scholarly journals High Glucose Enhances Transient Receptor Potential Channel Canonical Type 6–Dependent Calcium Influx in Human Platelets via Phosphatidylinositol 3-Kinase–Dependent Pathway

2008 ◽  
Vol 28 (4) ◽  
pp. 746-751 ◽  
Author(s):  
Daoyan Liu ◽  
Alexandra Maier ◽  
Alexandra Scholze ◽  
Ursula Rauch ◽  
Ulrike Boltzen ◽  
...  
Keyword(s):  
High Glucose ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Human Platelets ◽  
Phosphatidylinositol 3 Kinase ◽  
Transient Receptor ◽  
Canonical Type ◽  
Dependent Pathway

scholarly journals Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 519
Author(s):  
Sarah Mazzotta ◽  
Gabriele Carullo ◽  
Aniello Schiano Moriello ◽  
Pietro Amodeo ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Activities ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Design Synthesis ◽  
Cellular Assays ◽  
Transient Receptor ◽  
Trpv4 Channel

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.

scholarly journals The Calcium-Dependent Protease Calpain-1 Links TRPC6 Activity to Podocyte Injury

2018 ◽  
Vol 29 (8) ◽  
pp. 2099-2109 ◽  
Author(s):  
Kim A.T. Verheijden ◽  
Ramon Sonneveld ◽  
Marinka Bakker-van Bebber ◽  
Jack F.M. Wetzels ◽  
Johan van der Vlag ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Slit Diaphragm ◽  
Calpain Inhibitor ◽  
Podocyte Injury ◽  
Calcium Dependent ◽  
Transient Receptor ◽  
Calcineurin Activity

BackgroundThe hallmark of podocytopathies, such as FSGS, is podocyte injury resulting in proteinuria. Transient receptor potential channel C6 (TRPC6) is a calcium-conducting ion channel expressed at the slit diaphragm. TRPC6 gain-of-function mutations and glomerular TRPC6 overexpression are associated with proteinuria. However, the pathways linking TRPC6 to podocyte injury, which is characterized by loss of the slit diaphragm protein nephrin, activation of several intracellular pathways (including calcineurin-NFAT signaling), and cytoskeletal rearrangement, remain elusive.MethodsWe tested whether the calcium-dependent protease calpain-1 mediates TRPC6-dependent podocyte injury in human and experimental FSGS and cultured podocytes.ResultsCompared with kidneys of healthy controls, kidneys of patients with FSGS had increased TRPC6 expression, increased calpain and calcineurin activity, and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability. In a rat model of human FSGS, increased glomerular and urinary calpain activity associated with reduced Talin-1 abundance, enhanced calcineurin activity, and increased proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects. In cultured podocytes, pharmacologic stimulation of TRPC6-dependent calcium influx increased calpain-1 and calcineurin activity and reduced Talin-1 expression, and knockdown of TRPC6 or calpain-1 prevented these effects.ConclusionsWe elucidated a novel mechanism that links TRPC6 activity to calpain-1 activation and through Talin-1 loss and possibly, calcineurin activation, the podocyte injury characterizing FSGS. Therefore, calpain-1 and/or TRPC6 inhibition could be future therapeutic options to treat patients with FSGS or other podocytopathies.

Transient Receptor Potential Channel TRPM8 Agonists Stimulate Calcium Influx and Neurotensin Secretion in Neuroendocrine Tumor Cells

2007 ◽  
Vol 85 (2) ◽  
pp. 81-92 ◽  
Author(s):  
Stefan Mergler ◽  
Mathias Z. Strowski ◽  
Simone Kaiser ◽  
Thomas Plath ◽  
Yvonne Giesecke ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Tumor Cells ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transient Receptor

scholarly journals TRPC5 Does Not Cause or Aggravate Glomerular Disease

2017 ◽  
Vol 29 (2) ◽  
pp. 409-415 ◽  
Author(s):  
Xuexiang Wang ◽  
Ranadheer R. Dande ◽  
Hao Yu ◽  
Beata Samelko ◽  
Rachel E. Miller ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transgenic Mouse Models ◽  
Cytoskeletal Remodeling ◽  
Englerin A ◽  
Transient Receptor ◽  
Ion Pore

Transient receptor potential channel 5 (TRPC5) is highly expressed in brain and kidney and mediates calcium influx and promotes cell migration. In the kidney, loss of TRPC5 function has been reported to benefit kidney filter dynamics by balancing podocyte cytoskeletal remodeling. However, in vivo gain-in-function studies of TRPC5 with respect to kidney function have not been reported. To address this gap, we developed two transgenic mouse models on the C57BL/6 background by overexpressing either wild-type TRPC5 or a TRPC5 ion-pore mutant. Compared with nontransgenic controls, neither transgenic model exhibited an increase in proteinuria at 8 months of age or a difference in LPS-induced albuminuria. Moreover, activation of TRPC5 by Englerin A did not stimulate proteinuria, and inhibition of TRPC5 by ML204 did not significantly lower the level of LPS-induced proteinuria in any group. Collectively, these data suggest that the overexpression or activation of the TRPC5 ion channel does not cause kidney barrier injury or aggravate such injury under pathologic conditions.

