under hypoxic stress. Overall, this study demonstrates that TRPV1 activation mitigates hypoxic injury in cardiomyocytes by improving autophagy flux through the AMPK signaling pathway and highlights TRPV1 as a novel therapeutic target for the treatment of hypoxic cardiac disease.

scholarly journals Molecular mapping of transmembrane mechanotransduction through the β1 integrin–CD98hc–TRPV4 axis

2020 ◽  
Vol 133 (20) ◽  
pp. jcs248823 ◽  
Author(s):  
Ratnakar Potla ◽  
Mariko Hirano-Kobayashi ◽  
Hao Wu ◽  
Hong Chen ◽  
Akiko Mammoto ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Molecular Mapping ◽  
Calcium Influx ◽  
Focal Adhesions ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Β1 Integrin ◽  
Mechanical Forces ◽  
C Terminus ◽  
Transient Receptor

ABSTRACTOne of the most rapid (less than 4 ms) transmembrane cellular mechanotransduction events involves activation of transient receptor potential vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across cell surface β1 integrin receptors on endothelial cells, and the transmembrane solute carrier family 3 member 2 (herein denoted CD98hc, also known as SLC3A2) protein has been implicated in this response. Here, we show that β1 integrin, CD98hc and TRPV4 all tightly associate and colocalize in focal adhesions where mechanochemical conversion takes place. CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis reveals that forces applied to β1 integrin must be transmitted from its cytoplasmic C terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultrarapid, force-induced channel activation within the focal adhesion.

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