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TRPC6

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https://www.readbyqxmd.com/read/29785489/trpc6-inactivation-confers-protection-in-a-model-of-severe-nephrosis-in-rats
#1
Eun Young Kim, Parisa Yazdizadeh Shotorbani, Stuart E Dryer
Mutations in canonical transient receptor potential-6 (TRPC6) channels give rise to rare familial forms of focal and segmental glomerulosclerosis (FSGS). Here we examined a possible role for TRPC6 in the progression of chronic puromycin aminonucleoside (PAN) nephrosis in Sprague-Dawley rats, a classic model of acquired nephrotic syndromes. We used CRISPR/Cas9 technology to delete a 239-bp region within exon 2 of the Trpc6 gene (Trpc6del allele). Trpc6del/del rats expressed detectable Trpc6 transcripts missing exon 2, and TRPC6 proteins could be detected by immunoblot of renal cortex...
May 22, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29752403/cryo-em-structure-of-the-cytoplasmic-domain-of-murine-transient-receptor-potential-cation-channel-subfamily-c-member-6-trpc6
#2
Caleigh M Azumaya, Francisco Sierra-Valdez, Julio F Cordero-Morales, Terunaga Nakagawa
The kidney maintains the internal milieu by regulating the retention and excretion of proteins, ions, and small molecules. The glomerular podocyte forms the slit diaphragm of the ultrafiltration filter, whose damage leads to progressive kidney failure and focal segmental glomerulosclerosis (FSGS). The canonical transient receptor potential 6 (TRPC6) ion channel is expressed in the podocyte and mutations in its cytoplasmic domain cause FSGS in humans. In vitro evaluation of disease-causing mutations in TRPC6 has revealed that these genetic alterations result in abnormal ion channel gating...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29752182/discovery-of-a-bicyclo-4-3-0-nonane-derivative-ds88790512-as-a-potent-selective-and-orally-bioavailable-blocker-of-transient-receptor-potential-canonical-6-trpc6
#3
Keisuke Motoyama, Tsutomu Nagata, Jun Kobayashi, Akifumi Nakamura, Naoki Miyoshi, Miho Kazui, Ken Sakurai, Tomoko Sakakura
In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3 ). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV 1.5 channels, and was identified as an orally bioavailable compound...
March 22, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29747275/-the-mechanism-of-nicotine-on-human-bronchial-smooth-muscle-cell-contraction
#4
W Hong, B W Hao, F Peng, G Y Peng, L M Huang, J Xu, W T Cao, B L Liao, L H Tang, J D Pu, B Li, P X Ran
Objective: To investigate the molecular mechanism of contractility dysfunction of human bronchial smooth muscle cells induced by nicotine. Methods: Primary human bronchial smooth muscle cells were cultured in vitro. The cells were divided into a control group and a nicotine group which was treated with 10(-5) mol/L nicotine for 48 h and transfected with or without α7nAChR-siRNA (The siNC group, siNC + nicotine group and siα7nAChR + nicotine group). The effects of nicotine on the cell contractile function were examined by collagen gel shrinkage assay...
May 12, 2018: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/29717355/the-function-of-trp-channels-in-neutrophil-granulocytes
#5
REVIEW
Karolina Najder, Boris Musset, Otto Lindemann, Etmar Bulk, Albrecht Schwab, Benedikt Fels
Neutrophil granulocytes are exposed to widely varying microenvironmental conditions when pursuing their physiological or pathophysiological functions such as fighting invading bacteria or infiltrating cancer tissue. Examples for harsh environmental challenges include among others mechanical shear stress during the recruitment from the vasculature or the hypoxic and acidotic conditions within the tumor microenvironment. Chemokine gradients, reactive oxygen species, pressure, matrix elasticity, and temperature can be added to the list of potential challenges...
May 1, 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29700422/structure-of-the-receptor-activated-human-trpc6-and-trpc3-ion-channels
#6
Qinglin Tang, Wenjun Guo, Li Zheng, Jing-Xiang Wu, Meng Liu, Xindi Zhou, Xiaolin Zhang, Lei Chen
TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution...
April 26, 2018: Cell Research
https://www.readbyqxmd.com/read/29677904/re-vitamin-d3-prevents-calcium-induced-progression-of-early-stage-prostate-tumors-by-counteracting-trpc6-and-calcium-sensing-receptor-upregulation
#7
https://www.readbyqxmd.com/read/29643035/-correlation-between-expressions-of-vegf-and-trpc6-and-their-roles-in-podocyte-injury-in-rats-with-diabetic-nephropathy
#8
Xiao-Na Zhu, Yu-Huan Wang, Juan-Juan Wu, Peng Dong, Min Zhang
OBJECTIVE: To analyze the correlation between the expressions of vascular endothelial growth factor (VEGF) and transient receptor potential canonical 6 (TRPC6) and their role in podocyte injury in rats with diabetic nephropathy. METHODS: Forty SD rats with diabetic nephropathy induced by intraperitoneal injection of 65 mg/kg streptozotocin were randomized equally into 5 groups, including a diabetic nephropathy model group and 4 treatment groups, with 8 normal SD rats as the normal control group...
