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Michael Poteser, Gerd Leitinger, Elisabeth Pritz, Dieter Platzer, Irene Frischauf, Christoph Romanin, Klaus Groschner
Nanometer-spaced appositions between endoplasmic reticulum and plasma membrane (ER-PM junctions) stabilized by membrane-joining protein complexes are critically involved in cellular Ca(2+)-handling and lipid trafficking. ER-PM junctional architecture and plasticity associated with inter-membrane communication are as yet barely understood. Here, we introduce a method to precisely characterize ER-PM junction morphology and dynamics with high temporal resolution and minimal disturbance of junctional intermembrane communication...
October 19, 2016: Scientific Reports
Sher Ali, Tao Xu, Xiaolan Xu
Ca(2+) release-activated Ca(2+) (CRAC) channels play an essential role in the immune system. The pore-forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure-function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2-aminoethoxydiphenyl borate (2-APB). We first introduce the critical structural elements of Orai1, which include a Ca(2+) accumulating region (CAR), ion selectivity filter, hydrophobic centre, basic region, extended transmembrane orai1 N-terminal (ETON), transmembrane (TM) regions 2 and 3, P245 bend, (263) SHK(265) hinge linker and L273-L276 hydrophobic patch...
October 18, 2016: Journal of Physiology
Eduard Korkotian, Menahem Segal
No abstract text is available yet for this article.
October 13, 2016: Channels
Ming Wei, Yandong Zhou, Aomin Sun, Guolin Ma, Lian He, Lijuan Zhou, Shuce Zhang, Jin Liu, Shenyuan L Zhang, Donald L Gill, Youjun Wang
Store-operated Ca(2+) entry (SOCE) mediated by STIM1 and Orai1 is crucial for Ca(2+) signaling and homeostasis in most cell types. 2-Aminoethoxydiphenyl borate (2-APB) is a well-described SOCE inhibitor, but its mechanisms of action remain largely elusive. Here, we show that 2-APB does not affect the dimeric state of STIM1, but enhances the intramolecular coupling between the coiled-coil 1 (CC1) and STIM-Orai-activating region (SOAR) of STIM1, with subsequent reduction in the formation of STIM1 puncta in the absence of Orai1 overexpression...
October 10, 2016: Pflügers Archiv: European Journal of Physiology
Axel R Concepcion, Martin Vaeth, Larry E Wagner, Miriam Eckstein, Lee Hecht, Jun Yang, David Crottes, Maximilian Seidl, Hyosup P Shin, Carl Weidinger, Scott Cameron, Stuart E Turvey, Thomas Issekutz, Isabelle Meyts, Rodrigo S Lacruz, Mario Cuk, David I Yule, Stefan Feske
Eccrine sweat glands are essential for sweating and thermoregulation in humans. Loss-of-function mutations in the Ca2+ release-activated Ca2+ (CRAC) channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE), and patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures. Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development...
October 10, 2016: Journal of Clinical Investigation
Joo Hyun Nam, Dong-Ung Lee
BACKGROUND: Ultraviolet radiation exposure is the most important cause of extrinsic skin aging (photoaging), which causes skin wrinkling and hyperpigmentation. Although many factors are involved in the photoaging process, calcium release-activated calcium channel protein 1 (ORAI1) has been reported to be involved in UV-induced melanogenesis. OBJECTIVE: The aim of the present study was to find inhibitory effects of the extract of Foeniculum vulgare (fennel) fruits on ORAI1 ion channels and UV-induced melanogenesis in melanoma cells and to identify its active constituents...
September 28, 2016: Journal of Dermatological Science
Ching Man Chan, Jacqueline T M Aw, Sarah E Webb, Andrew L Miller
In zebrafish embryos, distinct Ca2+ transients are localized to the early cleavage furrows during the first few cell division cycles. These transients are generated mainly by release via IP3Rs in the endoplasmic reticulum, and they are necessary for furrow positioning, propagation, deepening and apposition. We previously showed, via the use of inhibitors, that store-operated Ca2+ entry (SOCE) also appears to be essential for maintaining the IP3R-mediated elevated levels of [Ca2+]i for the extended periods required for the completion of successful furrow deepening and daughter cell apposition in these large embryonic cells...
October 5, 2016: Zygote: the Biology of Gametes and Early Embryos
Susanne Smaardijk, Jialin Chen, Frank Wuytack, Peter Vangheluwe
Dysregulation of the Golgi/Secretory Pathway Ca(2+) transport ATPase SPCA2 is implicated in breast cancer. During lactation and in luminal breast cancer types, SPCA2 interacts with the plasma membrane Ca(2+) channel Orai1, promoting constitutive Ca(2+) influx, which is termed store independent Ca(2+) entry (SICE). The mechanism of SPCA2/Orai1 interaction depends on the N- and C-termini of SPCA2. These extensions may play a dual role in activating not only Orai1, but also Ca(2+) transport into the Golgi/secretory pathway, which we tested by investigating the impact of various SPCA2 N- and/or C-terminal truncations on SICE and Ca(2+) transport activity of SPCA2...
