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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
Clark A Briggs, Shreaya Chakroborty, Grace E Stutzmann
The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function...
September 20, 2016: Biochemical and Biophysical Research Communications
Elena Popugaeva, Ekaterina Pchitskaya, Ilya Bezprozvanny
Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca(2+)) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca(2+) signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca(2+) leak function of presenilins. Excessive ER Ca(2+) release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2...
September 15, 2016: Biochemical and Biophysical Research Communications
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
Xuhua Mao, Jianfeng Zhang, Yue Han, Chao Luan, Yu Hu, Zhimin Hao, Min Chen
Antigen specific B cells undergo a process termed affinity maturation in the germinal centers of secondary lymphoid organs where B cells with high affinity receptors are selected to mature into antibody-producing cells or to the memory B cell pool. It is known that B cell antigen receptor (BCR) signaling plays pivotal role in this selection process. Calcium influx is an essential component of BCR signaling. The current report is to determine the effect of calcium influx on antibody affinity maturation. In our studies, mice deficient for both endoplasmic reticulum calciumsensor Stim1 and Stim2 was immunized with T-cell dependent and independent antigens...
August 27, 2016: Oncotarget
Kenrick An Fu Yap, Mahesh Shivarama Shetty, Gisela Garcia-Alvarez, Bo Lu, Durgadevi Alagappan, Masatsugu Oh-Hora, Sreedharan Sajikumar, Marc Fivaz
STIM2 is an integral membrane protein of the endoplasmic reticulum (ER) that regulates the activity of plasma membrane (PM) channels at ER-PM contact sites. Recent studies show that STIM2 promotes spine maturation and surface expression of the AMPA receptor (AMPAR) subunit GluA1, hinting at a probable role in synaptic plasticity. Here, we used a Stim2 cKO mouse to explore the function of STIM2 in Long-Term Potentiation (LTP) and Depression (LTD), two widely-studied models of synaptic plasticity implicated in information storage...
August 18, 2016: Neurobiology of Learning and Memory
Eduard Korkotian, Efrat Oni-Biton, Menahem Segal
The possible role of store operated calcium entry (SOCE) through the Orai1 channel in the formation and functions of dendritic spines was studied in cultured hippocampal neurons. In calcium store-depleted neurons a transient elevation of extracellular calcium concentration ([Ca(2+) ]o) caused a rise in [Ca(2+) ]i that was mediated by activation of the SOCE. The store depletion resulted in an increase in STIM2 (an endoplasmic calcium sensor) association with Orai1 in dendritic spines. The response to the rise in [Ca(2+) ]o was larger in spines endowed with a cluster of Orai1 molecules than in spines devoid of Orai1...
July 9, 2016: Journal of Physiology
Francesco Moccia, Estella Zuccolo, Valentina Poletto, Ilaria Turin, Germano Guerra, Paolo Pedrazzoli, Vittorio Rosti, Camillo Porta, Daniela Montagna
An increase in intracellular Ca2+ concentration plays a key role in the establishment of many cancer hallmarks, including aberrant proliferation, migration, invasion, resistance to apoptosis and angiogenesis. The dysregulation of Ca2+ entry is one of the most subtle mechanisms by which cancer cells overwhelm their normal counterparts and gain the adaptive advantages that result in tumour growth, vascularisation and dissemination throughout the organism. Both constitutive and agonist-induced Ca2+ influx may be mediated by store-dependent as well as store-independent Ca2+ entry routes...
June 7, 2016: Current Medicinal Chemistry
Martin Vaeth, Miriam Eckstein, Patrick J Shaw, Lina Kozhaya, Jun Yang, Friederike Berberich-Siebelt, Robert Clancy, Derya Unutmaz, Stefan Feske
T follicular helper (Tfh) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (Tfr) cells limit the GC reaction. Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Conditional deletion of Stim1 and Stim2 genes in T cells abolished SOCE and strongly reduced antibody-mediated immune responses following viral infection caused by impaired differentiation and function of Tfh cells...
June 21, 2016: Immunity
Xinghua Gao, Jingsheng Xia, Frances M Munoz, Melissa T Manners, Rong Pan, Olimpia Meucci, Yue Dai, Huijuan Hu
BACKGROUND: Our previous study demonstrated that a store-operated calcium channel (SOCC) inhibitor (YM-58483) has central analgesic effects. However, the cellular and molecular mechanisms of such effects remain to be determined. It is well-known that glial cells play important roles in central sensitization. SOC entry (SOCE) has been implicated in many cell types including cortical astrocytes. However, the role of the SOCC family in the function of astrocytes has not been determined. Here, we thoroughly investigated the expression and the functional significance of SOCCs in spinal astrocytes...
2016: Journal of Neuroinflammation
Dong Min Shin, Aran Son, Seonghee Park, Min Seuk Kim, Malini Ahuja, Shmuel Muallem
The Ca(2+) second messenger is initiated at ER/PM junctions and propagates into the cell interior to convey the receptor information. The signal is maintained by Ca(2+) influx across the plasma membrane through the Orai and TRPC channels. These Ca(2+) influx channels form complexes at ER/PM junctions with the ER Ca(2+) sensor STIM1, which activates the channels. The function of STIM1 is modulated by other STIM isoforms like STIM1L, STIM2 and STIM2.1/STIM2β and by SARAF, which mediates the Ca(2+)-dependent inhibition of Orai channels...
