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Martin Vaeth, Jun Yang, Megumi Yamashita, Isabelle Zee, Miriam Eckstein, Camille Knosp, Ulrike Kaufmann, Peter Karoly Jani, Rodrigo S Lacruz, Veit Flockerzi, Imre Kacskovics, Murali Prakriya, Stefan Feske
Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function...
March 15, 2017: Nature Communications
Jea Kwon, Heeyoung An, Moonsun Sa, Joungha Won, Jeong Im Shin, C Justin Lee
Astrocytes are non-excitable cells in the brain and their activity largely depends on the intracellular calcium (Ca(2+)) level. Therefore, maintaining the intracellular Ca(2+) homeostasis is critical for proper functioning of astrocytes. One of the key regulatory mechanisms of Ca(2+) homeostasis in astrocytes is the store-operated Ca(2+) entry (SOCE). This process is mediated by a combination of the Ca(2+)-store-depletion-sensor, Stim, and the store-operated Ca(2+)-channels, Orai and TrpC families. Despite the existence of all those families in astrocytes, previous studies have provided conflicting results on the molecular identification of astrocytic SOCE...
February 2017: Experimental Neurobiology
Jiwang Chen, Justin R Sysol, Sunit Singla, Shuangping Zhao, Aya Yamamura, Daniela Valdez-Jasso, Taimur Abbasi, Krystyna M Shioura, Sakshi Sahni, Vamsi Reddy, Arvind Sridhar, Hui Gao, Jaime Torres, Sara M Camp, Haiyang Tang, Shui Qing Ye, Suzy Comhair, Raed Dweik, Paul Hassoun, Jason X-J Yuan, Joe G N Garcia, Roberto F Machado
BACKGROUND: Pulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension...
April 18, 2017: Circulation
Daniel Leon-Aparicio, Jonathan Pacheco, Jesus Chavez-Reyes, Jose M Galindo, Jesus Valdes, Luis Vaca, Agustin Guerrero-Hernandez
We have studied in HeLa cells the molecular nature of the 2-APB induced ER Ca(2+) leak using synthetic Ca(2+) indicators that report changes in both the cytoplasmic ([Ca(2+)]i) and the luminal ER ([Ca(2+)]ER) Ca(2+) concentrations. We have tested the hypothesis that Orai channels participate in the 2-APB-induced ER Ca(2+) leak that was characterized in the companion paper. The expression of the dominant negative Orai1 E106A mutant, which has been reported to block the activity of all three types of Orai channels, inhibited the effect of 2-APB on the [Ca(2+)]ER but did not decrease the ER Ca(2+) leak after thapsigargin (TG)...
January 23, 2017: Cell Calcium
Sylvain Chauvet, Louis Jarvis, Mireille Chevallet, Niroj Shrestha, Klaus Groschner, Alexandre Bouron
In the murine brain, the first post-mitotic cortical neurons formed during embryogenesis express store-operated channels (SOCs) sensitive to Pyr3, initially proposed as a blocker of the transient receptor potential channel of C type 3 (TRPC3 channel). However, Pyr3 does not discriminate between Orai and TRPC3 channels, questioning the contribution of TRPC3 in SOCs. This study was undertaken to clarify the molecular identity and the pharmacological profile of native SOCs from E13 cortical neurons. The mRNA expression of STIM1-2 and Orai1-3 was assessed by quantitative reverse transcription polymerase chain reaction...
2016: Frontiers in Pharmacology
Hua Zhang, Suya Sun, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Klementina Fon Tacer, Ilya Bezprozvanny
Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca(2+) influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca(2+) channel complex in hippocampal mushroom spines...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
R Diez-Bello, I Jardin, G M Salido, J A Rosado
Store-operated Ca(2+) entry (SOCE) is a major mechanism for the regulation of intracellular Ca(2+) homeostasis and cellular function. Emerging evidence has revealed that altered expression and function of the molecular determinants of SOCE play a critical role in the development or maintenance of several cancer hallmarks, including enhanced proliferation and migration. Here we show that, in the acute myeloid leukemia cell line HL60, Orai2 is highly expressed at the transcript level, followed by the expression of Orai1...
