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WILLIAMS, Richard T., Shehnaaz S. M. MANJI, Nigel J. PARKER, Manuela S. HANCOCK, Leonie van STEKELENBURG, Jean-Pierre EID, Paul V. SENIOR i in. "Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins". Biochemical Journal 357, nr 3 (25.07.2001): 673–85. http://dx.doi.org/10.1042/bj3570673.
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STIM1 (where STIM is stromal interaction molecule) is a candidate tumour suppressor gene that maps to human chromosome 11p15.5, a region implicated in a variety of cancers, particularly embryonal rhabdomyosarcoma. STIM1 codes for a transmembrane phosphoprotein whose structure is unrelated to that of any other known proteins. The precise pathway by which STIM1 regulates cell growth is not known. In the present study we screened gene databases for STIM1-related sequences, and have identified and characterized cDNA sequences representing a single gene in humans and other vertebrates, which we have called STIM2. We identified a single STIM homologue in Drosophila melanogaster (D-Stim) and Caenorhabditis elegans, but no homologues in yeast. STIM1, STIM2 and D-Stim have a conserved genomic organization, indicating that the vertebrate family of two STIM genes most probably arose from a single ancestral gene. The three STIM proteins each contain a single SAM (sterile α-motif) domain and an unpaired EF hand within the highly conserved extracellular region, and have coiled-coil domains that are conserved in structure and position within the cytoplasmic region. However, the STIM proteins diverge significantly within the C-terminal half of the cytoplasmic domain. Differential levels of phosphorylation appear to account for two molecular mass isoforms (105 and 115kDa) of STIM2. We demonstrate by mutation analysis and protein sequencing that human STIM2 initiates translation exclusively from a non-AUG start site in vivo. STIM2 is expressed ubiquitously in cell lines, and co-precipitates with STIM1 from cell lysates. This association into oligomers in vivo indicates a possible functional interaction between STIM1 and STIM2. The structural similarities between STIM1, STIM2 and D-STIM suggest conserved biological functions.
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Cully, Tanya R., Joshua N. Edwards, Oliver Friedrich, D. George Stephenson, Robyn M. Murphy i Bradley S. Launikonis. "Changes in plasma membrane Ca-ATPase and stromal interacting molecule 1 expression levels for Ca2+ signaling in dystrophic mdx mouse muscle". American Journal of Physiology-Cell Physiology 303, nr 5 (1.09.2012): C567—C576. http://dx.doi.org/10.1152/ajpcell.00144.2012.
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The majority of the skeletal muscle plasma membrane is internalized as part of the tubular (t-) system, forming a standing junction with the sarcoplasmic reticulum (SR) membrane throughout the muscle fiber. This arrangement facilitates not only a rapid and large release of Ca2+ from the SR for contraction upon excitation of the fiber, but has also direct implications for other interdependent cellular regulators of Ca2+. The t-system plasma membrane Ca-ATPase (PMCA) and store-operated Ca2+ entry (SOCE) can also be activated upon release of SR Ca2+. In muscle, the SR Ca2+ sensor responsible for rapidly activated SOCE appears to be the stromal interacting molecule 1L (STIM1L) isoform of STIM1 protein, which directly interacts with the Orai1 Ca2+ channel in the t-system. The common isoform of STIM1 is STIM1S, and it has been shown that STIM1 together with Orai1 in a complex with the partner protein of STIM (POST) reduces the activity of the PMCA. We have previously shown that Orai1 and STIM1 are upregulated in dystrophic mdx mouse muscle, and here we show that STIM1L and PMCA are also upregulated in mdx muscle. Moreover, we show that the ratios of STIM1L to STIM1S in wild-type (WT) and mdx muscle are not different. We also show a greater store-dependent Ca2+ influx in mdx compared with WT muscle for similar levels of SR Ca2+ release while normal activation and deactivation properties were maintained. Interestingly, the fiber-averaged ability of WT and mdx muscle to extrude Ca2+ via PMCA was found to be the same despite differences in PMCA densities. This suggests that there is a close relationship among PMCA, STIM1L, STIM1S, Orai1, and also POST expression in mdx muscle to maintain the same Ca2+ extrusion properties as in the WT muscle.
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Yoshikawa, Soichiro, Masatsugu Oh-hora, Ryota Hashimoto, Toshihisa Nagao, Louis Peters, Mayumi Egawa, Takuya Ohta i in. "Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3–stimulated murine basophils". Science Signaling 12, nr 576 (9.04.2019): eaav2060. http://dx.doi.org/10.1126/scisignal.aav2060.
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Basophils have nonredundant roles in various immune responses that require Ca2+influx. Here, we examined the role of two Ca2+sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)–containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca2+influx and transcription of theIl4gene that were elicited by each stimulus. Similarly, basophil-specific STIM1 expression was required for IgE-driven chronic allergic inflammation in vivo, whereas STIM2 was required for IL-4 production after combined IL-3 and IL-33 treatment in mice. These data indicate that STIM1 and STIM2 have differential roles in the production of IL-4, which are stimulus dependent. Furthermore, these results illustrate the vital role of STIM2 in basophils, which is often considered to be less important than STIM1.
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Skibinska-Kijek*, Anna, Marta Wisniewska, Joanna Gruszczynska-Biegala, Axel Methner i Jacek Kuznicki. "Immunolocalization of STIM1 in the mouse brain". Acta Neurobiologiae Experimentalis 69, nr 4 (31.12.2009): 413–28. http://dx.doi.org/10.55782/ane-2009-1753.
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Capacitative Calcium Entry (CCE) in neurons seems to depend, as in non-excitatory cells, on endoplasmic reticulum calcium sensors STIM1 or STIM2. We show localization of STIM1 in the mouse brain by immunohistochemistry with a specific antibody. STIM1 immunoreactivity has wide, but not uniform, distribution throughout the brain and is observed in neuropil and cells. The most intensive immunoreactivity is observed in Purkinje neurons of cerebellum. High/moderate levels of immunostaining are found in hippocampus, cerebral cortex and in cortico-medial amygdala, low in thalamus and basolateral amygdala. Co-staining with anti-NeuN antibody identify STIM1 immunopositive cells as neurons. Real time PCR demonstrates that Stim2 expression is 7-fold higher than that of Stim1 in hippocampus and 3-fold in other regions. Immunoblotting confirms that levels of STIMs vary in different brain regions. The data show that STIM1 and STIM2 are present in the brain, thus both can be involved in CCE, depending on neuronal type.
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Skopin, Anton Yu, Andrey D. Grigoryev, Lyubov N. Glushankova, Alexey V. Shalygin, Guanghui Wang, Viktor G. Kartzev i Elena V. Kaznacheyeva. "A Novel Modulator of STIM2-Dependent Store-Operated Ca2+ Channel Activity". Acta Naturae 13, nr 1 (15.03.2021): 140–46. http://dx.doi.org/10.32607/actanaturae.11269.
