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https://www.readbyqxmd.com/read/29776832/an-sar-study-of-hydroxy-trifluoromethylpyrazolines-as-inhibitors-of-orai1-mediated-store-operated-ca-2-entry-in-mda-mb-231-breast-cancer-cells-using-a-convenient-fluorescence-imaging-plate-reader-assay
#1
Ralph J Stevenson, Iman Azimi, Jack U Flanagan, Marco Inserra, Irina Vetter, Gregory R Monteith, William A Denny
The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes...
May 9, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29760086/mapping-the-functional-anatomy-of-orai1-transmembrane-domains-for-crac-channel-gating
#2
Priscilla S-W Yeung, Megumi Yamashita, Christopher E Ing, Régis Pomès, Douglas M Freymann, Murali Prakriya
Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1-4 whose perturbation activates Orai1 channels independently of STIM1...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29753044/hypoxia-induced-upregulation-of-orai1-drives-colon-cancer-invasiveness-and-angiogenesis
#3
Xiaoyu Liu, Xu Wan, Hao Kan, Yan Wang, Fan Yu, Lei Feng, Jian Jin, Peng Zhang, Xin Ma
In colon cancer, hypoxia promotes metastasis and angiogenesis, but little is known about the mediators of these effects. Here, we reported that expression of Orai1 is up-regulated in colon cancer cells in response to hypoxia, and the increase in Orai1 is mediated by Notch1 pathway. We also showed upregulation of Orai1 contributes to hypoxia-induced invasion and angiogenesis, and inhibition or downregulation of Orai1 reverses these effects. Mechanistic study revealed that upregulation of Orai1 by hypoxia potentiates store-operated Ca2+ entry (SOCE), and then causes activation of nuclear factor of activated T cells isoform c3 (NFATc3) in colon cancer cells...
May 9, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29719456/increased-store-operated-ca-2-entry-mediated-by-gnb5-and-stim1
#4
Namju Kang, Jung Yun Kang, Soonhong Park, Dong Min Shin
Recent human genetic studies have shown that Gβ5 is related to various clinical symptoms, such as sinus bradycardia, cognitive disability, and attention deficit hyperactivity disorder. Although the calcium signaling cascade is closely associated with a heterotrimeric G-protein, the function of Gβ5 in calcium signaling and its relevance to clinical symptoms remain unknown. In this study, we investigated the in vitro changes of store-operated calcium entry (SOCE) with exogenous expression of Gβ5. The cells expressing Gβ5 had enhanced SOCE after depletion of calcium ion inside the endoplasmic reticulum...
May 2018: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29712850/distinct-gating-mechanism-of-soc-channel-involving-stim-orai-coupling-and-an-intramolecular-interaction-of-orai-in-caenorhabditis-elegans
#5
Kyu Min Kim, Tharaka Wijerathne, Jin-Hoe Hur, Uk Jung Kang, Ihn Hyeong Kim, Yeong Cheon Kweon, Ah Reum Lee, Su Ji Jeong, Sang Kwon Lee, Yoon Young Lee, Bo-Woong Sim, Jong-Hee Lee, Chunggi Baig, Sun-Uk Kim, Kyu-Tae Chang, Kyu Pil Lee, Chan Young Park
Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29705071/s-nitrosylation-of-stim1-by-neuronal-nitric-oxide-synthase-inhibits-store-operated-ca-2-entry
#6
Le Gui, Jinhui Zhu, Xiangru Lu, Stephen M Sims, Wei-Yang Lu, Peter B Stathopulos, Qingping Feng
Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule-1 (STIM1) and Orai1 represents a major route of Ca2+ entry in mammalian cells and is initiated by STIM1 oligomerization in the endoplasmic or sarcoplasmic reticulum (ER/SR). However, the effects of nitric oxide (NO) on STIM1 function are unknown. Neuronal NO synthase (nNOS) is located in the SR of cardiomyocytes. Here, we show that STIM1 is susceptible to S-nitrosylation. nNOS deficiency or inhibition enhanced Ca2+ release-activated Ca2+ channel current (ICRAC ) and SOCE in cardiomyocytes...