September 17, 2016: Tissue & Cell
Wei Rao, Cheng Peng, Lei Zhang, Ning Su, Kai Wang, Hao Hui, Shu-Hui Dai, Yue-Fan Yang, Peng Luo, Zhou Fei
Calcium disequilibrium is extensively involved in oxidative stress-induced neuronal injury. Although Homer1a is known to regulate several neuronal calcium pathways, its effects on, or its exact relationship with, oxidative stress-induced neuronal injury has not yet been fully elucidated. We found that Homer1a protected HT-22 cells from glutamate-induced oxidative stress injury by inhibiting final-phase intracellular calcium overload and mitochondrial oxidative stress. In these cells, stromal interactive molecule 1 (STIM1) puncta, but not the protein level, was significantly increased after glutamate treatment...
September 29, 2016: Scientific Reports
Lisha Qi, Wangzhao Song, Lingmei Li, Lu Cao, Yue Yu, Chunmin Song, Yalei Wang, Fei Zhang, Yang Li, Bin Zhang, Wenfeng Cao
Several fibroblast growth factor (FGF) isoforms act to stimulate epithelial-mesenchymal transition (EMT) during cancer progression. FGF4 and FGF7 are two ligands of FGF receptor 2 (FGFR2). Using two lung adenocarcinoma (ADC) cell lines, A549 and H1299, we showed that FGF4, but not FGF7, altered cell morphology, promoted EMT-associated protein expression, and enhanced cell proliferation, migration/invasion and colony initiation. In addition, FGF4 increased store-operated calcium entry (SOCE) and expression of the calcium signal-associated protein Orai1...
September 22, 2016: Oncotarget
Judith A Stolwijk, Xuexin Zhang, Maxime Gueguinou, Wei Zhang, Khalid Matrougui, Christian Renken, Mohamed Trebak
Endothelial barrier function is tightly regulated by plasma membrane receptors and is crucial for tissue fluid homeostasis; its dysfunction causes disease, including sepsis and inflammation. The ubiquitous activation of Ca2+ signaling upon phospholipase C (PLC)-coupled receptor ligation leads quite naturally to the assumption that Ca2+ signaling is required for receptor-regulated endothelial barrier function. This widespread hypothesis draws analogy from smooth muscle and proposes the requirement of G protein coupled receptor (GPCR)-generated Ca2+ signaling in activating the endothelial contractile apparatus and generating inter-endothelial gaps...
September 13, 2016: Journal of Biological Chemistry
Dalia Alansary, Barbara Schmidt, Kathrin Dörr, Ivan Bogeski, Heiko Rieger, Achim Kless, Barbara A Niemeyer
Store-operated Ca(2+) entry mediated by STIM1-gated Orai1 channels is essential to activate immune cells and its inhibition or gain-of-function can lead to immune dysfunction and other pathologies. Reactive oxygen species interacting with cysteine residues can alter protein function. Pretreatment of the Ca(2+) selective Orai1 with the oxidant H2O2 reduces ICRAC with C195, distant to the pore, being its major redox sensor. However, the mechanism of inhibition remained elusive. Here we combine experimental and theoretical approaches and show that oxidation of Orai1 leads to reduced subunit interaction, slows diffusion and that either oxidized C195 or its oxidomimetic mutation C195D located at the exit of transmembrane helix 3 virtually eliminates channel activation by intramolecular interaction with S239 of transmembrane helix 4, thereby locking the channel in a closed conformation...
2016: Scientific Reports
Zili Zhang, Jian Wang, Jianxing He, Xiansheng Zeng, Xindong Chen, Mingmei Xiong, Qipeng Zhou, Meihua Guo, Defu Li, Wenju Lu
OBJECTIVE: Store operated calcium channels (SOCCs) and Receptor-operated calcium channels (ROCCs) are important pathways participating in regulation of intracellular Ca(2 +) concentration in various cell types. The purpose of our study is to determine whether genetic variations in key components of SOCCs and ROCCs are associated with lung cancer risk. METHODS: We identified 236 tagSNPs in 9 key genes related to SOCCs and ROCCs (TRPC1, TRPC3, TRPC4, TRPC6, TRPC7, ORAI1, ORAI2, STIM1, and STIM2) and evaluated their association with lung cancer risk in a two-stage case-control study with a total of 2433 lung cancer cases and 2433 cancer-free controls using Illumina high throughput genotyping platform...