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Store-operated Ca2+ entry is one of the main pathways of calcium influx into non-excitable cells, which entails the initiation of many intracellular processes. The endoplasmic reticulum Ca2+ sensors STIM1 and STIM2 are the key components of store-operated Ca2+ entry in mammalian cells. Under physiological conditions, STIM proteins are responsible for store-operated Ca2+ entry activation. The STIM1 and STIM2 proteins differ in their potency for activating different store-operated channels. At the moment, there are no selective modulators of the STIM protein activity. We screened a library of small molecules and found the 4-MPTC compound, which selectively inhibited STIM2-dependent store-operated Ca2+ entry (IC50 = 1 M) and had almost no effect on the STIM1-dependent activation of store-operated channels.
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Chung, Steve, MengQi Zhang i Peter Stathopulos. "The 2β Splice Variation Alters the Structure and Function of the Stromal Interaction Molecule Coiled-Coil Domains". International Journal of Molecular Sciences 19, nr 11 (25.10.2018): 3316. http://dx.doi.org/10.3390/ijms19113316.
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Stromal interaction molecule (STIM)-1 and -2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels after oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil (CC) domains couple to PM Orai1 proteins and gate these Ca2+ release-activated Ca2+ (CRAC) channels, which facilitate store-operated Ca2+ entry (SOCE). Unlike STIM1 and STIM2, which are SOCE activators, the STIM2β splice variant contains an 8-residue insert located within the conserved CCs which inhibits SOCE. It remains unclear if the 2β insert further depotentiates weak STIM2 coupling to Orai1 or independently causes structural perturbations which prevent SOCE. Here, we use far-UV circular dichroism, light scattering, exposed hydrophobicity analysis, solution small angle X-ray scattering, and a chimeric STIM1/STIM2β functional assessment to provide insights into the molecular mechanism by which the 2β insert precludes SOCE activation. We find that the 2β insert reduces the overall α-helicity and enhances the exposed hydrophobicity of the STIM2 CC domains in the absence of a global conformational change. Remarkably, incorporation of the 2β insert into the STIM1 context not only affects the secondary structure and hydrophobicity as observed for STIM2, but also eliminates the more robust SOCE response mediated by STIM1. Collectively, our data show that the 2β insert directly precludes Orai1 channel activation by inducing structural perturbations in the STIM CC region.
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Kim, Soo J., Roland R. Roy, Hui Zhong, Hideki Suzuki, Lusine Ambartsumyan, Fadia Haddad, Kenneth M. Baldwin i V. Reggie Edgerton. "Electromechanical stimulation ameliorates inactivity-induced adaptations in the medial gastrocnemius of adult rats". Journal of Applied Physiology 103, nr 1 (lipiec 2007): 195–205. http://dx.doi.org/10.1152/japplphysiol.01427.2006.
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The efficacy of high-load, short-duration isometric contractions, delivered as one vs. two sessions per day, on blunting inactivity-induced adaptations in the medial gastrocnemius (MG) were compared. Adult rats were assigned to a control (Con) or spinal cord-isolated (SI) group where one limb was stimulated (SI-Stim) while the other served as a SI control (SI-C). One bout of stimulation (BION microstimulator) consisted of a 100-Hz, 1-s stimulus, delivered every 30 s for 5 min with a 5-min rest period. This bout was repeated six times consecutively (SI-Stim1) or with a 9-h rest interval after the third bout (SI-Stim2) for 30 consecutive days. MG weights (relative to body weight) were 63, 72, and 79% of Con in SI-C, SI-Stim1, and SI-Stim2, respectively. Mean fiber size was 56% smaller in SI-C than in Con, and it was 19 and 31% larger in SI-Stim1 and SI-Stim2, respectively, compared with SI-C. Maximum tetanic tension was 42, 60, and 73% of Con in SI-C, SI-Stim1, and SI-Stim2, respectively. Specific tension was 77% of Con in SI-C, and at Con levels in both SI-Stim groups. SI increased the percent IIb myosin heavy chain composition (from 49 to 77%) and IIb+ fibers (from 63 to 79%): these adaptations were prevented by both Stim paradigms. These results demonstrate that 1) brief periods of high-load isometric contractions are effective in reducing inactivity-induced atrophy, functional deficits, and phenotypic adaptations in a fast hindlimb extensor, and 2) the same amount of stimulation distributed in two compared with one session per day is more effective in ameliorating inactivity-related adaptations.
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Skobeleva, Ksenia, Alexey Shalygin, Elena Mikhaylova, Irina Guzhova, Maria Ryazantseva i Elena Kaznacheyeva. "The STIM1/2-Regulated Calcium Homeostasis Is Impaired in Hippocampal Neurons of the 5xFAD Mouse Model of Alzheimer’s Disease". International Journal of Molecular Sciences 23, nr 23 (26.11.2022): 14810. http://dx.doi.org/10.3390/ijms232314810.
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Alzheimer’s disease (AD) is the most common cause of age-related dementia. Neuronal calcium homeostasis impairment may contribute to AD. Here we demonstrated that voltage-gated calcium (VGC) entry and store-operated calcium (SOC) entry regulated by calcium sensors of intracellular calcium stores STIM proteins are affected in hippocampal neurons of the 5xFAD transgenic mouse model. We observed excessive SOC entry in 5xFAD mouse neurons, mediated by STIM1 and STIM2 proteins with increased STIM1 contribution. There were no significant changes in cytoplasmic calcium level, endoplasmic reticulum (ER) bulk calcium levels, or expression levels of STIM1 or STIM2 proteins. The potent inhibitor BTP-2 and the FDA-approved drug leflunomide reduced SOC entry in 5xFAD neurons. In turn, excessive voltage-gated calcium entry was sensitive to the inhibitor of L-type calcium channels nifedipine but not to the T-type channels inhibitor ML218. Interestingly, the depolarization-induced calcium entry mediated by VGC channels in 5xFAD neurons was dependent on STIM2 but not STIM1 protein in cells with replete Ca2+ stores. The result gives new evidence on the VGC channel modulation by STIM2. Overall, the data demonstrate the changes in calcium signaling of hippocampal neurons of the AD mouse model, which precede amyloid plaque accumulation or other signs of pathology manifestation.
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Garcia-Alvarez, Gisela, Bo Lu, Kenrick An Fu Yap, Loo Chin Wong, Jervis Vermal Thevathasan, Lynette Lim, Fang Ji i in. "STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs". Molecular Biology of the Cell 26, nr 6 (15.03.2015): 1141–59. http://dx.doi.org/10.1091/mbc.e14-07-1222.
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STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum (ER) and regulate store-operated Ca2+ entry (SOCE). The function of STIMs in the brain is only beginning to be explored, and the relevance of SOCE in nerve cells is being debated. Here we identify STIM2 as a central organizer of excitatory synapses. STIM2, but not its paralogue STIM1, influences the formation of dendritic spines and shapes basal synaptic transmission in excitatory neurons. We further demonstrate that STIM2 is essential for cAMP/PKA-dependent phosphorylation of the AMPA receptor (AMPAR) subunit GluA1. cAMP triggers rapid migration of STIM2 to ER–plasma membrane (PM) contact sites, enhances recruitment of GluA1 to these ER-PM junctions, and promotes localization of STIM2 in dendritic spines. Both biochemical and imaging data suggest that STIM2 regulates GluA1 phosphorylation by coupling PKA to the AMPAR in a SOCE-independent manner. Consistent with a central role of STIM2 in regulating AMPAR phosphorylation, STIM2 promotes cAMP-dependent surface delivery of GluA1 through combined effects on exocytosis and endocytosis. Collectively our results point to a unique mechanism of synaptic plasticity driven by dynamic assembly of a STIM2 signaling complex at ER-PM contact sites.