April 26, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29698850/structural-elements-of-stromal-interaction-molecule-function
#7
REVIEW
Matthew J Novello, Jinhui Zhu, Qingping Feng, Mitsuhiko Ikura, Peter B Stathopulos
Stromal interaction molecule (STIM)-1 and -2 are multi-domain, single-pass transmembrane proteins involved in sensing changes in compartmentalized calcium (Ca2+ ) levels and transducing this cellular signal to Orai1 channel proteins. Our understanding of the molecular mechanisms underlying STIM signaling has been dramatically improved through available X-ray crystal and solution NMR structures. This high-resolution structural data has revealed that intricate intramolecular and intermolecular protein-protein interactions are involved in converting STIMs from the quiescent to activation-competent states...
April 18, 2018: Cell Calcium
https://www.readbyqxmd.com/read/29677491/the-allergen-der-p3-from-house-dust-mite-stimulates-store-operated-ca-2-channels-and-mast-cell-migration-through-par4-receptors
#8
Yu-Ping Lin, Charmaine Nelson, Holger Kramer, Anant B Parekh
The house dust mite is the principal source of perennial aeroallergens in man. How these allergens activate innate and adaptive immunity is unclear, and therefore, there are no therapies targeting mite allergens. Here, we show that house dust mite extract activates store-operated Ca2+ channels, a common signaling module in numerous cell types in the lung. Activation of channel pore-forming Orai1 subunits by mite extract requires gating by STIM1 proteins. Although mite extract stimulates both protease-activated receptor type 2 (PAR2) and PAR4 receptors, Ca2+ influx is more tightly coupled to the PAR4 pathway...
April 19, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29669320/camkii-potentiates-store-operated-ca2-entry-through-enhancing-stim1-aggregation-and-interaction-with-orai1
#9
Shu Li, Jingyi Xue, Zhipeng Sun, Tiantian Liu, Lane Zhang, Limin Wang, Hongjie You, Zheng Fan, Yuanyuan Zheng, Dali Luo
BACKGROUND/AIMS: Upon Ca2+ store depletion, stromal interaction molecule 1 (STIM1) oligomerizes, redistributes near plasmalemma to interact with Ca2+ selective channel-forming subunit (Orai1) and initiates store-operated Ca2+ entry (SOCE). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a regulator of SOCE, but how CaMKII regulates SOCE remains obscure. METHODS: Using Fura2, confocal microscopy, co-immunoprecipitation, specific blocker and overexpression/knockdown approaches, we evaluated STIM1 aggregation and its interaction with Orai1, and SOCE upon Ca2+ store depletion in thapsigargin (TG) treated HEK293 and HeLa cells...
April 13, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29661937/a-charge-sensing-region-in-the-stromal-interaction-molecule-1-luminal-domain-confers-stabilization-mediated-inhibition-of-soce-in-response-to-s-nitrosylation
#10
Jinhui Zhu, Xiangru Lu, Qingping Feng, Peter B Stathopulos
Store-operated calcium (Ca2+ ) entry (SOCE) is a major Ca2+ signaling pathway facilitating extracellular Ca2+ influx in response to the initial release of intracellular endo/sarcoplasmic reticulum (ER/SR) Ca2+ stores. Stromal interaction molecule-1 (STIM1) is the Ca2+ sensor which activates SOCE following ER/SR Ca2+ depletion. The EF-hand together with the adjacent sterile α motif (EFSAM) domains of STIM1 are essential for detecting changes in luminal Ca2+ concentrations. Low ER Ca2+ levels trigger STIM1 destabilization and oligomerization, culminating in the opening of Orai1-composed Ca2+ channels on the plasma membrane...
