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Xingjuan Chen, Wennan Li, Ashley M Riley, Mario Soliman, Saikat Chakraborty, Christopher W Stamatkin, Alexander G Obukhov
Transient Receptor Potential Canonical type 5 (TRPC5) is a Ca(2+) permeable cation channel that is highly expressed in the brain and is implicated in motor coordination, innate fear behavior, and seizure-genesis. The channel is activated by a signal downstream of the G-protein-coupled receptor (GPCR)-Gq/11-phospholipase C (PLC) pathway. In this study, we aimed to identify the molecular mechanisms involved in regulating TRPC5 activity. We report that R593, a residue located in the E4 loop near the TRPC5's extracellular Gd(3+)-binding site, is critical for conferring the sensitivity to GPCR-Gq/11-PLC-dependent gating on TRPC5...
December 5, 2016: Journal of Biological Chemistry
Zhen Chen, Chunlei Tang, Yaodan Zhu, Mingxu Xie, Dongxu He, Qiongxi Pan, Peng Zhang, Dong Hua, Teng Wang, Linfang Jin, Xiaowei Qi, Yifei Zhu, Xiaoqiang Yao, Jian Jin, Xin Ma
Transient receptor potential channel 5 (TrpC5) is member of the TrpC subgroup, and it forms a receptor-activated non-selective Ca(2+) channel. The architecture of the TrpC5 channel is poorly understood. Here, we report that TrpC5 is a key factor in regulating differentiation in colorectal cancer. Through a study of specimens from a large cohort of patients with colorectal cancer, we found that TrpC5 was highly expressed and its cellular level correlated with tumor grade. We further showed that up-regulated TrpC5 caused a robust [Ca(2+)]i rise, increased Wnt5a expression, and the nuclear translocation of β-catenin, leading to a reduction of cancer differentiation and an increase of cancer cell stemness...
November 28, 2016: Clinical Science (1979-)
Ling-Jun Jie, Wei-Yin Wu, Gang Li, Guo-Sheng Xiao, Shetuan Zhang, Gui-Rong Li, Yan Wang
BACKGROUND AND PURPOSE: Recent studies showed that clemizole has a potential therapeutic effect for hepatitis C infection and also potently inhibits TRPC5 channels. The aim of the present study was to investigate whether clemizole blocks cardiac K(+) currents and affects cardiac repolarization. EXPERIMENTAL APPROACH: Whole-cell patch technique was employed to examine the effects of clemizole on hERG channel current, IKs and Kv1.5 current in HEK 293 cell expression systems as well as on ventricular action potentials of guinea pig hearts...
November 25, 2016: British Journal of Pharmacology
Ai-Jun Ding, Gui-Sheng Wu, Bin Tang, Xuechuan Hong, Michael X Zhu, Huai-Rong Luo
With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C...
November 16, 2016: Molecular and Cellular Biochemistry
Christine Gebhardt, Oliver von Bohlen Und Halbach, Michael D Hadler, Christian Harteneck, Doris Albrecht
Recently we have shown that capsaicin attenuates the strength of LTP in the lateral amygdala (LA) and demonstrated that this effect is mediated by the transient receptor potential (TRP) channel TRPV1. Here we further show that capsaicin, which is thought to act primarily through TRPV1, modifies long term depression (LTD) in the LA. Yet the application of various TRPV1 antagonists does not reverse this effect and it remains in TRPV1-deficient mice. In addition, voltage gated calcium channels, nitric oxide and CB1 receptors are not involved...
December 2016: Neurobiology of Learning and Memory
On-Chai Lau, Bing Shen, Ching-On Wong, Yung-Wui Tjong, Chun-Yin Lo, Hui-Chuan Wang, Yu Huang, Wing-Ho Yung, Yang-Chao Chen, Man-Lung Fung, John Anthony Rudd, Xiaoqiang Yao
Blood pressure is maintained within a normal physiological range by a sophisticated regulatory mechanism. Baroreceptors serve as a frontline sensor to detect the change in blood pressure. Nerve signals are then sent to the cardiovascular control centre in the brain in order to stimulate baroreflex responses. Here, we identify TRPC5 channels as a mechanical sensor in aortic baroreceptors. In Trpc5 knockout mice, the pressure-induced action potential firings in the afferent nerve and the baroreflex-mediated heart rate reduction are attenuated...