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Walsh, Ciara M., Michael Chvanov, Lee P. Haynes, Ole H. Petersen, Alexei V. Tepikin i Robert D. Burgoyne. "Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry". Biochemical Journal 425, nr 1 (14.12.2009): 159–68. http://dx.doi.org/10.1042/bj20090884.
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Ca2+ entry through store-operated Ca2+ channels involves the interaction at ER–PM (endoplasmic reticulum–plasma membrane) junctions of STIM (stromal interaction molecule) and Orai. STIM proteins are sensors of the luminal ER Ca2+ concentration and, following depletion of ER Ca2+, they oligomerize and translocate to ER–PM junctions where they form STIM puncta. Direct binding to Orai proteins activates their Ca2+ channel function. It has been suggested that an additional interaction of the C-terminal polybasic domain of STIM1 with PM phosphoinositides could contribute to STIM1 puncta formation prior to binding to Orai. In the present study, we investigated the role of phosphoinositides in the formation of STIM1 puncta and SOCE (store-operated Ca2+ entry) in response to store depletion. Treatment of HeLa cells with inhibitors of PI3K (phosphatidylinositol 3-kinase) and PI4K (phosphatidylinositol 4-kinase) (wortmannin and LY294002) partially inhibited formation of STIM1 puncta. Additional rapid depletion of PtdIns(4,5)P2 resulted in more substantial inhibition of the translocation of STIM1–EYFP (enhanced yellow fluorescent protein) into puncta. The inhibition was extensive at a concentration of LY294002 (50 μM) that should primarily inhibit PI3K, consistent with a major role for PtdIns(4,5)P2 and PtdIns(3,4,5)P3 in puncta formation. Depletion of phosphoinositides also inhibited SOCE based on measurement of the rise in intracellular Ca2+ concentration after store depletion. Overexpression of Orai1 resulted in a recovery of translocation of STMI1 into puncta following phosphoinositide depletion and, under these conditions, SOCE was increased to above control levels. These observations support the idea that phosphoinositides are not essential but contribute to STIM1 accumulation at ER–PM junctions with a second translocation mechanism involving direct STIM1–Orai interactions.
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Diercks, Björn-Philipp, René Werner, Paula Weidemüller, Frederik Czarniak, Lola Hernandez, Cari Lehmann, Annette Rosche i in. "ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+microdomains upon T cell activation". Science Signaling 11, nr 561 (18.12.2018): eaat0358. http://dx.doi.org/10.1126/scisignal.aat0358.
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The earliest intracellular signals that occur after T cell activation are local, subsecond Ca2+microdomains. Here, we identified a Ca2+entry component involved in Ca2+microdomain formation in both unstimulated and stimulated T cells. In unstimulated T cells, spontaneously generated small Ca2+microdomains required ORAI1, STIM1, and STIM2. Super-resolution microscopy of unstimulated T cells identified a circular subplasmalemmal region with a diameter of about 300 nm with preformed patches of colocalized ORAI1, ryanodine receptors (RYRs), and STIM1. Preformed complexes of STIM1 and ORAI1 in unstimulated cells were confirmed by coimmunoprecipitation and Förster resonance energy transfer studies. Furthermore, within the first second after T cell receptor (TCR) stimulation, the number of Ca2+microdomains increased in the subplasmalemmal space, an effect that required ORAI1, STIM2, RYR1, and the Ca2+mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate). These results indicate that preformed clusters of STIM and ORAI1 enable local Ca2+entry events in unstimulated cells. Upon TCR activation, NAADP-evoked Ca2+release through RYR1, in coordination with Ca2+entry through ORAI1 and STIM, rapidly increases the number of Ca2+microdomains, thereby initiating spread of Ca2+signals deeper into the cytoplasm to promote full T cell activation.
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Rao, Jaladanki N., Navneeta Rathor, Ran Zhuang, Tongtong Zou, Lan Liu, Lan Xiao, Douglas J. Turner i Jian-Ying Wang. "Polyamines regulate intestinal epithelial restitution through TRPC1-mediated Ca2+ signaling by differentially modulating STIM1 and STIM2". American Journal of Physiology-Cell Physiology 303, nr 3 (1.08.2012): C308—C317. http://dx.doi.org/10.1152/ajpcell.00120.2012.
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Early epithelial restitution occurs as a consequence of intestinal epithelial cell (IEC) migration after wounding, and its defective regulation is implicated in various critical pathological conditions. Polyamines stimulate intestinal epithelial restitution, but their exact mechanism remains unclear. Canonical transient receptor potential-1 (TRPC1)-mediated Ca2+ signaling is crucial for stimulation of IEC migration after wounding, and induced translocation of stromal interaction molecule 1 (STIM1) to the plasma membrane activates TRPC1-mediated Ca2+ influx and thus enhanced restitution. Here, we show that polyamines regulate intestinal epithelial restitution through TRPC1-mediated Ca2+ signaling by altering the ratio of STIM1 to STIM2. Increasing cellular polyamines by ectopic overexpression of the ornithine decarboxylase (ODC) gene stimulated STIM1 but inhibited STIM2 expression, whereas depletion of cellular polyamines by inhibiting ODC activity decreased STIM1 but increased STIM2 levels. Induced STIM1/TRPC1 association by increasing polyamines enhanced Ca2+ influx and stimulated epithelial restitution, while decreased formation of the STIM1/TRPC1 complex by polyamine depletion decreased Ca2+ influx and repressed cell migration. Induced STIM1/STIM2 heteromers by polyamine depletion or STIM2 overexpression suppressed STIM1 membrane translocation and inhibited Ca2+ influx and epithelial restitution. These results indicate that polyamines differentially modulate cellular STIM1 and STIM2 levels in IECs, in turn controlling TRPC1-mediated Ca2+ signaling and influencing cell migration after wounding.
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Gruszczynska-Biegala, Joanna, Klaudia Strucinska, Filip Maciag, Lukasz Majewski, Maria Sladowska i Jacek Kuznicki. "STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons". Cells 9, nr 1 (9.01.2020): 160. http://dx.doi.org/10.3390/cells9010160.
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Neuronal Store-Operated Ca2+ Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca2+ stores and is critical for Ca2+-dependent neuronal processes. SOCE sensors, STIM1 and STIM2, can activate Orai, TRP channels and AMPA receptors, and inhibit voltage-gated channels in the plasma membrane. However, the link between STIM, SOCE, and NMDA receptors, another key cellular entry point for Ca2+ contributing to synaptic plasticity and excitotoxicity, remains unclear. Using Ca2+ imaging, we demonstrated that thapsigargin-induced nSOCE was inhibited in rat cortical neurons following NMDAR inhibitors. Blocking nSOCE by its inhibitor SKF96365 enhanced NMDA-driven [Ca2+]i. Modulating STIM protein level through overexpression or shRNA inhibited or activated NMDA-evoked [Ca2+]i, respectively. Using proximity ligation assays, immunofluorescence, and co-immunoprecipitation methods, we discovered that thapsigargin-dependent effects required interactions between STIMs and the NMDAR2 subunits. Since STIMs modulate NMDAR-mediated Ca2+ levels, we propose targeting this mechanism as a novel therapeutic strategy against neuropathological conditions that feature NMDA-induced Ca2+ overload as a diagnostic criterion.
