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Juan R Martinez-Galan, Ana Verdejo, Elena Caminos
Disturbances in calcium homeostasis due to canonical transient receptor potential (TRPC) and/or store-operated calcium (SOC) channels can play a key role in a large number of brain disorders. TRPC channels are plasma membrane cation channels included in the transient receptor potential (TRP) superfamily. The most widely distributed member of the TRPC subfamily in the brain is TRPC1, which is frequently linked to group I metabotropic glutamate receptors (mGluRs) and to the components of SOC channels. Proposing TRPC/SOC channels as a therapeutic target in neurological diseases previously requires a detailed knowledge of the distribution of such molecules in the brain...
2018: Frontiers in Neuroanatomy
Lai-Ling Du, Zhida Shen, Zhengwei Li, Xuewei Ye, Meiping Wu, Lihui Hong, Yanbo Zhao
Endothelial progenitor cells (EPCs) promote angiogenesis and play a pivotal role in endothelial repair and re-endothelialization after vascular injury. Transient receptor potential-canonical1 (TRPC1) has been recently implied to play important roles on EPC function. Here, we studied the role of TRPC1 in regulating EPC function in vivo and in vitro. EPCs were cultured from TRPC1-knockout mice and their controls. In vitro, TRPC1 knockout reduced EPC functional activities, including migration and tube formation...
March 12, 2018: Journal of Cardiovascular Translational Research
Wen-Tai Chiu, Heng-Ai Chang, Yi-Hsin Lin, Yu-Shan Lin, Hsiao-Tzu Chang, Hsi-Hui Lin, Soon-Cen Huang, Ming-Jer Tang, Meng-Ru Shen
Ca2+ plays a significant role in linking the induction of apoptosis. The key anti-apoptotic protein, Bcl-2, has been reported to regulate the movement of Ca2+ across the ER membrane, but the exact effect of Bcl-2 on Ca2+ levels remains controversial. Store-operated Ca2+ entry (SOCE), a major mode of Ca2+ uptake in non-excitable cells, is activated by depletion of Ca2+ in the ER. Depletion of Ca2+ in the ER causes translocation of the SOC channel activator, STIM1, to the plasma membrane. Thereafter, STIM1 binds to Orai1 or/and TRPC1 channels, forcing them to open and thereby allow Ca2+ entry...
December 2018: Cell Death Discovery
Mickaël F El Hachmane, Charlotta S Olofsson
Ca2+ impacts a large array of cellular processes in every known cell type. In the white adipocyte, Ca2+ is involved in regulation of metabolic processes such as lipolysis, glucose uptake and hormone secretion. Although the importance of Ca2+ in control of white adipocyte function is clear, knowledge is still lacking regarding the control of dynamic Ca2+ alterations within adipocytes and mechanisms inducing intracellular Ca2+ changes remain elusive. Own work has recently demonstrated the existence of store-operated Ca2+ entry (SOCE) in lipid filled adipocytes...
March 7, 2018: Biochemical and Biophysical Research Communications
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
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%O 2 and 30 s at 21%O 2 , 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
Elke Kaemmerer, Dane Turner, Amelia A Peters, Sarah J Roberts-Thomson, Gregory R Monteith
AKT is an enzyme of the PI3K/pAKT pathway, regulating proliferation and cell survival. High basal levels of active, phosphorylated AKT (pAKT) are associated with tumor progression and therapeutic resistance in some breast cancer subtypes, including HER2 positive breast cancers. Various stimuli can increase pAKT levels and elevated basal pAKT levels are a feature of PTEN-deficient breast cancer cell lines. The aim of this study was to develop an assay able to identify modulators of pAKT levels using an automated epifluorescence microscope and high content analysis...
February 10, 2018: Journal of Pharmacological and Toxicological Methods
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
Robin Sachdeva, Andrea Schlotterer, Dagmar Schumacher, Christin Matka, Ilka Mathar, Nadine Dietrich, Rebekka Medert, Ulrich Kriebs, Jihong Lin, Peter Nawroth, Lutz Birnbaumer, Thomas Fleming, Hans-Peter Hammes, Marc Freichel
OBJECTIVE: Diabetic retinopathy (DR) is induced by an accumulation of reactive metabolites such as ROS, RNS, and RCS species, which were reported to modulate the activity of cation channels of the TRPC family. In this study, we use Trpc1/4/5/6-/- compound knockout mice to analyze the contribution of these TRPC proteins to diabetic retinopathy. METHODS: We used Nanostring- and qPCR-based analysis to determine mRNA levels of TRPC channels in control and diabetic retinae and retinal cell types...
January 5, 2018: Molecular Metabolism
Florence Domenichini, Elodie Terrié, Patricia Arnault, Thomas Harnois, Christophe Magaud, Patrick Bois, Bruno Constantin, Valérie Coronas
The subventricular zone (SVZ) is the major stem cell niche in the brain of adult mammals. Within this region, neural stem cells proliferate, self-renew and give birth to neurons and glial cells. Previous studies underlined enrichment in calcium signaling-related transcripts in adult neural stem cells. Because of their ability to mobilize sustained calcium influxes in response to a wide range of extracellular factors, store-operated channels (SOC) appear to be, among calcium channels, relevant candidates to induce calcium signaling in neural stem cells whose cellular activities are continuously adapted to physiological signals from the microenvironment...