March 20, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/29628897/stanniocalcin-2-regulates-non-capacitative-ca-2-entry-and-aggregation-in-mouse-platelets
#9
Esther López, L Gómez-Gordo, Carlos Cantonero, Nuria Bermejo, Jorge Pérez-Gómez, María P Granados, Gines M Salido, Juan A Rosado Dionisio, Pedro C Redondo Liberal
Stanniocalcin 2 (STC2) is a fish protein that controls body Ca2+ and phosphate metabolism. STC2 has also been described in mammals, and as platelet function highly depends on both extracellular and intracellular Ca2+ , we have explored its expression and function in these cells. STC2-/- mice exhibit shorter tail bleeding time than WT mice. Platelets from STC2-deficient mice showed enhanced aggregation, as well as enhanced Ca2+ mobilization in response to the physiological agonist thrombin (Thr) and the diacylglycerol analog, OAG, a selective activator of the non-capacitative Ca2+ entry channels...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29619864/atra-attenuate-proteinuria-via-downregulation-of-trpc6-in-glomerulosclerosis-rats-induced-by-adriamycin
#10
Lei Zhang, Xiu-Ping Chen, He Qin, Ling Jiang, Yuan-Han Qin
OBJECTIVE: In this research, we explored the molecular mechanism of proteinuria in glomerulosclerosis rats and the protective effects of ATRA. METHODS: This research set up three groups: SHO group, GS group, and ATRA group (15 mg/(kg d), Sigma, St. Louis, MO). The serum creatinine (Scr), urea nitrogen (BUN), and 24-h proteinuria were detected 12 weeks after administration of ATRA. The pathological and ultrastructure changes were observed under light microscope and transmission electron microscope...
November 2018: Renal Failure
https://www.readbyqxmd.com/read/29560783/trpc6-and-trpc4-heteromultimerization-mediates-store-depletion-activated-ncx1-reversal-in-proliferative-vascular-smooth-muscle-cells
#11
Bin Zhang, Bei Liu, Carolyn M Roos, Michael A Thompson, Y S Prakash, Jordan D Miller, Rui-Wei Guo
Store depletion has been shown to induce Ca2+ entry by Na+/Ca+ exchange (NCX) 1 reversal in proliferative vascular smooth muscle cells (VSMCs). The study objective was to investigate the role of transient receptor potential canonical (TRPC) channels in store depletion and NCX1 reversal in proliferative VSMCs. In cultured VSMCs, expressing TRPC1, TRPC4, and TRPC6, the removal of extracellular Na+ was followed by a significant increase of cytosolic Ca2+ concentration that was inhibited by KBR, a selective NCX1 inhibitor...
March 21, 2018: Channels
https://www.readbyqxmd.com/read/29556761/recent-advances-of-animal-model-of-focal-segmental-glomerulosclerosis
#12
REVIEW
Jae Won Yang, Anne Katrin Dettmar, Andreas Kronbichler, Heon Yung Gee, Moin Saleem, Seong Heon Kim, Jae Il Shin
In the last decade, great advances have been made in understanding the genetic basis for focal segmental glomerulosclerosis (FSGS). Animal models using specific gene disruption of the slit diaphragm and cytoskeleton of the foot process mirror the etiology of the human disease. Many animal models have been developed to understand the complex pathophysiology of FSGS. Therefore, we need to know the usefulness and exact methodology of creating animal models. Here, we review classic animal models and newly developed genetic animal models...
March 20, 2018: Clinical and Experimental Nephrology
https://www.readbyqxmd.com/read/29556099/an-optically-controlled-probe-identifies-lipid-gating-fenestrations-within-the-trpc3-channel
#13
Michaela Lichtenegger, Oleksandra Tiapko, Barbora Svobodova, Thomas Stockner, Toma N Glasnov, Wolfgang Schreibmayer, Dieter Platzer, Gema Guedes de la Cruz, Sarah Krenn, Romana Schober, Niroj Shrestha, Rainer Schindl, Christoph Romanin, Klaus Groschner
Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light. A structure-guided mutagenesis screen of the TRPC3 pore domain unveiled a single glycine residue behind the selectivity filter (G652) that is exposed to lipid through a subunit-joining fenestration...