2016: Advances in Experimental Medicine and Biology
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
Tünde Molnár, Oleg Yarishkin, Anthony Iuso, Peter Barabas, Bryan Jones, Robert E Marc, Tam T T Phuong, David Križaj
UNLABELLED: The endoplasmic reticulum (ER) is at the epicenter of astrocyte Ca(2+) signaling. We sought to identify the molecular mechanism underlying store-operated calcium entry that replenishes ER stores in mouse Müller cells. Store depletion, induced through blockade of sequestration transporters in Ca(2+)-free saline, induced synergistic activation of canonical transient receptor potential 1 (TRPC1) and Orai channels. Store-operated TRPC1 channels were identified by their electrophysiological properties, pharmacological blockers, and ablation of the Trpc1 gene...
March 16, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Xiu-Li Kuang, Yimei Liu, Yuhua Chang, Jing Zhou, He Zhang, Yiping Li, Jia Qu, Shengzhou Wu
Dysfunction of the ubiquitin-proteasome system (UPS) and calcium homeostasis has been implicated in the neurodegeneration of Alzheimer's and Parkinson's diseases. The cytosolic calcium concentration is maintained by store-operated calcium entry (SOCE), which is repressed by Alzheimer's disease-associated mutants, such as mutant presenilins. We hypothesized that inhibition of UPS impacts SOCE. This study showed that pretreatment with sub-lethal levels of proteasome inhibitors, including MG-132 and clasto-lactacystin-β-lactone (LA), reduced SOCE after depletion of endoplasmic reticulum calcium in rat neurons...
April 2016: Cell Calcium
Kathrin Dörr, Tatiana Kilch, Sven Kappel, Dalia Alansary, Gertrud Schwär, Barbara A Niemeyer, Christine Peinelt
N-glycosylation of cell surface proteins affects protein function, stability, and interaction with other proteins. Orai channels, which mediate store-operated Ca(2+) entry (SOCE), are composed of N-glycosylated subunits. Upon activation by Ca(2+) sensor proteins (stromal interaction molecules STIM1 or STIM2) in the endoplasmic reticulum, Orai Ca(2+) channels in the plasma membrane mediate Ca(2+) influx. Lectins are carbohydrate-binding proteins, and Siglecs are a family of sialic acid-binding lectins with immunoglobulin-like repeats...
March 8, 2016: Science Signaling
Yoshihiro Baba
Alterations in the cytosolic concentration of calcium ions (Ca(2+)) are important signals for various physiological events. The engagement of B cell receptors (BCR) results in the transient release of Ca(2+) into cytosol from endoplasmic reticulum (ER) stores. In turn, this decrease in ER luminal Ca(2+) concentration triggers the opening of Ca(2+) channels in the plasma membrane, inducing a sustained influx of extracellular Ca(2+) into cells. These processes are referred to as store-operated Ca(2+) entry (SOCE), which is an essential pathway for continuous Ca(2+) signaling...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Barbara A Niemeyer
A wide variety of cellular function depends on the dynamics of intracellular Ca(2+) signals. Especially for relatively slow and lasting processes such as gene expression, cell proliferation, and often migration, cells rely on the store-operated Ca(2+) entry (SOCE) pathway, which is particularly prominent in immune cells. SOCE is initiated by the sensor proteins (STIM1, STIM2) located within the endoplasmic reticulum (ER) registering the Ca(2+) concentration within the ER, and upon its depletion, cluster and trap Orai (Orai1-3) proteins located in the plasma membrane (PM) into ER-PM junctions...
May 1, 2016: American Journal of Physiology. Cell Physiology
Shyh-Ing Jang, Hwei Ling Ong, Xibao Liu, Ilias Alevizos, Indu S Ambudkar
The signaling pathways involved in the generation and maintenance of exocrine gland acinar cells have not yet been established. Primary human salivary gland epithelial cells, derived from salivary gland biopsies, acquired an acinar-like phenotype when the [Ca(2+)] in the serum-free medium (keratinocyte growth medium, KGM) was increased from 0.05 mm (KGM-L) to 1.2 mm (KGM-H). Here we examined the mechanism underlying this Ca(2+)-dependent generation of the acinar cell phenotype. Compared with cells in KGM-L, those in KGM-H display enhancement of Orai1, STIM1, STIM2, and nuclear factor of activated T cells 1 (NFAT1) expression together with an increase in store-operated Ca(2+) entry (SOCE), SOCE-dependent nuclear translocation of pGFP-NFAT1, and NFAT-dependent but not NFκB-dependent gene expression...
April 15, 2016: Journal of Biological Chemistry
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
Rodrigo S Lacruz, Stefan Feske
Ca(2+) release-activated Ca(2+) (CRAC) channels mediate a specific form of Ca(2+) influx called store-operated Ca(2+) entry (SOCE) that contributes to the function of many cell types. CRAC channels are composed of ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes...
November 2015: Annals of the New York Academy of Sciences
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