July 14, 2016: Nature Communications
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
June 9, 2016: ACS Medicinal Chemistry Letters
Hannah J Gaunt, Naveen S Vasudev, David J Beech
Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca(2+) entry because of the critical roles played by Ca(2+) in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (-)-englerin A...
June 11, 2016: European Biophysics Journal: EBJ
Xudong Wu, Artur A Indzhykulian, Paul D Niksch, Roxanna M Webber, Miguel Garcia-Gonzalez, Terry Watnick, Jing Zhou, Melissa A Vollrath, David P Corey
Members of the TRP superfamily of ion channels mediate mechanosensation in some organisms, and have been suggested as candidates for the mechanotransduction channel in vertebrate hair cells. Some TRP channels can be ruled out based on lack of an inner ear phenotype in knockout animals or pore properties not similar to the hair-cell channel. Such studies have excluded Trpv4, Trpa1, Trpml3, Trpm1, Trpm3, Trpc1, Trpc3, Trpc5, and Trpc6. However, others remain reasonable candidates. We used data from an RNA-seq analysis of gene expression in hair cells as well as data on TRP channel conductance to narrow the candidate group...
2016: PloS One
Khadija M Alawi, Fiona A Russell, Aisah A Aubdool, Salil Srivastava, Yanira Riffo-Vasquez, Lineu Baldissera, Pratish Thakore, Nurjahan Saleque, Elizabeth S Fernandes, David A Walsh, Susan D Brain
OBJECTIVE: Transient receptor potential canonical 5 (TRPC5) is functionally expressed on a range of cells including fibroblast-like synoviocytes, which play an important role in arthritis. A role for TRPC5 in inflammation has not been previously shown in vivo. We investigated the contribution of TRPC5 in arthritis. METHODS: Male wild-type and TRPC5 knockout (KO) mice were used in a complete Freund's adjuvant (CFA)-induced unilateral arthritis model, assessed over 14 days...
May 10, 2016: Annals of the Rheumatic Diseases
Jongyun Myeong, Juyeon Ko, Chansik Hong, Dongki Yang, Kyu Pil Lee, Ju-Hong Jeon, Insuk So
Transient receptor potential canonical (TRPC) family contains a non-selective cation channel, and four TRPC subunits form a functional tetrameric channel. TRPC4/5 channels form not only the homotetrameric channel but also a heterotetrameric channel with TRPC1. We investigated the interaction domain required for TRPC1/4 or TRPC1/5 heteromultimeric channels using FRET and the patch-clamp technique. TRPC1 only localized at the plasma membrane (PM) when it was coexpressed with TRPC4 or TRPC5. The TRPC1/4 or TRPC1/5 heteromultimeric showed the typical outward rectifying I/V curve...
June 3, 2016: Biochemical and Biophysical Research Communications
Jessica Sabourin, Fiona Bartoli, Fabrice Antigny, Ana Maria Gomez, Jean-Pierre Benitah
Store-operated Ca(2+) entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca(2+) influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes...
June 17, 2016: Journal of Biological Chemistry
Nozomi Ogawa, Tatsuki Kurokawa, Yasuo Mori
Cellular redox status is maintained by the balance between series of antioxidant systems and production of reactive oxygen/nitrogenous species. Cells utilize this redox balance to mediate diverse physiological functions. Transient receptor potential (TRP) channels are non-selective cation channels that act as biosensors for environmental and noxious stimuli, such as capsaicin and allicin, as well as changes in temperature and conditions inside the cell. TRP channels also have an emerging role as essential players in detecting cellular redox status to regulate cellular signals mediating physiological phenomena...
