scholarly journals Aconitine Induces TRPV2-Mediated Ca2+ Influx through the p38 MAPK Signal and Promotes Cardiomyocyte Apoptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Chunai Yang ◽  
Xiaoyan Zeng ◽  
Zhongfeng Cheng ◽  
Junbo Zhu ◽  
Yangshan Fu
Keyword(s):  
P38 Mapk ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mapk Signaling ◽  
Cardiomyocyte Apoptosis ◽  
Dependent Manner ◽  
H9c2 Cardiomyocytes ◽  
Transient Receptor ◽  
Effective Component ◽  
Dose Dependent

Aconitine is the main effective component of traditional Chinese medicine Aconitum, which has been proved to have severe cardiovascular toxicity. The toxic effect of aconitine on cardiomyocytes is related to intracellular calcium overload, but the mechanism remains unclear. The aim of this study was to explore the mechanism of aconitine inducing intracellular Ca2+ overload and promoting H9c2 cardiomyocyte apoptosis through transient receptor potential cation channel subfamily V member 2 (TRPV2). After treated with different concentrations of aconitine, the level of cell apoptosis, intracellular Ca2+, and expression of p-p38 MAPK and TRPV2 of H9c2 cardiomyocytes were detected. The results showed that aconitine induced Ca2+ influx and H9c2 cardiomyocyte apoptosis in a dose-dependent manner and promoted p38 MAPK activation as well as TRPV2 expression and plasma membrane (PM) metastasis. siTRPV2, tranilast, and SB202190 reversed intracellular Ca2+ overload and H9c2 cardiomyocyte apoptosis induced by aconitine. These results suggested that aconitine promoted TRPV2 expression and PM metastasis through p38 MAPK signaling, thus inducing intracellular Ca2+ overload and cardiomyocyte apoptosis. Furthermore, TRPV2 is a potential molecular target for the treatment of aconitine poisoning.

scholarly journals TRPA1 triggers hyperalgesia and inflammation after tooth bleaching

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chang Chen ◽  
Xiansheng Huang ◽  
Wenqiang Zhu ◽  
Chen Ding ◽  
Piaopiao Huang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Critical Role ◽  
Receptor Potential ◽  
Tooth Bleaching ◽  
Dependent Manner ◽  
Protein Levels ◽  
Solid Foundation ◽  
Transient Receptor ◽  
Dose Dependent ◽  
Bleaching Gels

AbstractHyperalgesia 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, Ca2+, 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.

scholarly journals Potentiation of TRPC5 by Protons

2007 ◽  
Vol 282 (46) ◽  
pp. 33868-33878 ◽  
Author(s):  
Marcus Semtner ◽  
Michael Schaefer ◽  
Olaf Pinkenburg ◽  
Tim D. Plant
Keyword(s):  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
High Sensitivity ◽  
Transient Receptor Potential Channel ◽  
Extracellular Ph ◽  
Dependent Manner ◽  
Open Probability ◽  
Transient Receptor

Mammalian members of the classical transient receptor potential channel subfamily (TRPC) are Ca2+-permeable cation channels involved in receptor-mediated increases in intracellular Ca2+. TRPC4 and TRPC5 form a group within the TRPC subfamily and are activated in a phospholipase C-dependent manner by an unidentified messenger. Unlike most other Ca2+-permeable channels, TRPC4 and -5 are potentiated by micromolar concentrations of La3+ and Gd3+. This effect results from an action of the cations at two glutamate residues accessible from the extracellular solution. Here, we show that TRPC4 and -5 respond to changes in extracellular pH. Lowering the pH increased both G protein-activated and spontaneous TRPC5 currents. Both effects were already observed with small reductions in pH (from 7.4 to 7.0) and increased up to pH 6.5. TRPC4 was also potentiated by decreases in pH, whereas TRPC6 was only inhibited, with a pIC50 of 5.7. Mutation of the glutamate residues responsible for lanthanoid sensitivity of TRPC5 (E543Q and E595Q) modified the potentiation of TRPC5 by acid. Further evidence for a similarity in the actions of lanthanoids and H+ on TRPC5 is the reduction in single channel conductance and dramatic increase in channel open probability in the presence of either H+ or Gd3+ that leads to larger integral currents. In conclusion, the high sensitivity of TRPC5 to H+ indicates that, in addition to regulation by phospholipase C and other factors, the channel may act as a sensor of pH that links decreases in extracellular pH to Ca2+ entry and depolarization.

scholarly journals The Na+/Ca2+ Exchanger Inhibitor, KB-R7943, Blocks a Nonselective Cation Channel Implicated in Chemosensory Transduction

2009 ◽  
Vol 101 (3) ◽  
pp. 1151-1159 ◽  
Author(s):  
A. Pezier ◽  
Y. V. Bobkov ◽  
B. W. Ache
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Dependent Manner ◽  
Open Probability ◽  
Olfactory Transduction ◽  
Voltage Dependent ◽  
Chemosensory Transduction ◽  
Transient Receptor