scholarly journals Glutathione depletion activates the yeast vacuolar transient receptor potential channel, Yvc1p, by reversible glutathionylation of specific cysteines

2016 ◽  
Vol 27 (24) ◽  
pp. 3913-3925 ◽  
Author(s):  
Avinash Chandel ◽  
Krishna K. Das ◽  
Anand K. Bachhawat
Keyword(s):  
Calcium Channel ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Trp Channels ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Glutathione Depletion ◽  
Glutathione S Transferase ◽  
Transient Receptor

Glutathione depletion and calcium influx into the cytoplasm are two hallmarks of apoptosis. We have been investigating how glutathione depletion leads to apoptosis in yeast. We show here that glutathione depletion in yeast leads to the activation of two cytoplasmically inward-facing channels: the plasma membrane, Cch1p, and the vacuolar calcium channel, Yvc1p. Deletion of these channels partially rescues cells from glutathione depletion–induced cell death. Subsequent investigations on the Yvc1p channel, a homologue of the mammalian TRP channels, revealed that the channel is activated by glutathionylation. Yvc1p has nine cysteine residues, of which eight are located in the cytoplasmic regions and one on the transmembrane domain. We show that three of these cysteines, Cys-17, Cys-79, and Cys-191, are specifically glutathionylated. Mutation of these cysteines to alanine leads to a loss in glutathionylation and a concomitant loss in calcium channel activity. We further investigated the mechanism of glutathionylation and demonstrate a role for the yeast glutathione S-transferase Gtt1p in glutathionylation. Yvc1p is also deglutathionylated, and this was found to be mediated by the yeast thioredoxin, Trx2p. A model for redox activation and deactivation of the yeast Yvc1p channel is presented.

scholarly journals Transient Receptor Potential Channel Canonical Type 3 Deficiency Antagonizes Myofibroblast Transdifferentiation In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Weijie Xia ◽  
Qianran Wang ◽  
Yuangang Lu ◽  
Yingru Hu ◽  
Xingcun Zhang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Mitochondrial Calcium ◽  
Ros Production ◽  
Transient Receptor ◽  
Canonical Type ◽  
Type 3

Objective. Myofibroblast transformation has been shown to be associated with the reactive oxygen species- (ROS-) producing enzyme NADPH oxidase (Nox4). Inhibition of transient receptor potential channel canonical type 3 (TRPC3) attenuates mitochondrial calcium handling and ROS production in the vasculature of hypertensive rats. However, it remains elusive whether TRPC3 regulates mitochondrial calcium and ROS production and participates in myofibroblast transdifferentiation during wound healing. Methods and Results. In this study, we demonstrated that activation of TRPC3 by transforming growth factor β (TGFβ1) elevated myofibroblast transdifferentiation by upregulating the myofibroblast marker alpha smooth muscle actin (αSMA). Inhibition of TRPC3 with its specific inhibitor, Pyr3, significantly decreased TGFβ1-induced αSMA expression, as demonstrated by immunofluorescence. Real-time PCR and immunohistochemistry revealed higher TRPC3 and TGFβ1 mRNA expression levels in fibroblasts from hypertrophic scar (HTS) tissue than in those from normal skin tissue. TGFβ1 treatment increased TRPC3-mediated mitochondrial calcium uptake and ROS production but decreased ATP content in human fibroblasts, whereas inhibition of TRPC3 significantly reversed these effects. The beneficial effects were associated with improvements in mitochondrial respiratory function mediated by recovery of the activity of pyruvate dehydrogenase (PDH). In vivo, Trpc3-/- mice exhibited significantly attenuated myofibroblast transdifferentiation, as demonstrated by decreased αSMA, TGFβ1, fibronectin, and collagen-1 (Col1a1) protein expression in wound granulation tissues. Furthermore, TGFβ1-induced store-operated calcium entry (SOCE) was significantly decreased in fibroblasts from Trpc3-/- mice compared with those from Trpc3+/+ mice. In addition, Trpc3-/- mice exhibited significantly decreased Nox4 and phosphorylated Smad2/3 protein expression in wound granulation tissues. Conclusions. Our data indicate that TGFβ1-mediated activation of TRPC3 enhances mitochondrial calcium and ROS production, which promotes myofibroblast transdifferentiation and HTS formation. Inhibition of the TRPC3-mediated Nox4/pSmad2/3 pathway may be a useful strategy to limit HTS formation after injury.

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