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Xi Luo, Lu Xue, Hao Xu, Qing-Yang Zhao, Qian Wang, Yu-Shan She, Dun-An Zang, Jinhua Shen, Yong-Bo Peng, Ping Zhao, Meng-Fei Yu, Weiwei Chen, Li-Qun Ma, Shu Chen, Shanshan Chen, Xiangning Fu, Sheng Hu, Xiaowei Nie, Chenyou Shen, Chunbin Zou, Gangjian Qin, Jiapei Dai, Guangju Ji, Yunchao Su, Shen Hu, Jingyu Chen, Qing-Hua Liu
Because of the serious side effects of the currently used bronchodilators, new compounds with similar functions must be developed. We screened several herbs and found that Polygonum aviculare L. contains ingredients that inhibit the precontraction of mouse and human airway smooth muscle (ASM). High K+ -induced precontraction in ASM was completely inhibited by nifedipine, a selective blocker of L-type voltage-dependent Ca2+ channels (LVDCCs). However, nifedipine only partially reduced the precontraction induced by acetylcholine chloride (ACH)...
February 15, 2018: Scientific Reports
Xin Yang, Guorong Wen, Biguang Tuo, Fenglian Zhang, Hanxing Wan, Jialin He, Shiming Yang, Hui Dong
Background and Purpose: Although Ca2+ signaling may stimulate small intestinal ion secretion, little is known about its critical role and the molecular mechanisms of Ca2+-mediated biological action. Key Results: Activation of muscarinic receptors by carbachol(CCh) stimulated mouse duodenal Isc, which was significantly inhibited in Ca2+-free serosal solution and by several selective store-operated Ca2+ channels(SOC) blockers added to the serosal side of duodenal tissues...
January 9, 2018: Oncotarget
Petr Rathner, Michael Stadlbauer, Christoph Romanin, Marc Fahrner, Isabella Derler, Norbert Müller
We report a new NMR-scale purification procedure for two recombinant wild type fragments of the stromal interaction molecule 1 (STIM1). This protein acts as a calcium sensor in the endoplasmic reticulum (ER) and extends into the cytosol accumulating at ER - plasma membrane (PM) junctions upon calcium store depletion ultimately leading to activation of the Orai/CRAC channel. The functionally relevant cytosolic part of STIM1 consists of three coiled coil domains, which are mainly involved in intra- and inter-molecular homomeric interactions as well as coupling to and gating of CRAC channels...
February 1, 2018: Protein Expression and Purification
Bernard T Drumm, Benjamin E Rembetski, Caroline A Cobine, Salah A Baker, Gerard P Sergeant, Mark A Hollywood, Keith D Thornbury, Kenton M Sanders
Urethral smooth muscle cells (USMC) generate myogenic tone and contribute to urinary continence. Currently, little is known about Ca2+ signalling in USMC in situ, and therefore little is known about the source(s) of Ca2+ required for excitation-contraction coupling. We characterized Ca2+ signalling in USMC within intact urethral muscles using a genetically encoded Ca2+ sensor, GCaMP3, expressed selectively in USMC. USMC fired spontaneous intracellular Ca2+ waves that did not propagate cell-to-cell across muscle bundles...
January 31, 2018: Journal of Physiology
Xi He, Shanshan Song, Ramon J Ayon, Angela Balisterieri, Stephen M Black, Ayako Makino, W Gil Wier, Wei-Jin Zang, Jason X-J Yuan
Ca2+ signaling, particularly the mechanism via store-operated Ca2+ entry (SOCE) and receptor-operated Ca2+ entry (ROCE), plays a critical role in the development of acute hypoxia-induced pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension. This study aimed to test the hypothesis that chronic hypoxia differentially regulates the expression of proteins that mediate SOCE and ROCE (STIM, Orai, and TRPC6) in pulmonary (PASMC) and coronary (CASMC) artery smooth muscle cells. The resting cytosolic [Ca2+] ([Ca2+]cyt) and the stored [Ca2+] in the sarcoplasmic reticulum (SR) were not different in CASMC and PASMC...