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Son, Ga-Yeon, Krishna Prasad Subedi, Hwei Ling Ong, Lucile Noyer, Hassan Saadi, Changyu Zheng, Rajesh Bhardwaj, Stefan Feske i Indu Suresh Ambudkar. "STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and confers coupling of Ca2+entry with NFAT1 activation". Proceedings of the National Academy of Sciences 117, nr 28 (29.06.2020): 16638–48. http://dx.doi.org/10.1073/pnas.1915386117.
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The Orai1 channel is regulated by stromal interaction molecules STIM1 and STIM2 within endoplasmic reticulum (ER)-plasma membrane (PM) contact sites. Ca2+signals generated by Orai1 activate Ca2+-dependent gene expression. When compared with STIM1, STIM2 is a weak activator of Orai1, but it has been suggested to have a unique role in nuclear factor of activated T cells 1 (NFAT1) activation triggered by Orai1-mediated Ca2+entry. In this study, we examined the contribution of STIM2 in NFAT1 activation. We report that STIM2 recruitment of Orai1/STIM1 to ER-PM junctions in response to depletion of ER-Ca2+promotes assembly of the channel with AKAP79 to form a signaling complex that couples Orai1 channel function to the activation of NFAT1. Knockdown of STIM2 expression had relatively little effect on Orai1/STIM1 clustering or local and global [Ca2+]iincreases but significantly attenuated NFAT1 activation and assembly of Orai1 with AKAP79. STIM1ΔK, which lacks the PIP2-binding polybasic domain, was recruited to ER-PM junctions following ER-Ca2+depletion by binding to Orai1 and caused local and global [Ca2+]iincreases comparable to those induced by STIM1 activation of Orai1. However, in contrast to STIM1, STIM1ΔK induced less NFAT1 activation and attenuated the association of Orai1 with STIM2 and AKAP79. Orai1-AKAP79 interaction and NFAT1 activation were recovered by coexpressing STIM2 with STIM1ΔK. Replacing the PIP2-binding domain of STIM1 with that of STIM2 eliminated the requirement of STIM2 for NFAT1 activation. Together, these data demonstrate an important role for STIM2 in coupling Orai1-mediated Ca2+influx to NFAT1 activation.
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Fresquez, Adriana M., i Carl White. "Extracellular cysteines C226 and C232 mediate hydrogen sulfide-dependent inhibition of Orai3-mediated store-operated calcium entry". American Journal of Physiology-Cell Physiology 322, nr 1 (1.01.2022): C38—C48. http://dx.doi.org/10.1152/ajpcell.00490.2019.
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The gaseous signaling molecule hydrogen sulfide (H2S) physiologically regulates store-operated Ca2+ entry (SOCE). The SOCE machinery consists of the plasma membrane-localized Orai channels (Orai1-3) and endoplasmic reticulum-localized stromal interaction molecule (STIM)1 and STIM2 proteins. H2S inhibits Orai3- but not Orai1- or Orai2-mediated SOCE. The current objective was to define the mechanism by which H2S selectively modifies Orai3. We measured SOCE and STIM1/Orai3 dynamics and interactions in HEK293 cells exogenously expressing fluorescently tagged human STIM1 and Orai3 in the presence and absence of the H2S donor GYY4137. Two cysteines (C226 and C232) are present in Orai3 that are absent in the Orai1 and Orai2. When we mutated either of these cysteines to serine, alone or in combination, SOCE inhibition by H2S was abolished. We also established that inhibition was dependent on an interaction with STIM1. To further define the effects of H2S on STIM1/Orai3 interaction, we performed a series of fluorescence recovery after photobleaching (FRAP), colocalization, and fluorescence resonance energy transfer (FRET) experiments. Treatment with H2S did not affect the mobility of Orai3 in the membrane, nor did it influence STIM1/Orai3 puncta formation or STIM1-Orai3 protein-protein interactions. These data support a model in which H2S modification of Orai3 at cysteines 226 and 232 limits SOCE evoked upon store depletion and STIM1 engagement, by a mechanism independent of the interaction between Orai3 and STIM1.
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Berna-Erro, Alejandro, Jose Sanchez-Collado, Joel Nieto-Felipe, Alvaro Macias-Diaz, Pedro C. Redondo, Tarik Smani, Jose J. Lopez, Isaac Jardin i Juan A. Rosado. "The Ca2+ Sensor STIM in Human Diseases". Biomolecules 13, nr 9 (22.08.2023): 1284. http://dx.doi.org/10.3390/biom13091284.
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The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca2+ sensors in the endoplasmic reticulum (ER) and, upon Ca2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca2+ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.
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Nelson, Heather A., i Michael W. Roe. "Molecular physiology and pathophysiology of stromal interaction molecules". Experimental Biology and Medicine 243, nr 5 (24.01.2018): 451–72. http://dx.doi.org/10.1177/1535370218754524.
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Ca2+ release from the endoplasmic reticulum is an important component of Ca2+ signal transduction that controls numerous physiological processes in eukaryotic cells. Release of Ca2+ from the endoplasmic reticulum is coupled to the activation of store-operated Ca2+ entry into cells. Store-operated Ca2+ entry provides Ca2+ for replenishing depleted endoplasmic reticulum Ca2+ stores and a Ca2+ signal that regulates Ca2+-dependent intracellular biochemical events. Central to connecting discharge of endoplasmic reticulum Ca2+ stores following G protein-coupled receptor activation with the induction of store-operated Ca2+ entry are stromal interaction molecules (STIM1 and STIM2). These highly homologous endoplasmic reticulum transmembrane proteins function as sensors of the Ca2+ concentration within the endoplasmic reticulum lumen and activators of Ca2+ release-activated Ca2+ channels. Emerging evidence indicates that in addition to their role in Ca2+ release-activated Ca2+ channel gating and store-operated Ca2+ entry, STIM1 and STIM2 regulate other cellular signaling events. Recent studies have shown that disruption of STIM expression and function is associated with the pathogenesis of several diseases including autoimmune disorders, cancer, cardiovascular disease, and myopathies. Here, we provide an overview of the latest developments in the molecular physiology and pathophysiology of STIM1 and STIM2. Impact statement Intracellular Ca2+ signaling is a fundamentally important regulator of cell physiology. Recent studies have revealed that Ca2+-binding stromal interaction molecules (Stim1 and Stim2) expressed in the membrane of the endoplasmic reticulum (ER) are essential components of eukaryote Ca2+ signal transduction that control the activity of ion channels and other signaling effectors present in the plasma membrane. This review summarizes the most recent information on the molecular physiology and pathophysiology of stromal interaction molecules. We anticipate that the work presented in our review will provide new insights into molecular interactions that participate in interorganelle signaling crosstalk, cell function, and the pathogenesis of human diseases.
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Vashisht, Ayushi, Mohamed Trebak i Rajender K. Motiani. "STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis". American Journal of Physiology-Cell Physiology 309, nr 7 (1.10.2015): C457—C469. http://dx.doi.org/10.1152/ajpcell.00064.2015.