August 2016: Cell Calcium
Dhananjay P Thakur, Jin-bin Tian, Jaepyo Jeon, Jian Xiong, Yu Huang, Veit Flockerzi, Michael X Zhu
Transient Receptor Potential Canonical (TRPC) proteins form nonselective cation channels commonly known to be activated downstream from receptors that signal through phospholipase C (PLC). Although TRPC3/C6/C7 can be directly activated by diacylglycerols produced by PLC breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2), the mechanism by which the PLC pathway activates TRPC4/C5 remains unclear. We show here that TRPC4 activation requires coincident stimulation of Gi/o subgroup of G proteins and PLCδ, with a preference for PLCδ1 over PLCδ3, but not necessarily the PLCβ pathway commonly thought to be involved in receptor-operated TRPC activation...
January 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Dong-xu He, Xin Ma
The transient receptor potential (TRP) superfamily contains at least 28 homologs in mammalian. These proteins form TRP channels are permeable to monovalent and divalent cations and participate in a variety of physiological functions. Dysregulation of TRP channels is responsible for numerous diseases. This review provides a brief short overview of mammalian TRP channels with a focus on TRPC5 and its role in cancers. Dysregulation of TRPC5 interrupts Ca(2+) homeostasis in cancer cells, which activates signaling pathways that are highly associated with cancer progression, especially cancer chemoresistance...
January 2016: Acta Pharmacologica Sinica
Jinsung Kim, Sang Hui Moon, Young-Cheul Shin, Ju-Hong Jeon, Kyu Joo Park, Kyu Pil Lee, Insuk So
Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis...
April 2016: Pflügers Archiv: European Journal of Physiology
Jacqueline Naylor, Aisling Minard, Hannah J Gaunt, Mohamed S Amer, Lesley A Wilson, Marco Migliore, Sin Y Cheung, Hussein N Rubaiy, Nicola M Blythe, Katie E Musialowski, Melanie J Ludlow, William D Evans, Ben L Green, Hongjun Yang, Yun You, Jing Li, Colin W G Fishwick, Katsuhiko Muraki, David J Beech, Robin S Bon
BACKGROUND AND PURPOSE: The TRPC5 proteins assemble to create calcium-permeable, non-selective, cationic channels. We sought novel modulators of these channels through studies of natural products. EXPERIMENTAL APPROACH: Intracellular calcium measurements and patch clamp recordings were made from cell lines. Compounds were generated by synthetic chemistry. KEY RESULTS: Through a screen of natural products used in traditional Chinese medicines, the flavonol galangin was identified as an inhibitor of lanthanide-evoked calcium entry in TRPC5 overexpressing HEK 293 cells (IC50 0...
February 2016: British Journal of Pharmacology
Gusheng Wu, Zi-Hua Lu, Sabine André, Hans-Joachim Gabius, Robert W Ledeen
Axon-like neuritogenesis in neuroblastoma (NG108-15) cells and primary cerebellar granular neurons is furthered by the presence of ganglioside GM1. We describe here that galectin-1 (Gal-1), a homobivalent endogenous lectin, is an effector by cross-linking the ganglioside and its associated glycoprotein α5 β1 -integrin. The thereby triggered signaling cascade involves autophosphorylation of focal adhesion kinase and activation of phospholipase Cγ and phosphoinositide-3 kinase. This leads to a transient increase in the intracellular Ca(2+) concentration by opening of TRPC5 channels, which belong to the signal transduction-gated cation channels...
February 2016: Journal of Neurochemistry
Jane E Sexton, Terri Desmonds, Kathryn Quick, Ruth Taylor, Joel Abramowitz, Andy Forge, Corné J Kros, Lutz Birnbaumer, John N Wood
Transient receptor potential channels have diverse roles in mechanosensation. Evidence is accumulating that members of the canonical subfamily of TRP channels (TRPC) are involved in touch and hearing. Characteristic features of TRP channels include their high structural homology and their propensity to form heteromeric complexes which suggests potential functional redundancy. We previously showed that TRPC3 and TRPC6 double knockout animals have deficits in light touch and hearing whilst single knockouts were apparently normal...
January 1, 2016: Neuroscience Letters
Nicolas Wieder, Anna Greka
With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca(2+))-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier...
July 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
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