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Elizabeth L Evans, Kevin Cuthbertson, Naima Endesh, Baptiste Rode, Nicola M Blythe, Adam J Hyman, Sally J Hall, Hannah J Gaunt, Melanie J Ludlow, Richard Foster, David J Beech
BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ and Tl+ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in human umbilical vein endothelial cells (HUVECs) which natively express Piezo1...
March 2, 2018: British Journal of Pharmacology
Misun Kwak, Chansik Hong, Jongyun Myeong, Eunice Yon June Park, Ju-Hong Jeon, Insuk So
Hypertension and aneurysm are frequently associated with autosomal dominant polycystic kidney disease (ADPKD) caused by polycystin-1 (PC1) mutations, which is closely related to endothelial dysfunction. PC1 is an atypical G-protein-coupled receptor that activates G-proteins by self-cleavage; currently, however, the molecular and cellular mechanisms of the associated intracellular signaling and ion channel activation remain poorly elucidated. Here, we report an activation mechanism of a calcium-permeable canonical transient receptor potential 4 (TRPC4) channel by PC1 and its endothelial function...
February 22, 2018: Scientific Reports
Anees A Banday, Mustafa F Lokhandwala
Reactive oxygen species induce vascular dysfunction and hypertension by directly interacting with nitric oxide (NO) which leads to NO inactivation. In addition to a decrease in NO bioavailability, there is evidence that oxidative stress can also modulate NO signaling during hypertension. Here, we investigated the effect of oxidative stress on NO signaling molecules cGMP-dependent protein kinase (PKG) and vasodilator-stimulated phosphoprotein (VASP) which are known to mediate vasodilatory actions of NO. Male Sprague Dawley (SD) rats were provided with tap water (control), 30 mM L-buthionine sulfoximine (BSO, a pro-oxidant), 1 mM tempol (T, an antioxidant) and BSO + T for 3 wks...
February 9, 2018: Clinical and Experimental Hypertension: CHE
Stefan Just, Bertrand L Chenard, Angelo Ceci, Timothy Strassmaier, Jayhong A Chong, Nathaniel T Blair, Randall J Gallaschun, Donato Del Camino, Susan Cantin, Marc D'Amours, Christian Eickmeier, Christopher M Fanger, Carsten Hecker, David P Hessler, Bastian Hengerer, Katja S Kroker, Sam Malekiani, Robert Mihalek, Joseph McLaughlin, Georg Rast, JoAnn Witek, Achim Sauer, Christopher R Pryce, Magdalene M Moran
BACKGROUND: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. HC-070 IN VITRO: To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070...
2018: PloS One
Hitesh Soni, Adebowale Adebiyi
Glomerular mesangial cell (GMC) proliferation and matrix expansion are pathological hallmarks of a wide range of kidney diseases, including diabetic nephropathy. Although the circulating level of peptide hormone urotensin II (UII) and kidney tissue expression of UII and UII receptors (UTR) are increased in diabetic nephropathy, it remains unclear whether UII regulates GMC growth and extracellular matrix (ECM) accumulation. In this study, we tested the hypothesis that UII-induced Ca2+ signaling controls GMC proliferation and ECM production under normal and high glucose conditions...
December 22, 2017: Scientific Reports
Hussein N Rubaiy, Tobias Seitz, Sven Hahn, Axel Choidas, Peter Habenberger, Bert Klebl, Klaus Dinkel, Peter Nussbaumer, Herbert Waldmann, Mathias Christmann, David J Beech
BACKGROUND AND PURPOSE: (-)-Englerin A (EA) is a potent cytotoxic agent against renal cell carcinoma cells. It achieves its effects by activation of TRPC4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Here we sought an EA analogue which might enable better understanding of these EA effects. EXPERIMENTAL APPROACH: Renal cell carcinoma A498 cells and HEK 293 cells overexpressing TRPC4 or TRPC5 were studied by intracellular Ca2+ measurement or whole-cell patch-clamp...
December 16, 2017: British Journal of Pharmacology
Dariia O Dryn, Mariia I Melnyk, Lina T Al Kury, Yuriy I Prylutskyy, Uwe Ritter, Alexander V Zholos
The effect of water-soluble pristine C60 fullerene nanoparticles (C60NPs) on receptor-operated cation channels formed by TRPC4/C6 proteins in ileal smooth muscle cells was investigated for the first time. Activation of these channels subsequent to acetylcholine binding to the expressed in these cells M2 and M3 muscarinic receptors represents the key event in the parasympathetic control of gastrointestinal smooth muscle motility and cholinergic excitation-contraction coupling. Experiments were performed on single collagenase-dispersed mouse ileal myocytes using patch-clamp techniques with symmetrical 125mM Cs+ solutions and [Ca2+]i 'clamped' at 100nM in order to isolate the muscarinic cation current (mICAT)...