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Calcium (Ca2+) regulates a plethora of cellular functions including hallmarks of cancer development such as cell cycle progression and cellular migration. Receptor-regulated calcium rise in nonexcitable cells occurs through store-dependent as well as store-independent Ca2+ entry pathways. Stromal interaction molecules (STIM) and Orai proteins have been identified as critical constituents of both these Ca2+ influx pathways. STIMs and Orais have emerged as targets for cancer therapeutics as their altered expression and function have been shown to contribute to tumorigenesis. Recent data demonstrate that they play a vital role in development and metastasis of a variety of tumor types including breast, prostate, cervical, colorectal, brain, and skin tumors. In this review, we will retrospect the data supporting a key role for STIM1, STIM2, Orai1, and Orai3 proteins in tumorigenesis and discuss the potential of targeting these proteins for cancer therapy.
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Graham, Sarah J. L., Marie A. Dziadek i Lorna S. Johnstone. "A Cytosolic STIM2 Preprotein Created by Signal Peptide Inefficiency Activates ORAI1 in a Store-independent Manner". Journal of Biological Chemistry 286, nr 18 (7.03.2011): 16174–85. http://dx.doi.org/10.1074/jbc.m110.206946.
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Calcium (Ca2+) influx through the plasma membrane store-operated Ca2+ channel ORAI1 is controlled by Ca2+ sensors of the stromal interaction molecule (STIM) family. STIM1 responds to endoplasmic reticulum (ER) Ca2+ store depletion by redistributing and activating ORAI1 from regions of the ER juxtaposed to the plasma membrane. Unlike STIM1, STIM2 can regulate ORAI1 in a store-dependent and store-independent manner, but the mechanism by which this is achieved is unknown. Here we find that STIM2 is translated from a highly conserved methionine residue and is directed to the ER by an incredibly long 101-amino acid signal peptide. We find that although the majority of the total STIM2 population resides on the ER membrane, a second population escapes ER targeting to accumulate as a full-length preprotein in the cytosol, signal peptide intact. Unlike STIM2, preSTIM2 localizes to the inner leaflet of the plasma membrane where it interacts with ORAI1 to regulate basal Ca2+ concentration and Ca2+-dependent gene transcription in a store-independent manner. Furthermore, a third protein comprising a fragment of the STIM2 signal peptide is released from the ER membrane into the cytosol where it regulates gene transcription in a Ca2+-independent manner. This study establishes a new model for STIM2-mediated regulation of ORAI1 in which two distinct proteins, STIM2 and preSTIM2, control store-dependent and store-independent modes of ORAI1 activation.
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Lu, Wenju, Jian Wang, Gongyong Peng, Larissa A. Shimoda i J. T. Sylvester. "Knockdown of stromal interaction molecule 1 attenuates store-operated Ca2+ entry and Ca2+ responses to acute hypoxia in pulmonary arterial smooth muscle". American Journal of Physiology-Lung Cellular and Molecular Physiology 297, nr 1 (lipiec 2009): L17—L25. http://dx.doi.org/10.1152/ajplung.00063.2009.
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Stromal interaction molecule 1 (STIM1) is a recently discovered membrane-spanning protein thought to sense lumenal Ca2+ in sarco(endo)plasmic reticulum (SR/ER) and transduce activation of Ca2+-permeable store-operated channels (SOC) in plasmalemma in response to SR/ER Ca2+ depletion. To evaluate the role of STIM1 and a closely related protein, STIM2, in Ca2+ signaling of rat distal pulmonary arterial smooth muscle cells (PASMC) during hypoxia, we used fluorescent microscopy and the Ca2+-sensitive dye, fura 2, to measure basal intracellular Ca2+ concentration ([Ca2+]i), store-operated Ca2+ entry (SOCE), and increases in [Ca2+]i caused by acute hypoxia (4% O2) or depolarization (60 mmol/l KCl) in cells treated with small interfering RNA targeted to STIM1 (siSTIM1) or STIM2 (siSTIM2). As determined by real-time quantitative PCR analysis (qPCR), STIM1 mRNA was 200-fold more abundant than STIM2 in untreated control PASMC. siSTIM1 and siSTIM2 caused specific and significant knockdown of both mRNA measured by qPCR and protein measured by Western blotting. siSTIM1 markedly inhibited SOCE and abolished the sustained [Ca2+]i response to hypoxia but did not alter the initial transient [Ca2+]i response to hypoxia, the [Ca2+]i response to depolarization, or basal [Ca2+]i. The only effect of siSTIM2 was a smaller inhibition of SOCE. We conclude that STIM1 was quantitatively more important than STIM2 in activation of SOC in rat distal PASMC and that the increase in [Ca2+]i induced by acute hypoxia in these cells required SR Ca2+ release and STIM1-dependent activation of SOC.
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Maus, Mate, Amit Jairaman, Peter B. Stathopulos, Martin Muik, Marc Fahrner, Carl Weidinger, Melina Benson i in. "Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation". Proceedings of the National Academy of Sciences 112, nr 19 (27.04.2015): 6206–11. http://dx.doi.org/10.1073/pnas.1418852112.
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Store-operated Ca2+ entry (SOCE) is a universal Ca2+ influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca2+ stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca2+ channel ORAI1 and the ER Ca2+ sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER–PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1–ORAI1 interactions. Thus, despite its constitutive localization at ER–PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra- and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1–ORAI1 binding required for ORAI1 activation.
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Thiel, Markus, Reinhold Penner i Annette Lis. "STIM2 drives calcium oscillations through store-operated calcium entry caused by mild store depletion (P1160)". Journal of Immunology 190, nr 1_Supplement (1.05.2013): 190.5. http://dx.doi.org/10.4049/jimmunol.190.supp.190.5.
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Abstract The main source of calcium in T cells is through a mechanism known as store-operated calcium entry (SOCE). STIM1 and STIM2 serve as ER calcium sensors that, upon store depletion, activate calcium release-activated calcium (CRAC) channels (Orai1-3,CRACM1-3) in the plasma membrane. In the absence of sustained calcium influx through CRAC channels, numerous lymphocyte functions are severely compromised, as demonstrated in patients suffering from SCID. Agonist-induced calcium oscillations in many cell types are triggered by calcium release from intracellular stores and driven by SOCE. However, their relative roles in agonist-mediated calcium oscillations remain ambiguous. We here report that while both STIM1 and STIM2 contribute to store-refilling during calcium oscillations in T cells, RBL and HEK cells, they do so dependent on the level of store depletion. Molecular silencing of STIM2 by siRNA or inhibition by G418 selectively suppresses SOCE and agonist-mediated calcium oscillations at low levels of store depletion, without interfering with STIM1-mediated signals induced by full store depletion. Thus, STIM2 is preferentially activated by low-level physiological agonist concentrations that cause mild reductions in ER calcium levels. We conclude that with increasing agonist concentrations, SOCE is mediated initially by endogenous STIM2 and incrementally by STIM1, enabling differential modulation of calcium entry over a range of stimulus intensities and levels of store depletion.