January 3, 2018: American Journal of Physiology. Cell Physiology
Jie-Bin Zhou, Ying-Ying Sun, Ying-Lin Zheng, Chu-Qin Yu, Hua-Qing Lin, Ji-Yan Pang
In this study, the effect of four xyloketals 1-4 on store-operated calcium entry (SOCE) was investigated in primary distal pulmonary arterial smooth muscle cells (PASMCs) isolated from mice. The results showed that xyloketal A (1), an unusual ketal with C-3 symmetry, exhibited strong SOCE blocking activity. Secretion of interleukin-8 (IL-8) was also inhibited by xyloketal A. The parallel artificial membrane permeability assay (PAMPA) of 1-4 suggested that these xyloketals penetrated easily through the cell membrane...
December 20, 2017: Acta Pharmaceutica
Jill L Thompson, Yue Zhao, Peter B Stathopulos, Alan Grossfield, Trevor J Shuttleworth
The low-conductance, highly calciumselective channels formed by the Orai proteins are known to take two major forms, namely the storeoperated CRAC channels, and store-independent, arachidonic acid-activated ARC channels. Both are activated by STIM1, but whereas CRAC channels are activated by the stromal-interacting STIM1 located in the endoplasmic reticulum membrane, ARC channels are activated by the minor pool of STIM1 located in the plasma membrane. Critically, maximally activated CRAC channel currents and ARC channel currents are completely additive within the same cell, demonstrating that these two channels are entirely distinct entities...
January 11, 2018: Journal of Biological Chemistry
Jessy Hasna, Frédéric Hague, Lise Rodat-Despoix, Dirk Geerts, Catherine Leroy, David Tulasne, Halima Ouadid-Ahidouch, Philippe Kischel
Orai proteins are highly selective calcium channels playing an important role in calcium entry. Orai3 channels are overexpressed in breast cancer (BC) tissues, and involved in their proliferation, cell cycle progression and survival. Herein, we sought to address the involvement of Orai3 in resistance to chemotherapeutic drugs. Using high-throughput approaches, we investigated major changes induced by Orai3 overexpression, including downstream signaling mechanisms involved in BC chemotherapy resistance. Resistance was dependent on external calcium presence and thus Orai3 functionality...
January 11, 2018: Cell Death and Differentiation
Nupura Hirve, Vangipurapu Rajanikanth, Patrick G Hogan, Aparna Gudlur
STIM1 and STIM2 are endoplasmic reticulum (ER) membrane proteins that sense decreases in ER-luminal free Ca2+ and, through a conformational change in the STIM cytoplasmic domain, control gating of the plasma membrane Ca2+ channel ORAI1. To determine how STIM1 conveys a signal from the ER lumen to the cytoplasm, we studied the Ca2+-dependent conformational change of engineered STIM1 proteins in isolated ER membranes and, in parallel, physiological activation of these proteins in cells. We find that conserved "sentinel" features of the CC1 region help to prevent activation while Ca2+ is bound to STIM ER-luminal domains...
January 2, 2018: Cell Reports
Isabella Derler, Carmen Butorac, Adela Krizova, Michael Stadlbauer, Martin Muik, Marc Fahrner, Irene Frischauf, Christoph Romanin
Calcium (Ca2+) is an essential second messenger required for diverse signaling processes in immune cells. Ca2+ release-activated Ca2+ (CRAC) channels represent one main Ca2+ entry pathway into the cell. They are fully reconstituted via two proteins, the stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum and the Ca2+ ion channel Orai in the plasma membrane. After Ca2+ store depletion, STIM1 and Orai couple to each other allowing Ca2+ influx. CRAC-/STIM1-mediated Orai channel currents display characteristic hallmarks such as high Ca2+ selectivity, an increase in current density when switching from a Ca2+-containing solution to a divalent-free Na+ one and fast Ca2+ dependent inactivation...