December 11, 2017: Cellular Signalling
Katsuhiko Muraki, Kaori Ohnishi, Akiho Takezawa, Hiroka Suzuki, Noriyuki Hatano, Yukiko Muraki, Nurasyikin Hamzah, Richard Foster, Herbert Waldmann, Peter Nussbaumer, Mathias Christmann, Robin S Bon, David J Beech
The sesquiterpene (-)Englerin A (EA) is an organic compound from the plant Phyllanthus engleri which acts via heteromeric TRPC4/C1 channels to cause cytotoxicity in some types of cancer cell but not normal cells. Here we identified selective cytotoxicity of EA in human synovial sarcoma cells (SW982 cells) and investigated the mechanism. EA induced cation channel current (Icat) in SW982 cells with biophysical characteristics of heteromeric TRPC4/C1 channels. Inhibitors of homomeric TRPC4 channels were weak inhibitors of the Icat and EA-induced cytotoxicity whereas a potent inhibitor of TRPC4/C1 channels (Pico145) strongly inhibited Icat and cytotoxicity...
December 5, 2017: Scientific Reports
Dariia Dryn, Jialie Luo, Mariia Melnyk, Alexander Zholos, Hongzhen Hu
Gastrointestinal tract motility may be demoted significantly after surgery operations at least in part due to anaesthetic agents, but there is no comprehensive explanation of the molecular mechanism(s) of such adverse effects. Anesthetics are known to interact with various receptors and ion channels including several subtypes of transient receptor potential (TRP) channels. Two members of the canonical subfamily of TRP channels (TRPC), TRPC4 and TRPC6 are Ca2+ -permeable cation channels involved in visceral smooth muscle contractility induced by acetylcholine, the primary excitatory neurotransmitter in the gut...
February 5, 2018: European Journal of Pharmacology
John Wesley Maddox, Nikka Khorsandi, Evanna L Gleason
GABAergic signaling from amacrine cells (ACs) is a fundamental aspect of visual signal processing in the inner retina. We have previously shown that nitric oxide (NO) can elicit release of GABA independently from activation of voltage-gated Ca(2+) channels in cultured retinal ACs. This voltage-independent quantal GABA release relies on a Ca(2+) influx mechanism with pharmacological characteristics consistent with the involvement of transient receptor potential canonical (TRPC) channels TRPC4 and/or TRPC5. To determine the identity of these channels, we evaluate the ability of NO to elevate dendritic Ca(2+) and to stimulate GABA release from cultured ACs under conditions known to alter the function of TRPC4 and 5...
October 4, 2017: Journal of Neurophysiology
Petra Eder
TRPC channels have been suggested as potential candidates mediating store-operated Ca2+ entry (SOCE) in cardiomyocytes. There is increasing evidence that the TRPC isoforms TRPC1 and TRPC4 might fulfill the function as SOCs, in concert with or in parallel to the key players of SOCE, Orai1, and STIM1. Several other isoforms, e.g., TRPC3, TRPC6, and TRPC7, might rather associate to receptor-activated diacylglycerol (DAG)-sensitive ion channels. However, the exact activation mode has not been elucidated yet, given the characteristic of TRPC channels to heteromerize to unpredictable ion channel assemblies...
2017: Advances in Experimental Medicine and Biology
Irfan V Düzen, Fethi Yavuz, Ertan Vuruskan, Erhan Saracoglu, Fatih Poyraz, Hüseyin Göksülük, Basar Candemir, Seniz Demiryürek
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a major cause of morbidity and mortality. The upregulation of TRP channels is believed to mediate the progression of electrical remodelling and the arrhythmogenesis of the diseased heart. However, there is limited data about the contribution of the TRP channels to development of AF. The aim of this study was to investigate leukocyte TRP channels gene expressions in non-valvular atrial fibrillation (NVAF) patients. The study included 47 NVAF patients and 47 sex and age matched controls...
August 24, 2017: Scientific Reports
Holger Beckmann, Julia Richter, Kerstin Hill, Nicole Urban, Horst Lemoine, Michael Schaefer
The transient receptor potential canonical channel 5 (TRPC5) is a Ca(2+)-permeable ion channel, which is predominantly expressed in the brain. TRPC5-deficient mice exhibit a reduced innate fear response and impaired motor control. In addition, outgrowth of hippocampal and cerebellar neurons is retarded by TRPC5. However, pharmacological evidence of TRPC5 function on cellular or organismic levels is sparse. Thus, there is still a need for identifying novel and efficient TRPC5 channel modulators. We, therefore, screened compound libraries and identified the glucocorticoid methylprednisolone and N-[3-(adamantan-2-yloxy)propyl]-3-(6-methyl-1,1-dioxo-2H-1λ(6),2,4-benzothiadiazin-3-yl)propanamide (BTD) as novel TRPC5 activators...