November 16, 2016: Biochimica et Biophysica Acta
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
Hideto Yamamura, Yoshiaki Suzuki, Hisao Yamamura, Kiyofumi Asai, Yuji Imaizumi
The blood-brain barrier (BBB) is mainly composed of brain capillary endothelial cells (BCECs), astrocytes and pericytes. Brain ischemia causes hypoxic encephalopathy and damages BBB. However, it remains still unclear how hypoxia affects BCECs. In the present study, t-BBEC117 cells, an immortalized bovine brain endothelial cell line, were cultured under hypoxic conditions at 4-5% oxygen for 72 h. This hypoxic stress caused hyperpolarization of resting membrane potential. Patch-clamp recordings revealed a marked increase in Ba(2+)-sensitive inward rectifier K(+) current in t-BBEC117 cells after hypoxic culture...
August 5, 2016: Biochemical and Biophysical Research Communications
Rajesh Bhardwaj, Matthias A Hediger, Nicolas Demaurex
STIM1 and ORAI1 constitute the core machinery of the ubiquitous store-operated calcium entry pathway and loss of function in these proteins is associated with severe immune and muscular disorders. Other isoforms-STIM1L, STIM2, ORAI2 and ORAI3 exhibit varied expression levels in different cell types along with several other interaction partners and thereby play different roles to facilitate, regulate and fine-tune the calcium entry. STIM proteins convey the Ca(2+) store-depletion message to the PM and thereby participate in refilling of the ER by physically interacting with the Ca(2+)-selective ORAI channels at the PM...
August 2016: Cell Calcium
Meerim K Nurbaeva, Miriam Eckstein, Axel R Concepcion, Charles E Smith, Sonal Srikanth, Michael L Paine, Yousang Gwack, Michael J Hubbard, Stefan Feske, Rodrigo S Lacruz
Dental enamel formation requires large quantities of Ca(2+) yet the mechanisms mediating Ca(2+) dynamics in enamel cells are unclear. Store-operated Ca(2+) entry (SOCE) channels are important Ca(2+) influx mechanisms in many cells. SOCE involves release of Ca(2+) from intracellular pools followed by Ca(2+) entry. The best-characterized SOCE channels are the Ca(2+) release-activated Ca(2+) (CRAC) channels. As patients with mutations in the CRAC channel genes STIM1 and ORAI1 show abnormal enamel mineralization, we hypothesized that CRAC channels might be an important Ca(2+) uptake mechanism in enamel cells...
October 30, 2015: Scientific Reports
Robert Kraft
Stromal interaction molecules (STIM) 1 and 2 are sensors of the calcium concentration in the endoplasmic reticulum. Depletion of endoplasmic reticulum calcium stores activates STIM proteins which, in turn, bind and open calcium channels in the plasma membrane formed by the proteins ORAI1, ORAI2, and ORAI3. The resulting store-operated calcium entry (SOCE), mostly controlled by the principal components STIM1 and ORAI1, has been particularly characterized in immune cells. In the nervous system, all STIM and ORAI homologs are expressed...
2015: Channels
S Mark Duffy, Ian Ashmole, Dawn T Smallwood, Mark L Leyland, Peter Bradding
BACKGROUND: Orai/CRACM1 ion channels provide the major Ca(2+) influx pathway for FcεRI-dependent human lung mast cell (HLMC) mediator release. The Ca(2+)-activated K(+) channel KCa3.1 modulates Ca(2+) influx and the secretory response through hyperpolarisation of the plasma membrane. We hypothesised that there is a close functional and spatiotemporal interaction between these Ca(2+)- and K(+)-selective channels. RESULTS: Activation of FcεRI-dependent HLMC KCa3...
July 16, 2015: Cell Communication and Signaling: CCS
Francesco Moccia, Estella Zuccolo, Teresa Soda, Franco Tanzi, Germano Guerra, Lisa Mapelli, Francesco Lodola, Egidio D'Angelo
Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca(2+) release-activated Ca(2+) (CRAC) current (ICRAC) and store-operated Ca(2+) entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca(2+) stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca(2+) reservoir and engage specific Ca(2+)-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression...