December 13, 2017: Journal of Biological Chemistry
Marc Fahrner, Saurabh K Pandey, Martin Muik, Lukas Traxler, Carmen Butorac, Michael Stadlbauer, Vasilina Zayats, Adéla Krizova, Peter Plenk, Irene Frischauf, Rainer Schindl, Hermann J Gruber, Peter Hinterdorfer, Rüdiger Ettrich, Christoph Romanin, Isabella Derler
Ca2+ release-activated Ca2+ (CRAC) channels constitute the major Ca2+ entry pathway into the cell. They are fully reconstituted via intermembrane coupling of the Ca2+ selective Orai channel and the Ca2+ sensing protein STIM1. In addition to the Orai C-terminus, the main coupling site for STIM1, the Orai N-terminus is indispensable for Orai channel gating. Although the extended transmembrane Orai N-terminal (ETON) region (Orai1: aa73-91; Orai3: aa48-65) is fully conserved in the Orai1 and Orai3 isoforms, Orai3 tolerates larger N-terminal truncations than Orai1 in retaining store-operated activation...
December 13, 2017: Journal of Biological Chemistry
James W Putney
Calcium signals arise by multiple mechanisms, including mechanisms of release of intracellular stored Ca2+ , and the influx of Ca2+ through channels in the plasma membrane. One mechanism that links these two sources of Ca2+ is store-operated Ca2+ entry, the most commonly encountered version of which involves the extensively studied calcium-release-activated Ca2+ (CRAC) channel. The minimal and essential molecular components of the CRAC channel are the STIM proteins that function as Ca2+ sensors in the endoplasmic reticulum, and the Orai proteins that comprise the pore forming subunits of the CRAC channel...
November 22, 2017: Advances in Biological Regulation
Tamas Balla
Discovery of the STIM1 and Orai proteins as the principal components of store-operated Ca2+ entry has drawn attention to contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM). Such contacts between adjacent membranes of different cellular organelles, primarily between the mitochondria and the ER, had already been known as the sites where Ca2+ released from the ER can be efficiently channelled to the mitochondria and also where phosphatidylserine synthesis and transfer takes place...
December 6, 2017: Journal of Physiology
Bo Zeng, Gui-Lan Chen, Eliana Garcia-Vaz, Sunil Bhandari, Nikoleta Daskoulidou, Lisa M Berglund, Hongni Jiang, Thomas Hallett, Lu-Ping Zhou, Li Huang, Zi-Hao Xu, Viji Nair, Robert G Nelson, Wenjun Ju, Matthias Kretzler, Stephen L Atkin, Maria F Gomez, Shang-Zhong Xu
Impaired albumin reabsorption by proximal tubular epithelial cells (PTECs) has been highlighted in diabetic nephropathy (DN), but little is known about the underlying molecular mechanisms. Here we find that ORAI1-3, are preferentially expressed in PTECs and downregulated in patients with DN. Hyperglycemia or blockade of insulin signaling reduces the expression of ORAI1-3. Inhibition of ORAI channels by BTP2 and diethylstilbestrol or silencing of ORAI expression impairs albumin uptake. Transgenic mice expressing a dominant-negative Orai1 mutant (E108Q) increases albuminuria, and in vivo injection of BTP2 exacerbates albuminuria in streptozotocin-induced and Akita diabetic mice...
December 4, 2017: Nature Communications
Jian Wang, Chuyi Xu, Qiuyu Zheng, Kai Yang, Ning Lai, Tao Wang, Haiyang Tang, Wenju Lu
Previous studies have demonstrated that besides the classic canonical transient receptor potential channel family, Orai family and stromal interaction molecule 1 (STIM1) might also be involved in the regulation of store-operated calcium channels (SOCCs). An increase in cytosolic free Ca2+ concentration promoted by store-operated Ca2+ entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) is a major trigger for pulmonary vasoconstriction and proliferation and migration of PASMCs. In this study, our data revealed the following: (1) in both rat distal pulmonary arteries and PASMCs, chronic hypoxia exposure upregulated the expression of Orai1 and Orai2, without affecting Orai3 and STIM1; (2) either heterozygous knockout of HIF-1 α in mice or knockdown of HIF-1 α in PASMCs abolished the hypoxic upregulation of Orai2, but not Orai1, suggesting the hypoxic upregulation of Orai2 depends on HIF-1 α ; and (3) using small interference RNA knockdown strategies, Orai1, 2, 3 and STIM1 were all shown to mediate SOCE in hypoxic PASMCs...