April 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29628897/stanniocalcin-2-regulates-non-capacitative-ca-2-entry-and-aggregation-in-mouse-platelets
#11
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/29618985/the-complex-role-of-store-operated-calcium-entry-pathways-and-related-proteins-in-the-function-of-cardiac-skeletal-and-vascular-smooth-muscle-cells
#12
REVIEW
Javier Avila-Medina, Isabel Mayoral-Gonzalez, Alejandro Dominguez-Rodriguez, Isabel Gallardo-Castillo, Juan Ribas, Antonio Ordoñez, Juan A Rosado, Tarik Smani
Cardiac, skeletal, and smooth muscle cells shared the common feature of contraction in response to different stimuli. Agonist-induced muscle's contraction is triggered by a cytosolic free Ca2+ concentration increase due to a rapid Ca2+ release from intracellular stores and a transmembrane Ca2+ influx, mainly through L-type Ca2+ channels. Compelling evidences have demonstrated that Ca2+ might also enter through other cationic channels such as Store-Operated Ca2+ Channels (SOCCs), involved in several physiological functions and pathological conditions...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29613974/fatal-p-jirovecii-and-cytomegalovirus-infections-in-an-infant-with-normal-trecs-count-pitfalls-of-newborn-screening-for-severe-combined-immunodeficiency
#13
Ana Mendez-Echevarria, Gonzalez-Granado Luis Ignacio, Luis M Allende, De Felipe Beatriz, Del Rosal Teresa, Calvo Cristina, Perez-Martinez Antonio, Ruiz Garcia Raquel, Neth Olaf
Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T-cell receptor-excision circles (TRECs) allows prompt diagnosis and initiation of supportive and curative therapy thereby reducing morbidity and mortality. However, profound combined immunodeficiencies with normal numbers of non-functional T cells will go undetected. We present a patient with ORAI1 deficiency and normal TREC numbers observed after diagnosis at the age of 14 months who suffered from disseminated fatal cytomegalovirus and Pneumocystis jirovecii infection, demonstrating a potential pitfall of the current NBS program...
April 2, 2018: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/29604968/a-critical-appraisal-of-the-role-of-intracellular-ca-2-signaling-pathways-in-kawasaki-disease
#14
REVIEW
Jeroen Bijnens, Ludwig Missiaen, Geert Bultynck, Jan B Parys
Kawasaki disease is a multi-systemic vasculitis that generally occurs in children and that can lead to coronary artery lesions. Recent studies showed that Kawasaki disease has an important genetic component. In this review, we discuss the single-nucleotide polymorphisms in the genes encoding proteins with a role in intracellular Ca2+ signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca2+ -entry channel ORAI1, the type-3 inositol 1,4,5-trisphosphate receptor, the Na+ /Ca2+ exchanger 1, and phospholipase Cß4 and Cß1...
May 2018: Cell Calcium
https://www.readbyqxmd.com/read/29604963/stim1-and-trpv4-regulate-fluid-flow-induced-calcium-oscillation-at-early-and-late-stages-of-osteoclast-differentiation
#15
Ping Li, Xueyan Bian, Chenglin Liu, Shurong Wang, Mengmeng Guo, Yingjie Tao, Bo Huo
Bone resorption is mainly mediated by osteoclasts (OCs), whose formation and function are regulated by intracellular Ca2+ oscillation. Our previous studies demonstrated that fluid shear stress (FSS) lead to Ca2+ oscillation through mechanosensitive cation-selective channels. However, the specific channels responsible for this FSS-induced Ca2+ oscillation remain unknown. In the present study, we examined the expression of several Ca2+ channels in OCs, including STIM1, ORAI1, TRPV1, TRPV4, TRPV5, and TRPV6, by western blotting and reverse transcription-polymerase chain reaction...
May 2018: Cell Calcium
https://www.readbyqxmd.com/read/29604961/deletion-of-orai2-augments-endogenous-crac-currents-and-degranulation-in-mast-cells-leading-to-enhanced-anaphylaxis
#16
Volodymyr Tsvilovskyy, Alejandra Solís-López, Dagmar Schumacher, Rebekka Medert, Axel Roers, Ulrich Kriebs, Marc Freichel
All three members of the Orai family of cation channels-Orai1, Orai2 and Orai3-are integral membrane proteins that can form store-operated Ca2+ channels resembling endogenous calcium release-activated channels (CRAC) in many aspects. Loss of function studies in human and murine models revealed many functions of Orai1 proteins not only for Ca2+ homeostasis, but also for cellular and systemic functions in many cell types. By contrast, the knowledge regarding the contribution of Orai2 and Orai3 proteins in these processes is sparse...