September 2016: Meta Gene
Shaqiu Zhang, Tamer Al-Maghout, Yuetao Zhou, Rosi Bissinger, Abeer Abousaab, Madhuri S Salker, Lisann Pelzl, Bradley S Cobb, Anchun Cheng, Yogesh Singh, Florian Lang
BACKGROUND/AIMS: Activation of T cell receptors (TCRs) in CD4+ T cells leads to a cascade of signalling reactions including increase of intracellular calcium (Ca2+) levels with subsequent Ca2+ dependent stimulation of gene expression, proliferation, cell motility and cytokine release. The increase of cytosolic Ca2+ results from intracellular Ca2+ release with subsequent activation of store-operated Ca2+ entry (SOCE). Previous studies suggested miRNAs are required for the development and functions of CD4+ T cells...
2016: Cellular Physiology and Biochemistry
Amit Jairaman, Chelsea H Maguire, Robert P Schleimer, Murali Prakriya
Aberrant immune responses to environmental allergens including insect allergens from house dust mites and cockroaches contribute to allergic inflammatory diseases such as asthma in susceptible individuals. Airway epithelial cells (AECs) play a critical role in this process by sensing the proteolytic activity of allergens via protease-activated receptors (PAR2) to initiate inflammatory and immune responses in the airway. Elevation of cytosolic Ca(2+) is an important signaling event in this process, yet the fundamental mechanism by which allergens induce Ca(2+) elevations in AECs remains poorly understood...
2016: Scientific Reports
Jessica Sabourin, Florent Allagnat
Normal plasma glucose level is ensured by the action of insulin, the major hypoglycemic hormone. Therefore, it is not surprising that insulin release from pancreatic β-cells of the Langerhans islets is controlled by an array of balanced mechanisms in which glucose plays the leading role. Glucose triggers insulin secretion through the well described pathway of ATP-driven closure of ATP-sensitive potassium channels (KATP), depolarization of the plasma membrane and opening of the voltage-dependent Ca2+ channels (VDCC)...
September 2, 2016: Journal of Molecular Endocrinology
Ellie M Carrell, Aundrea R Coppola, Helen J McBride, Robert T Dirksen
Orai1 is a transmembrane protein that forms homomeric, calcium-selective channels activated by stromal interaction molecule 1 (STIM1) after depletion of intracellular calcium stores. In adult skeletal muscle, depletion of sarcoplasmic reticulum calcium activates STIM1/Orai1-dependent store-operated calcium entry. Here, we used constitutive and inducible muscle-specific Orai1 knockout (KO) mice to determine the acute and long-term developmental effects of Orai1 ablation on muscle structure and function. Skeletal muscles from constitutive, muscle-specific Orai1 KO mice exhibited normal postnatal growth and fiber type differentiation...
September 1, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Susana Cubillos, Johannes Norgauer
Psoriasis is an inflammatory skin disease with or without joint involvement. In this disease, the thickened epidermis and impaired barrier are associated with altered calcium gradients. Calcium and vitamin D are known to play important roles in keratinocyte differentiation and bone metabolism. Intracellular calcium is regulated by calcium-sensing receptor (CASR), calcium release-activated calcium modulator (ORAI) and stromal interaction molecule (STIM). Other proteins modulated by vitamin D play important roles in calcium regulation e...
October 2016: International Journal of Molecular Medicine
Hyun Jong Kim, Joohan Woo, Yuran Nam, Joo Hyun Nam, Woo Kyung Kim
Pyrazole derivatives were originally suggested as selective blockers of the transient receptor potential cation 3 (TRPC3) and channel. In particular, pyr3 and 10 selectively inhibit TRPC3, whereas pyr2 (BTP2) and 6 inhibit ORAI1. However, their effects on background K(+) channel activity have not been elucidated. In this study, the effects of BTP2, pyr3, pyr6, and pyr10 were studied on cloned human TWIK-related K(+) channels (TREKs) and TWIK-related acid-sensitive K(+) channel 2 (TASK-2) channels, which modulate Ca(2+) signaling by controlling membrane potential, in HEK293T-overexpressing cells by using a whole-cell patch clamp technique...
August 26, 2016: European Journal of Pharmacology
Haidong Yao, Ruifeng Fan, Xia Zhao, Wenchao Zhao, Wei Liu, Jie Yang, Hamid Sattar, Jinxin Zhao, Ziwei Zhang, Shiwen Xu
Selenium (Se) deficiency induces Ca2+ leak and calcification in mammal skeletal muscles; however, the exact mechanism is still unclear. In the present study, both Se-deficient chicken muscle models and selenoprotein W (SelW) gene knockdown myoblast and embryo models were used to study the mechanism. The results showed that Se deficiency-induced typical muscular injuries accompanied with Ca2+ leak and oxidative stress (P < 0.05) injured the ultrastructure of the sarcoplasmic reticulum (SR) and mitochondria; decreased the levels of the Ca2+ channels, SERCA, SLC8A, CACNA1S, ORAI1, STIM1, TRPC1, and TRPC3 (P < 0...
August 20, 2016: Oncotarget
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