2017: Cell Death Discovery
Yoshihiro Onouchi
Kawasaki disease (KD) is a complex disorder which affects genetically susceptible infants and children. Several susceptibility genes (e.g., ITPKC, CASP3, CD40 and ORAI) and chromosomal regions have been identified through genome-wide association and genome-wide linkage studies to have association with KD. Knowledge of susceptibility genes involved in the pathogenesis of KD may provide new insights into diagnosis and treatment of this condition. However, there is much that we still do not know about the genetic basis of KD...
November 19, 2017: International Journal of Rheumatic Diseases
Lukas Traxler, Petr Rathner, Marc Fahrner, Michael Stadlbauer, Felix Faschinger, Tatsiana Charnavets, Norbert Müller, Christoph Romanin, Peter Hinterdorfer, Hermann J Gruber
Calmodulin (CaM) binds most of its targets by wrapping around an amphipathic α-helix. The N-terminus of Orai proteins contains a conserved CaM-binding segment but the binding mechanism has been only partially characterized. Here, microscale thermophoresis (MST), surface plasmon resonance (SPR), and atomic force microscopy (AFM) were employed to study the binding equilibria, the kinetics, and the single-molecule interaction forces involved in the binding of CaM to the conserved helical segments of Orai1 and Orai3...
December 4, 2017: Angewandte Chemie
Takahiro Sato, Yoshihisa Orai, Yuya Suzuki, Hiroyuki Ito, Toshiyuki Isshiki, Munetoshi Fukui, Kuniyasu Nakamura, C T Schamp
To improve the reliability of silicon carbide (SiC) electronic power devices, the characteristics of various kinds of crystal defects should be precisely understood. Of particular importance is understanding the correlation between the surface morphology and the near surface dislocations. In order to analyze the dislocations near the surface of 4H-SiC wafers, a dislocation analysis protocol has been developed. This protocol consists of the following process: (1) inspection of surface defects using low energy scanning electron microscopy (LESEM), (2) identification of small and shallow etch pits using KOH low temperature etching, (3) classification of etch pits using LESEM, (4) specimen preparation of several hundred nanometer thick sample using the in-situ focused ion beam micro-sampling® technique, (5) crystallographic analysis using the selected diffraction mode of the scanning transmission electron microscope (STEM), and (6) determination of the Burgers vector using multi-directional STEM (MD-STEM)...
October 1, 2017: Microscopy
Jia Song, Sisi Zheng, Nhung Nguyen, Youjun Wang, Yubin Zhou, Kui Lin
BACKGROUND: Because phylogenetic inference is an important basis for answering many evolutionary problems, a large number of algorithms have been developed. Some of these algorithms have been improved by integrating gene evolution models with the expectation of accommodating the hierarchy of evolutionary processes. To the best of our knowledge, however, there still is no single unifying model or algorithm that can take all evolutionary processes into account through a stepwise or simultaneous method...
October 3, 2017: BMC Bioinformatics
Kripa Elizabeth Cherian, Nitin Kapoor, Sahana Shetty, Dukhabandhu Naik, Nihal Thomas, Thomas V Paul
The measurement of bone mineral density by dual-energy X-ray absorptiometry scan is the "gold standard" for the diagnosis of osteoporosis, which has limited availability in many parts of India. This study was done to assess the diagnostic performance of 6 internationally validated tools (Simple Calculated Osteoporosis Risk Estimation [SCORE], age, bulk, one or never estrogen [ABONE], Osteoporosis Risk Assessment Instrument [ORAI] and Osteoporosis Self-Assessment Tool for Asians [OSTA], Fracture Risk Assessment Tool [FRAX®], and calcaneal quantitative ultrasound [QUS]) for the diagnosis of osteoporosis at the femoral neck (FN)...
September 25, 2017: Journal of Clinical Densitometry
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