The mechanism(s) of olfactory transduction in invertebrates remains to be fully understood. In lobster olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presumptive transient receptor potential (TRP)C channel homolog, plays a crucial role in olfactory transduction, at least in part by amplifying the primary transduction current. To better determine the functional role of the channel, it is important to selectively block the channel independently of other elements of the transduction cascade, causing us to search for specific pharmacological blockers of the SGC channel. Given evidence that the Na+/Ca2+ exchange inhibitor, KB-R7943, blocks mammalian TRPC channels, we studied this probe as a potential blocker of the lobster SGC channel. KB-R7943 reversibly blocked the SGC current in both inside- and outside-out patch recordings in a dose- and voltage-dependent manner. KB-R7943 decreased the channel open probability without changing single channel amplitude. KB-R7943 also reversibly and in a dose-dependent manner inhibited both the odorant-evoked discharge of lobster ORNs and the odorant-evoked whole cell current. Our findings strongly imply that KB-R7943 potently blocks the lobster SGC channel and likely does so directly and not through its ability to block the Na+/Ca2+ exchanger.

Abstract 232: Role of Transient Receptor Potential Melastatin 2 in Cardiomyocyte Apoptosis Induced by TNF-α

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shuzhuang Li ◽  
Xuan Liu ◽  
Deqin Yu ◽  
Chong Chen ◽  
Xiaolong Chen
Keyword(s):  
Myocardial Injury ◽  
Caspase 3 ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cardiomyocyte Apoptosis ◽  
Mechanical Trauma ◽  
Causative Role ◽  
Transient Receptor Potential Melastatin ◽  
Tnf Α ◽  
Transient Receptor

Mechanical trauma, such as that induced by motor vehicle crashes, represents a major medical and economic problem in the world. Identifying the mechanisms responsible for post-traumatic secondary myocardial injury is critical in order to reduce overall mortality and improve quality of life after trauma. We have previously demonstrated that mechanical trauma-induced overproduction of TNF-α plays a causative role in cardiomyocyte apoptosis via oxidative/nitrative stress. Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ permeable non-selective cation channel activated by oxidative stress, expressed in the cardiomyocytes. The present study attempted to identify whether TRPM2 is involved in TNF-α-induced cardiomyocyte apoptosis. Cardiomyocytes were isolated from adult male Sprague Dawley rats and cultured with TNF-α (10 ng/ml) for 12h. RT-PCR and semi-quantitative immunohistochemistry were used to quantify TRPM2 mRNA and protein levels respectively. Significant increases in TRPM2 mRNA and protein expression were observed in TNF-α-treated cardiomyocytes, suggesting that TRPM2 may contribute to TNF-α-induced cardiomyocyte apoptosis. To identify the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, cardiomyocytes were cultured with TNF-α or TNF-α + TRPM2 inhibitor (flufenamic acid (FFA) 100uM or clotrimazole 30uM), respectively. Exposure of cardiomyocytes to TNF-α for 12h induced significant apoptosis as determined by caspase-3 activation (1.7-fold increase vs. control, P < 0.01). In contrast, TNF-α-induced caspase-3 activity increases were significantly depressed by FFA and clotrimazole, respectively (P < 0.05). To further confirm the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, we tested the effects of TRPM2-specific small interfering RNA (siRNA). As a result, impressively, TNF-α-induced increases of caspase-3 activity and lysate nucleosomes were significantly reduced in TRPM2-specific siRNA-treated cardiomyocytes (P < 0.01). These results indicate that TRPM2 plays an important role in TNF-α-induced cardiomyocyte apoptosis. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating mechanical trauma-induced secondary myocardial injury.

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 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.

scholarly journals Structure of the human TRPM4 ion channel in a lipid nanodisc

Science ◽  
2017 ◽  
Vol 359 (6372) ◽  
pp. 228-232 ◽  
Author(s):  
Henriette E. Autzen ◽  
Alexander G. Myasnikov ◽  
Melody G. Campbell ◽  
Daniel Asarnow ◽  
David Julius ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Calcium Binding ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Dependent Manner ◽  
Calcium Binding Site ◽  
Voltage Dependent ◽  
Transient Receptor ◽  
Lipid Nanodiscs

Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo–electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

scholarly journals Structural insight into TRPV5 channel function and modulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8869-8878 ◽  
Author(s):  
Shangyu Dang ◽  
Mark K. van Goor ◽  
Daniel Asarnow ◽  
YongQiang Wang ◽  
David Julius ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Resolution Electron ◽  
Trpv Channels ◽  
Transient Receptor ◽  
Lipid Nanodiscs ◽  
Insight Into

TRPV5 (transient receptor potential vanilloid 5) is a unique calcium-selective TRP channel essential for calcium homeostasis. Unlike other TRPV channels, TRPV5 and its close homolog, TRPV6, do not exhibit thermosensitivity or ligand-dependent activation but are constitutively open at physiological membrane potentials and modulated by calmodulin (CaM) in a calcium-dependent manner. Here we report high-resolution electron cryomicroscopy structures of truncated and full-length TRPV5 in lipid nanodiscs, as well as of a TRPV5 W583A mutant and TRPV5 in complex with CaM. These structures highlight the mechanism of calcium regulation and reveal a flexible stoichiometry of CaM binding to TRPV5.

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