May 2018: Cell Calcium
https://www.readbyqxmd.com/read/29587570/mutyh-and-orai1-polymorphisms-are-associated-with-susceptibility-to-osteoarthritis-in-the-chinese-han-population
#17
Shifeng Zhang, Haohui Guo, Da Chen, Xi Chen, Qunhua Jin
Background This study analyzed the associations between single nucleotide polymorphisms (SNPs) in the mutY homolog gene ( MUTYH) and the calcium release-activated calcium channel gene ( ORAI1) with susceptibility to osteoarthritis in the Chinese Han population. Methods A total of 350 patients diagnosed with osteoarthritis from October 2013 to May 2016 were selected as the study group, together with 350 age- and gender-matched healthy controls. MUTYH SNP rs3219463 and ORAI1 SNPs rs712853, rs12313273, rs6486795, rs12320939, and rs7135617 were analyzed by Sanger sequencing...
January 1, 2018: Journal of International Medical Research
https://www.readbyqxmd.com/read/29581306/cross-linking-of-orai1-channels-by-stim-proteins
#18
Yandong Zhou, Robert M Nwokonko, Xiangyu Cai, Natalia A Loktionova, Raz Abdulqadir, Ping Xin, Barbara A Niemeyer, Youjun Wang, Mohamed Trebak, Donald L Gill
The transmembrane docking of endoplasmic reticulum (ER) Ca2+ -sensing STIM proteins with plasma membrane (PM) Orai Ca2+ channels is a critical but poorly understood step in Ca2+ signal generation. STIM1 protein dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions. We reveal that each monomer within the SOAR dimer interacts independently with single Orai1 subunits to mediate cross-linking between Orai1 channels. Superresolution imaging and mobility measured by fluorescence recovery after photobleaching reveal that SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29555205/store-independent-coupling-between-the-secretory-pathway-ca-2-transport-atpase-spca1-and-orai1-in-golgi-stress-and-hailey-hailey-disease
#19
Susanne Smaardijk, Jialin Chen, Sara Kerselaers, Thomas Voets, Jan Eggermont, Peter Vangheluwe
The Secretory Pathway Ca2+ ATPases SPCA1 and SPCA2 transport Ca2+ and Mn2+ into the Golgi and Secretory Pathway. SPCA2 mediates store-independent Ca2+ entry (SICE) via STIM1-independent activation of Orai1, inducing constitutive Ca2+ influx in mammary epithelial cells during lactation. Here, we show that like SPCA2, also the overexpression of the ubiquitous SPCA1 induces cytosolic Ca2+ influx, which is abolished by Orai1 knockdown and occurs independently of STIM1. This process elevates the Ca2+ concentration in the cytosol and in the non-endoplasmic reticulum (ER) stores, pointing to a functional coupling between Orai1 and SPCA1...
March 16, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29551286/up-regulation-of-microrna-93-inhibits-tgf-%C3%AE-1-induced-emt-and-renal-fibrogenesis-by-down-regulation-of-orai1
#20
Jifang Ma, Lei Zhang, Jianbing Hao, Naqi Li, Jie Tang, Lirong Hao
TGF-β1-induced excessive deposition of ECM and EMT process of tubular epithelial cells play critical roles in the development and progression of fibrosis in diabetic nephropathy (DN). Orai1 has been demonstrated to be involved in TGF-β1-induced EMT via TGF-β/Smad3 pathway. We are aimed to explore the effects of miR-93 on TGF-β1-induced EMT process in HK2 cells. In this study, our data showed that miR-93 was dramatically decreased in renal tissues of patients with DN and TGF-β1-stimulated HK2 cells. Moreover, the decreased level of miR-93 was closely associated with the increased expression of Orai1...
February 14, 2018: Journal of Pharmacological Sciences
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