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Liu, Xiaoling, Tianyuan Zheng, Yan Jiang, Lei Wang, Yuchen Zhang, Qiyu Liang i Yuejie Chen. "Molecular Mechanism Analysis of STIM1 Thermal Sensation". Cells 12, nr 22 (12.11.2023): 2613. http://dx.doi.org/10.3390/cells12222613.
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STIM1 has been identified as a new warm sensor, but the exact molecular mechanism remains unclear. In this study, a variety of mutants of STIM1, Orai1 and Orai3 were generated. The single–cell calcium imaging and confocal analysis were used to evaluate the thermal sensitivity of the resulting STIM mutants and the interaction between STIM1 and Orai mutants in response to temperature. Our results suggested that the CC1–SOAR of STIM1 was a direct activation domain of temperature, leading to subsequent STIM1 activation, and the transmembrane (TM) region and K domain but not EF–SAM were needed for this process. Furthermore, both the TM and SOAR domains exhibited similarities and differences between STIM1–mediated thermal sensation and store–operated calcium entry (SOCE), and the key sites of Orai1 showed similar roles in these two responses. Additionally, the TM23 (comprising TM2, loop2, and TM3) region of Orai1 was identified as the key domain determining the STIM1/Orai1 thermal response pattern, while the temperature reactive mode of STIM1/Orai3 seemed to result from a combined effect of Orai3. These findings provide important support for the specific molecular mechanism of STIM1–induced thermal response, as well as the interaction mechanism of STIM1 with Orai1 and Orai3 after being activated by temperature.
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Rana, Anshul, Michelle Yen, Amir Masoud Sadaghiani, Seth Malmersjö, Chan Young Park, Ricardo E. Dolmetsch i Richard S. Lewis. "Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels". Journal of Cell Biology 209, nr 5 (1.06.2015): 653–70. http://dx.doi.org/10.1083/jcb.201412060.
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Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca2+ stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca2+-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2β, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2β does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2β mutants and Orai1-STIM2β chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca2+ signals.
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Wang, Yanxia, Sarika Chaudhari, Yuezhong Ren i Rong Ma. "Impairment of hepatic nuclear factor-4α binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells". American Journal of Physiology-Renal Physiology 308, nr 10 (15.05.2015): F1135—F1145. http://dx.doi.org/10.1152/ajprenal.00563.2014.
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The present study was carried out to investigate if hepatic nuclear factor (HNF)4α contributed to the high glucose-induced increase in stromal interacting molecule (STIM)1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence experiments showed HNF4α expression in MCs. Knockdown of HNF4α using a small interfering RNA approach significantly increased mRNA expression levels of both STIM1 and Orai1 and protein expression levels of STIM1 in cultured human MCs. Consistently, overexpression of HNF4α reduced expressed STIM1 protein expression in human embryonic kidney-293 cells. Furthermore, high glucose treatment did not significantly change the abundance of HNF4α protein in MCs but significantly attenuated HNF4α binding activity to the Stim1 promoter. Moreover, knockdown of HNF4α significantly augmented store-operated Ca2+ entry, which is known to be gated by STIM1 and has recently been found to be antifibrotic in MCs. In agreement with those results, knockdown of HNF4α significantly attenuated the fibrotic response of high glucose. These results suggest that HNF4α negatively regulates STIM1 transcription in MCs. High glucose increases STIM1 expression levels by impairing HNF4α binding activity to the Stim1 promoter, which subsequently releases Stim1 transcription from HNF4α repression. Since the STIM1-gated store-operated Ca2+ entry pathway in MCs has an antifibrotic effect, inhibition of HNF4α in MCs might be a potential therapeutic option for diabetic kidney disease.
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Clemens, Regina A., Joshua Chong, Derayvia Grimes, Yongmei Hu i Clifford A. Lowell. "STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production". Blood 130, nr 13 (28.09.2017): 1565–77. http://dx.doi.org/10.1182/blood-2016-11-751230.
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Key Points STIM1 and STIM2 cooperatively regulate neutrophil SOCE. The interaction of oxidative stress and calcium signaling pathways imparts a specific role for STIM2 in neutrophil cytokine synthesis.
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Roos, Jack, Paul J. DiGregorio, Andriy V. Yeromin, Kari Ohlsen, Maria Lioudyno, Shenyuan Zhang, Olga Safrina i in. "STIM1, an essential and conserved component of store-operated Ca2+ channel function". Journal of Cell Biology 169, nr 3 (2.05.2005): 435–45. http://dx.doi.org/10.1083/jcb.200502019.
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Store-operated Ca2+ (SOC) channels regulate many cellular processes, but the underlying molecular components are not well defined. Using an RNA interference (RNAi)-based screen to identify genes that alter thapsigargin (TG)-dependent Ca2+ entry, we discovered a required and conserved role of Stim in SOC influx. RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. Patch-clamp recording revealed nearly complete suppression of the Drosophila Ca2+ release-activated Ca2+ (CRAC) current that has biophysical characteristics similar to CRAC current in human T cells. Similarly, knockdown of the human homologue STIM1 significantly reduced CRAC channel activity in Jurkat T cells. RNAi-mediated knockdown of STIM1 inhibited TG- or agonist-dependent Ca2+ entry in HEK293 or SH-SY5Y cells. Conversely, overexpression of STIM1 in HEK293 cells modestly enhanced TG-induced Ca2+ entry. We propose that STIM1, a ubiquitously expressed protein that is conserved from Drosophila to mammalian cells, plays an essential role in SOC influx and may be a common component of SOC and CRAC channels.
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Wu, Minnie M., Elizabeth D. Covington i Richard S. Lewis. "Single-molecule analysis of diffusion and trapping of STIM1 and Orai1 at endoplasmic reticulum–plasma membrane junctions". Molecular Biology of the Cell 25, nr 22 (5.11.2014): 3672–85. http://dx.doi.org/10.1091/mbc.e14-06-1107.
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Following endoplasmic reticulum (ER) Ca2+ depletion, STIM1 and Orai1 complexes assemble autonomously at ER–plasma membrane (PM) junctions to trigger store-operated Ca2+ influx. One hypothesis to explain this process is a diffusion trap in which activated STIM1 diffusing in the ER becomes trapped at junctions through interactions with the PM, and STIM1 then traps Orai1 in the PM through binding of its calcium release-activated calcium activation domain. We tested this model by analyzing STIM1 and Orai1 diffusion using single-particle tracking, photoactivation of protein ensembles, and Monte Carlo simulations. In resting cells, STIM1 diffusion is Brownian, while Orai1 is slightly subdiffusive. After store depletion, both proteins slow to the same speeds, consistent with complex formation, and are confined to a corral similar in size to ER–PM junctions. While the escape probability at high STIM:Orai expression ratios is <1%, it is significantly increased by reducing the affinity of STIM1 for Orai1 or by expressing the two proteins at comparable levels. Our results provide direct evidence that STIM-Orai complexes are trapped by their physical connections across the junctional gap, but also reveal that the complexes are surprisingly dynamic, suggesting that readily reversible binding reactions generate free STIM1 and Orai1, which engage in constant diffusional exchange with extrajunctional pools.
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Alansary, Dalia, i Barbara A. Niemeyer. "Stepping out of the shadow: STIM2 promotes IL-3–induced cytokine release". Science Signaling 12, nr 576 (9.04.2019): eaax0210. http://dx.doi.org/10.1126/scisignal.aax0210.