January 23, 2018: Stem Cells
Francesco Moccia
Intracellular Ca2+ signaling drives angiogenesis and vasculogenesis by stimulating proliferation, migration, and tube formation in both vascular endothelial cells and endothelial colony forming cells (ECFCs), which represent the only endothelial precursor truly belonging to the endothelial phenotype. In addition, local Ca2+ signals at the endoplasmic reticulum (ER)-mitochondria interface regulate endothelial cell fate by stimulating survival or apoptosis depending on the extent of the mitochondrial Ca2+ increase...
January 11, 2018: International Journal of Molecular Sciences
Qianran Yin, Dehua Jiang, Lei Li, Yu Yang, Pei Wu, Yuanyuan Luo, Rongli Yang, Dongye Li
BACKGROUND/AIMS: Lipopolysaccharide (LPS) is a potent activator of vascular smooth muscle cells (VSMCs) proliferation, but the underlying mechanism remains unknown. In this study, we knocked down Toll-like receptor 4 (TLR4) and Ras-related C3 botulinum toxin substrate 1 (Rac1) expression using small interfering RNA (siRNA) in order to investigate the effects and possible mechanisms of LPS-induced VSMCs proliferation. METHODS: VSMCs proliferation was monitored by 5-ethynyl-2'-deoxyuridine staining, and Rac1 activity was measured via Glutathione S-transferase pull-down assay...
December 13, 2017: Cellular Physiology and Biochemistry
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
Isaac Jardín, Letizia Albarran, Ginés M Salido, Jose J López, Stewart O Sage, Juan A Rosado
Store-operated Ca2+ entry (SOCE) is a functionally relevant mechanism for Ca2+ influx present in electrically excitable and non-excitable cells. Regulation of Ca2+ entry through store-operated channels is essential to maintain an appropriate intracellular Ca2+ homeostasis and prevent cell damage. Calcium-release activated channels exhibit Ca2+ -dependent inactivation mediated by two temporally separated mechanisms: fast Ca2+ -dependent inactivation takes effect in the order of milliseconds and involves the interaction of Ca2+ with residues in the channel pore while slow Ca2+ -dependent inactivation (SCDI) develops over tens of seconds, requires a global rise in [Ca2+ ]cyt and is a mechanism regulated by mitochondria...
March 2018: Biochimica et Biophysica Acta
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
L M Wang, H Zhong, N Tang, L J Pang, C J Zhang, F He
Objective: To investigate the interaction of Ca(2+) protein TRPC1 and STIM1 in extracellular Ca(2+) -sensing receptor (CaR)-induced extracellular Ca(2+) influx and the production of nitric oxide (NO). Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and incubated with CaR agonist spermine (activating store-operates cation channels (SOC) and receptor-operated channels (ROC)), CaR negative allosteric modulator Calhex231 (blocking SOC, activating ROC) and ROC analogue TPA (activating ROC, blocking SOC), protein kinase C (PKC) inhibitor Ro31-8220, PKCs and PKCμ inhibitor Go6967(activate SOC, blocking ROC), respectively...
November 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
Pramod Sukumaran, Yuyang Sun, Neil Antonson, Brij B Singh
Alterations in Ca(2+) homeostasis affect neuronal survival. However, the identity of Ca(2+) channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl -4-phenylpyridium ions (MPP(+)/MPTP), which mimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca(2+) entry. The function of the transient receptor potential canonical (TRPC)-1 channel was decreased upon exposure to the neurotoxins, followed by a decrease in TRPC1 expression...
November 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Kenji Iino, Takeshi Adachi, Yoshihiro Baba, Tomohiro Kurosaki, Kyoichi Ono, Hiroshi Ito
Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+-dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1+/-) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2...
2017: PloS One
Xin-Dong Wang, Xiao-Xia Qi, Yong Bian, Xiao-Dong Chen, Yi-Yan Zhang, Zhu-Yuan Fang
To investigate the inhibitory effect of Huangqi Danshen decoction (HDD) on isoproterenol (ISO)-induced myocardial remodeling and explore its effect on STIM1, TRPC1, CaN and NFATc3 expressions. ISO (2.5 mg•kg⁻¹•d⁻¹×14 d) was given by subcutaneous injection to establish myocardial remodeling models in rats, and then were randomly divided into control group, ISO model group, HDD5 group (HDD 5 g•kg⁻¹•d⁻¹+ISO), and HDD10 group (HDD 10 g•kg⁻¹•d⁻¹+ISO). After intervention for 4 weeks, the heart mass index (HW/BW) and the left ventricular mass index (LVW/BW) were calculated; the structure of myocardium was observed by echocardiography; the pathological changes of myocardium were observed by HE staining; levels of BNP, CaN and CaM kinases II in serum were detected by ELISA, and the protein expression levels of STIM1, TRPC1, p-CaN, p-NFATc3, and NFATc3 in left ventricular tissues were detected by Western blot...
July 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Fei He, Qianfu Wu, Banglong Xu, Xiaocheng Wang, Jixiong Wu, Li Huang, Jing Cheng
OBJECTIVE: Previous studies have demonstrated Stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) contributes to intracellular Ca2+ accumulation. The present study aimed to investigate the expression of STIM1 and its downstream molecules Orai1/TRPC1 in the context of myocardial ischemia/reperfusion injury (MIRI) and the effect of STIM1 inhibition on Ca2+ accumulation and apoptosis in H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R). METHODS: Expression of STIM1/Orai1/TRPC1 was determined by RT-PCR and Western blot in mice subjected to MIRI and H9C2 cardiomyocytes subjected to H/R...
December 22, 2017: Bioscience Reports
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