March 19, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29522264/a-larixol-congener-with-high-affinity-and-subtype-selectivity-toward-trpc6
#14
Stephanie Häfner, Finn Burg, Martina Kannler, Nicole Urban, Peter Mayer, Alexander Dietrich, Dirk Trauner, Johannes Broichhagen, Michael Schaefer
Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)-larixol and its acetylated congeners demonstrated selective inhibition of the second-messenger-gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)-larixol mostly at position C6. Implementing high-throughput Ca2+ FLIPR screening assays and electrophysiological patch-clamp recordings, we showcase larixyl N-methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13-fold subtype selectivity over TRPC3 in stably expressing HEK293 cells...
March 9, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29500176/the-ncx1-trpc6-complex-mediates-tgf%C3%AE-driven-migration-and-invasion-of-human-hepatocellular-carcinoma-cells
#15
Jingyu Xu, Yuan Yang, Rui Xie, Jilong Liu, Xubiao Nie, Jiaxing An, Guorong Wen, Xuemei Liu, Hai Jin, Biguang Tuo
TGFβ plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+ /Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29480205/inhibition-of-trpc1-dependent-store-operated-calcium-entry-improves-synaptic-stability-and-motor-performance-in-a-mouse-model-of-huntington-s-disease
#16
Jun Wu, Daniel Ryskamp, Lutz Birnbaumer, Ilya Bezprozvanny
BACKGROUND: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. We previously discovered that mutant Huntingtin sensitizes type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) to InsP3. This causes calcium leakage from the endoplasmic reticulum (ER) and a compensatory increase in neuronal store-operated calcium (nSOC) entry. We previously demonstrated that supranormal nSOC leads to synaptic loss in striatal medium spiny neurons (MSNs) in YAC128 HD mice...
2018: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/29478534/activation-of-membrane-located-ca-2-channels-by-hop-beta-acids-and-their-tricyclic-transformation-products
#17
Carolin Schulz, Nikolas Fritz, Thomas Sommer, Karel Krofta, Kristina Friedland, Monika Pischetsrieder
Beta-bitter acids of hops (lupulones) revealed sedative and antidepressant-like effects in animal studies. Transformation of β-acids during beer brewing leads to the formation of tricyclic transformation products, which have a close structural analogy to hyperforin. The latter compound is responsible for the antidepressant activity of St. John's wort by activation of TRPC6 cation channels in neuronal-like cells leading to Ca2+ influx. In this study, nortricyclolupones, dehydrotricyclolupones, and tricyclolupones were isolated from a wort-boiling model and their structures were elucidated by UHPLC-DAD, UHPLC-ESI- -MS/MS and 1D/2D-NMR spectroscopy...
June 30, 2018: Food Chemistry
https://www.readbyqxmd.com/read/29469570/ribemansides-a-and-b-trpc6-inhibitors-from-ribes-manshuricum-that-suppress-tgf-%C3%AE-1-induced-fibrogenesis-in-hk-2-cells
#18
Baoping Zhou, Yange Wang, Chunlei Zhang, Guolin Yang, Fan Zhang, Boyang Yu, Chengzhi Chai, Zhengyu Cao
Two new acylated β-hydroxynitrile glycosides, ribemansides A (1) and B (2), were isolated from the aerial parts of Ribes manshuricum. Their structures were elucidated by comprehensive spectroscopic analysis. Ribemansides A and B inhibited transforming growth factor β1 (TGF-β1)-induced expression of α-smooth muscle actin, fibronectin release, and changes in cell morphology in the human proximal tubular epithelial cell line (human kidney-2, HK-2). Further biological evaluation demonstrated that both 1 and 2 inhibit the activity of canonical transient receptor potential cation channel 6 (TRPC6), with IC50 values of 24...
April 27, 2018: Journal of Natural Products
https://www.readbyqxmd.com/read/29461053/research-progress-of-polycyclic-polyprenylated-acylphloroglucinols
#19
Xing-Wei Yang, Robert B Grossman, Gang Xu
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid natural products sharing the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways and showing considerable structure and bioactivity diversity. This review discusses the progress of research into the chemistry and biological activity of 421 natural PPAPs in the past 11 years as well as in-depth studies of biological activities and total synthesis of some PPAPs isolated before 2006. We created an online database of all PPAPs known to date at http://www...
April 11, 2018: Chemical Reviews
https://www.readbyqxmd.com/read/29445096/chronic-intermittent-hypoxia-promotes-myocardial-ischemia-related-ventricular-arrhythmias-and-sudden-cardiac-death
#20
Jessica Morand, Claire Arnaud, Jean-Louis Pepin, Diane Godin-Ribuot
We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30 s at 5%O2 and 30 s at 21%O2 , 8 h·day-1 ) or normoxia (N, similar air-air cycles) and submitted to a 30-min coronary ligature. Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification...
February 14, 2018: Scientific Reports
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