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Basophils are a small population of innate immune cells, but their release of the cytokine interleukin-4 (IL-4) is important for mounting an efficient immune response against distinct parasites. Yoshikawa et al. (in the 9 April 2019 issue) showed that whereas STIM1 is essential for IL-4 release after stimulation of FcεRI, STIM2 mediates a delayed IL-3/IL-33–induced IL-4 release independent of STIM1.
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Spinelli, Amy M., i Mohamed Trebak. "Orai channel-mediated Ca2+ signals in vascular and airway smooth muscle". American Journal of Physiology-Cell Physiology 310, nr 6 (15.03.2016): C402—C413. http://dx.doi.org/10.1152/ajpcell.00355.2015.
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Orai (Orai1, Orai2, and Orai3) proteins form a family of highly Ca2+-selective plasma membrane channels that are regulated by stromal-interacting molecules (STIM1 and STIM2); STIM proteins are Ca2+ sensors located in the membrane of the endoplasmic reticulum. STIM and Orai proteins are expressed in vascular and airway smooth muscle and constitute the molecular components of the ubiquitous store-operated Ca2+ entry pathway that mediate the Ca2+ release-activated Ca2+ current. STIM/Orai proteins also encode store-independent Ca2+ entry pathways in smooth muscle. Altered expression and function of STIM/Orai proteins have been linked to vascular and airway pathologies, including restenosis, hypertension, and atopic asthma. In this review we discuss our current understanding of Orai proteins and the store-dependent and -independent signaling pathways mediated by these proteins in vascular and airway smooth muscle. We also discuss the current studies linking altered expression and function of Orai proteins with smooth muscle-related pathologies.
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Smyth, Jeremy T., i James W. Putney. "Regulation of store-operated calcium entry during cell division". Biochemical Society Transactions 40, nr 1 (19.01.2012): 119–23. http://dx.doi.org/10.1042/bst20110612.
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Store-operate Ca2+ channels gate Ca2+ entry into the cytoplasm in response to the depletion of Ca2+ from endoplasmic reticulum Ca2+ stores. The major molecular components of store-operated Ca2+ entry are STIM (stromal-interacting molecule) 1 (and in some instances STIM2) that serves as the endoplasmic reticulum Ca2+ sensor, and Orai (Orai1, Orai2 and Orai3) which function as pore-forming subunits of the store-operated channel. It has been known for some time that store-operated Ca2+ entry is shut down during cell division. Recent work has revealed complex mechanisms regulating the functions and locations of both STIM1 and Orai1 in dividing cells.
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Perni, Stefano, Joseph L. Dynes, Andriy V. Yeromin, Michael D. Cahalan i Clara Franzini-Armstrong. "Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry". Proceedings of the National Academy of Sciences 112, nr 40 (8.09.2015): E5533—E5542. http://dx.doi.org/10.1073/pnas.1515606112.
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Stromal interacting molecule (STIM) and Orai proteins constitute the core machinery of store-operated calcium entry. We used transmission and freeze–fracture electron microscopy to visualize STIM1 and Orai1 at endoplasmic reticulum (ER)–plasma membrane (PM) junctions in HEK 293 cells. Compared with control cells, thin sections of STIM1-transfected cells possessed far more ER elements, which took the form of complex stackable cisternae and labyrinthine structures adjoining the PM at junctional couplings (JCs). JC formation required STIM1 expression but not store depletion, induced here by thapsigargin (TG). Extended molecules, indicative of STIM1, decorated the cytoplasmic surface of ER, bridged a 12-nm ER-PM gap, and showed clear rearrangement into small clusters following TG treatment. Freeze–fracture replicas of the PM of Orai1-transfected cells showed extensive domains packed with characteristic “particles”; TG treatment led to aggregation of these particles into sharply delimited “puncta” positioned upon raised membrane subdomains. The size and spacing of Orai1 channels were consistent with the Orai crystal structure, and stoichiometry was unchanged by store depletion, coexpression with STIM1, or an Orai1 mutation (L273D) affecting STIM1 association. Although the arrangement of Orai1 channels in puncta was substantially unstructured, a portion of channels were spaced at ∼15 nm. Monte Carlo analysis supported a nonrandom distribution for a portion of channels spaced at ∼15 nm. These images offer dramatic, direct views of STIM1 aggregation and Orai1 clustering in store-depleted cells and provide evidence for the interaction of a single Orai1 channel with small clusters of STIM1 molecules.
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Giachini, Fernanda R. C., Victor V. Lima, Fernando P. Filgueira, Anne M. Dorrance, Maria Helena C. Carvalho, Zuleica B. Fortes, R. Clinton Webb i Rita C. Tostes. "STIM1/Orai1 contributes to sex differences in vascular responses to calcium in spontaneously hypertensive rats". Clinical Science 122, nr 5 (28.10.2011): 215–26. http://dx.doi.org/10.1042/cs20110312.
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Sex differences in Ca2+-dependent signalling and homoeostasis in the vasculature of hypertensive rats are well characterized. However, sex-related differences in SOCE (store-operated Ca2+ entry) have been minimally investigated. We hypothesized that vascular protection in females, compared with males, reflects decreased Ca2+ mobilization due to diminished activation of Orai1/STIM1 (stromal interaction molecule 1). In addition, we investigated whether ovariectomy in females affects the activation of the Orai1/STIM1 pathway. Endothelium-denuded aortic rings from male and female SHRSP (stroke-prone spontaneously hypertensive rats) and WKY (Wistar–Kyoto) rats and from OVX (ovariectomized) or sham female SHRSP and WKY rats were used to functionally evaluate Ca2+ influx-induced contractions. Compared with females, aorta from male SHRSP displayed: (i) increased contraction during the Ca2+-loading period; (ii) similar transient contraction during Ca2+ release from the intracellular stores; (iii) increased activation of STIM1 and Orai1, as shown by the blockade of STIM1 and Orai1 with neutralizing antibodies, which reversed the sex differences in contraction during the Ca2+-loading period; and (iv) increased expression of STIM1 and Orai1. Additionally, we found that aortas from OVX-SHRSP showed increased contraction during the Ca2+-loading period and increased Orai1 expression, but no changes in the SR (sarcoplasmic reticulum)-buffering capacity or STIM1 expression. These findings suggest that augmented activation of STIM1/Orai1 in aortas from male SHRSP represents a mechanism that contributes to sex-related impaired control of intracellular Ca2+ levels. Furthermore, female sex hormones may negatively modulate the STIM/Orai1 pathway, contributing to vascular protection observed in female rats.
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Bisaillon, Jonathan M., Rajender K. Motiani, José C. Gonzalez-Cobos, Marie Potier, Katharine E. Halligan, Wael F. Alzawahra, Margarida Barroso, Harold A. Singer, David Jourd'heuil i Mohamed Trebak. "Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration". American Journal of Physiology-Cell Physiology 298, nr 5 (maj 2010): C993—C1005. http://dx.doi.org/10.1152/ajpcell.00325.2009.