2015: Frontiers in Cellular Neuroscience
Dalia Alansary, Ivan Bogeski, Barbara A Niemeyer
Orai1 subunits interacting with STIM1 molecules comprise the major components responsible for calcium release-activated calcium (CRAC) channels. The homologs Orai2 and Orai3 yield smaller store-operated currents when overexpressed and are mostly unable to substitute Orai1. Orai3 subunits are also essential components of store independent channel complexes and also tune inhibition of ICRAC by reactive oxygen species. Here we use patch-clamp, microscopy, Ca(2+)-imaging and biochemical experiments to investigate the interdependence of Orai2, Orai3 and Orai1...
July 2015: Biochimica et Biophysica Acta
Munenori Inayama, Yoshiaki Suzuki, Satoshi Yamada, Takashi Kurita, Hisao Yamamura, Susumu Ohya, Wayne R Giles, Yuji Imaizumi
Ca(2+) influx via store-operated Ca(2+) entry (SOCE) plays critical roles in many essential cellular functions. The Ca(2+) release-activated Ca(2+) (CRAC) channel complex, consisting of Orai and STIM, is one of the major components of store-operated Ca(2+) (SOC) channels. Our previous study demonstrated that histamine can cause sustained Ca(2+) entry through SOC channels in OUMS-27 cells derived from human chondrosarcoma. This SOCE was increased by low- and decreased by high-concentrations of 2-aminoethoxydiphenyl borate...
May 2015: Cell Calcium
Hiroaki Kito, Hisao Yamamura, Yoshiaki Suzuki, Hideto Yamamura, Susumu Ohya, Kiyofumi Asai, Yuji Imaizumi
Store-operated Ca(2+) entry (SOCE) via Orai1 and STIM1 complex is supposed to have obligatory roles in the regulation of cellular functions of vascular endothelial cells, while little is known about the contribution of Orai2. Quantitative PCR and Western blot analyses indicated the expression of Orai2 and STIM2, in addition to Orai1 and STIM1 in bovine brain capillary endothelial cell line, t-BBEC117. During the exponential growth of t-BBEC117, the knockdown of Orai1 and STIM1 significantly reduced the SOCE activity, whereas Orai2 and STIM2 siRNAs had no effect...
April 10, 2015: Biochemical and Biophysical Research Communications
Ruby A Fernandez, Jun Wan, Shanshan Song, Kimberly A Smith, Yali Gu, Mohammad Tauseef, Haiyang Tang, Ayako Makino, Dolly Mehta, Jason X-J Yuan
Pulmonary arterial hypertension (PAH) is a progressive disease that, if left untreated, eventually leads to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PAH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two major causes for elevated PVR in patients with PAH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent phenotype to a proliferative or synthetic phenotype...
April 15, 2015: American Journal of Physiology. Cell Physiology
Eunan Hendron, Xizhuo Wang, Yandong Zhou, Xiangyu Cai, Jun-ichi Goto, Katsuhiko Mikoshiba, Yoshihiro Baba, Tomohiro Kurosaki, Youjun Wang, Donald L Gill
The coupling of ER Ca(2+)-sensing STIM proteins and PM Orai Ca(2+) entry channels generates "store-operated" Ca(2+) signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2-APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200 nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L-type or TRPC channels or Ca(2+) pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2-mediated effects...
December 2014: Cell Calcium
Dae Keon Heo, Hye Min Lim, Joo Hyun Nam, Min Goo Lee, Joo Young Kim
Microglia are immune effector cells in the central nervous system that participate in tissue repair, inflammatory responses, and neuronal degeneration. The most important signaling factor in the differentiation of immune-active cells after stimulation is the sustained high calcium concentration in the cytosol, which is called store-operated calcium entry (SOCE). Recently, the molecular identity of the store-operated channel (SOC) has revealed that Orai1, Orai2, Orai3, Stim1, and Stim2 constitute the most of SOC...
January 2015: Cellular Signalling
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