September 2017: Cell Calcium
Jenny Bröker-Lai, Astrid Kollewe, Barbara Schindeldecker, Jörg Pohle, Vivan Nguyen Chi, Ilka Mathar, Raul Guzman, Yvonne Schwarz, Alan Lai, Petra Weißgerber, Herbert Schwegler, Alexander Dietrich, Martin Both, Rolf Sprengel, Andreas Draguhn, Georg Köhr, Bernd Fakler, Veit Flockerzi, Dieter Bruns, Marc Freichel
Canonical transient receptor potential (TRPC) channels influence various neuronal functions. Using quantitative high-resolution mass spectrometry, we demonstrate that TRPC1, TRPC4, and TRPC5 assemble into heteromultimers with each other, but not with other TRP family members in the mouse brain and hippocampus. In hippocampal neurons from Trpc1/Trpc4/Trpc5-triple-knockout (Trpc1/4/5(-/-)) mice, lacking any TRPC1-, TRPC4-, or TRPC5-containing channels, action potential-triggered excitatory postsynaptic currents (EPSCs) were significantly reduced, whereas frequency, amplitude, and kinetics of quantal miniature EPSC signaling remained unchanged...
September 15, 2017: EMBO Journal
Masatoshi Fujita, Tadasu Sato, Takehiro Yajima, Eiji Masaki, Hiroyuki Ichikawa
TRPC (transient receptor potential cation channel subfamily C) members are nonselective monovalent cation channels and control Ca2+ inflow. In this study, immunohistochemistry for TRPC1, TRPC3, and TRPC4 was performed on rat oral and craniofacial structures to elucidate their distribution and function in the peripheries. In the trigeminal ganglion (TG), 56.1, 84.1, and 68.3% of sensory neurons were immunoreactive (IR) for TRPC1, TRPC3, and TRPC4, respectively. A double immunofluorescence method revealed that small to medium-sized TG neurons co-expressed TRPCs and calcitonin gene-related peptide...
July 12, 2017: Cells, Tissues, Organs
Pedro L Flores, Emma Rodríguez, Estrella Zapata, Roxana Carbó, José María Farías, Martín Martínez
Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels...
June 25, 2017: Marine Drugs
Thabet Belkacemi, Alexander Niermann, Laura Hofmann, Ulrich Wissenbach, Lutz Birnbaumer, Petra Leidinger, Christina Backes, Eckart Meese, Andreas Keller, Xianshu Bai, Anja Scheller, Frank Kirchhoff, Stephan E Philipp, Petra Weissgerber, Veit Flockerzi, Andreas Beck
Following brain injury astrocytes change into a reactive state, proliferate and grow into the site of lesion, a process called astrogliosis, initiated and regulated by changes in cytoplasmic Ca(2+) . Transient receptor potential canonical (TRPC) channels may contribute to Ca(2+) influx but their presence and possible function in astrocytes is not known. By RT-PCR and RNA sequencing we identified transcripts of Trpc1, Trpc2, Trpc3, and Trpc4 in FACS-sorted glutamate aspartate transporter (GLAST)-positive cultured mouse cortical astrocytes and subcloned full-length Trpc1 and Trpc3 cDNAs from these cells...
September 2017: Glia
Wei-Chun Wei, Wan-Chen Huang, Yu-Ping Lin, Esther B E Becker, Olaf Ansorge, Veit Flockerzi, Daniele Conti, Giovanna Cenacchi, Maike D Glitsch
KEY POINTS: The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4-containing channels in DAOY cells, but not non-transformed granule precursor cells, results in prominent increases in [Ca(2+) ]i and promotes cell motility in wound healing and transwell migration assays...
August 15, 2017: Journal of Physiology
Sung Noh Hong, Je-Gun Joung, Joon Seol Bae, Chan Soo Lee, Ja Seol Koo, Soo Jung Park, Jong Pil Im, You Sun Kim, Ji Won Kim, Woong Yang Park, Young-Ho Kim
BACKGROUND: Aberrant gene expression in the gut mucosa might contribute to the initiation and progression of Crohn's disease (CD). RNA sequencing (RNA-seq) provides precise measurements of expression levels of transcripts and their isoforms. The aim of this study was to use RNA-seq to investigate transcriptomic differences and identify significantly differentially expressed transcripts in inflamed and noninflamed intestinal mucosa of CD patients. METHODS: RNA-seq was performed on 13 pairs of inflamed and noninflamed intestinal mucosa from 13 CD patients and on sex-matched normal mucosa of 13 healthy controls...
July 2017: Inflammatory Bowel Diseases
Takuji Machida, Akina Onoguchi, Kenji Iizuka, Sayuri Ishibashi, Mikiko Yutani, Masahiko Hirafuji
We previously reported that docosahexaenoic acid (DHA) inhibits an increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in cultured rat vascular smooth muscle cells (VSMCs) through a mechanism involving mainly voltage-dependent Ca(2+) channels; however, the effect of DHA on voltage-independent pathways, such as store-operated and receptor-operated Ca(2+) entry, and Ca(2+) entry through Na(+)/Ca(2+) exchanger (NCX), has not been clarified. In the present study, we investigated the effect of DHA treatment on the expression of transient receptor potential canonical (TRPC) channels, capacitative Ca(2+) entry, and Ca(2+) entry through NCX in rat cultured VSMCs stimulated with 5-hydroxytryptamine (5-HT)...
2017: Biological & Pharmaceutical Bulletin
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