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We recently demonstrated that thapsigargin-induced passive store depletion activates Ca2+ entry in vascular smooth muscle cells (VSMC) through stromal interaction molecule 1 (STIM1)/Orai1, independently of transient receptor potential canonical (TRPC) channels. However, under physiological stimulations, despite the ubiquitous depletion of inositol 1,4,5-trisphosphate-sensitive stores, many VSMC PLC-coupled agonists (e.g., vasopressin and endothelin) activate various store-independent Ca2+ entry channels. Platelet-derived growth factor (PDGF) is an important VSMC promigratory agonist with an established role in vascular disease. Nevertheless, the molecular identity of the Ca2+ channels activated by PDGF in VSMC remains unknown. Here we show that inhibitors of store-operated Ca2+ entry (Gd3+ and 2-aminoethoxydiphenyl borate at concentrations as low as 5 μM) prevent PDGF-mediated Ca2+ entry in cultured rat aortic VSMC. Protein knockdown of STIM1, Orai1, and PDGF receptor-β (PDGFRβ) impaired PDGF-mediated Ca2+ influx, whereas Orai2, Orai3, TRPC1, TRPC4, and TRPC6 knockdown had no effect. Scratch wound assay showed that knockdown of STIM1, Orai1, or PDGFRβ inhibited PDGF-mediated VSMC migration, but knockdown of STIM2, Orai2, and Orai3 was without effect. STIM1, Orai1, and PDGFRβ mRNA levels were upregulated in vivo in VSMC from balloon-injured rat carotid arteries compared with noninjured control vessels. Protein levels of STIM1 and Orai1 were also upregulated in medial and neointimal VSMC from injured carotid arteries compared with noninjured vessels, as assessed by immunofluorescence microscopy. These results establish that STIM1 and Orai1 are important components for PDGF-mediated Ca2+ entry and migration in VSMC and are upregulated in vivo during vascular injury and provide insights linking PDGF to STIM1/Orai1 during neointima formation.
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Zhou, Yandong, Robert M. Nwokonko, Xiangyu Cai, Natalia A. Loktionova, Raz Abdulqadir, Ping Xin, Barbara A. Niemeyer, Youjun Wang, Mohamed Trebak i Donald L. Gill. "Cross-linking of Orai1 channels by STIM proteins". Proceedings of the National Academy of Sciences 115, nr 15 (26.03.2018): E3398—E3407. http://dx.doi.org/10.1073/pnas.1720810115.
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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. A concatenated SOAR1 heterodimer containing one monomer point mutated at its critical Orai1 binding residue (F394H), although fully activating Orai channels, is completely defective in cross-linking Orai1 channels. Importantly, the naturally occurring STIM2 variant, STIM2.1, has an eight-amino acid insert in its SOAR unit that renders it functionally identical to the F394H mutant in SOAR1. Contrary to earlier predictions, the SOAR1–SOAR2.1 heterodimer fully activates Orai1 channels but prevents cross-linking and clustering of channels. Interestingly, combined expression of full-length STIM1 with STIM2.1 in a 5:1 ratio causes suppression of sustained agonist-induced Ca2+ oscillations and protects cells from Ca2+ overload, resulting from high agonist-induced Ca2+ release. Thus, STIM2.1 exerts a powerful regulatory effect on signal generation likely through preventing Orai1 channel cross-linking. Overall, STIM-mediated cross-linking of Orai1 channels is a hitherto unrecognized functional paradigm that likely provides an organizational microenvironment within ER–PM junctions with important functional impact on Ca2+ signal generation.
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Zou, Jin-jing, Ya-dong Gao, Shuang Geng i Jiong Yang. "Role of STIM1/Orai1-mediated store-operated Ca2+ entry in airway smooth muscle cell proliferation". Journal of Applied Physiology 110, nr 5 (maj 2011): 1256–63. http://dx.doi.org/10.1152/japplphysiol.01124.2010.
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Hyperplasia of airway smooth muscle cells (ASMCs) is a characteristic change of chronic asthma patients. However, the underlying mechanisms that trigger this process are not yet completely understood. Store-operated Ca2+ (SOC) entry (SOCE) occurs in response to the intracellular sarcoplasma reticulum (SR)/endoplasmic reticulum (ER) Ca2+ store depletion. SOCE plays an important role in regulating Ca2+ signaling and cellular responses of ASMCs. Stromal interaction molecule (STIM)1 has been proposed as an ER/SR Ca2+ sensor and translocates to the ER underneath the plasma membrane upon depletion of the ER Ca2+ store, where it interacts with Orai1, the molecular component of SOC channels, and brings about SOCE. STIM1 and Orai1 have been proved to mediate SOCE of ASMCs. In this study, we investigated whether STIM1/Orai1-mediated SOCE is involved in rat ASMC proliferation. We found that SOCE was upregulated during ASMC proliferation accompanied by a mild increase of STIM1 and a significant increase of Orai1 mRNA expression, whereas the proliferation of ASMCs was partially inhibited by the SOC channel blockers SKF-96365, NiCl2, and BTP-2. Suppressing the mRNA expression of STIM1 or Orai1 with specific short hairpin RNA resulted in the attenuation of SOCE and ASMC proliferation. Moreover, after knockdown of STIM1 or Orai1, the SOC channel blocker SKF-96365 had no inhibitory effect on the proliferation of ASMCs anymore. These results suggested that STIM1/Orai1-mediated SOCE is involved in ASMC proliferation.
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Sanchez-Collado, Jose, Isaac Jardin, Jose J. López, Victor Ronco, Gines M. Salido, Charlotte Dubois, Natalia Prevarskaya i Juan A. Rosado. "Role of Orai3 in the Pathophysiology of Cancer". International Journal of Molecular Sciences 22, nr 21 (22.10.2021): 11426. http://dx.doi.org/10.3390/ijms222111426.
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The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca2+ currents, the store-operated current, Icrac, involving functional interactions between the stromal interaction molecules (STIM), STIM1/STIM2, and Orai1/Orai2/Orai3, as well as the store-independent arachidonic acid (AA) (or leukotriene C4)-regulated current Iarc, which involves Orai1, Orai3 and STIM1. Overexpression of functional Orai3 has been described in different neoplastic cells and cancer tissue samples as compared to non-tumor cells or normal adjacent tissue. In these cells, Orai3 exhibits a cell-specific relevance in Ca2+ influx. In estrogen receptor-positive breast cancer cells and non-small cell lung cancer (NSCLC) cells store-operated Ca2+ entry (SOCE) is strongly dependent on Orai3 expression while in colorectal cancer and pancreatic adenocarcinoma cells Orai3 predominantly modulates SOCE. On the other hand, in prostate cancer cells Orai3 expression has been associated with the formation of Orai1/Orai3 heteromeric channels regulated by AA and reduction in SOCE, thus leading to enhanced proliferation. Orai3 overexpression is associated with supporting several cancer hallmarks, including cell cycle progression, proliferation, migration, and apoptosis resistance. This review summarizes the current knowledge concerning the functional role of Orai3 in the pathogenesis of cancer.
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Serwach, Karolina, i Joanna Gruszczynska-Biegala. "STIM Proteins and Glutamate Receptors in Neurons: Role in Neuronal Physiology and Neurodegenerative Diseases". International Journal of Molecular Sciences 20, nr 9 (9.05.2019): 2289. http://dx.doi.org/10.3390/ijms20092289.
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Neuronal calcium (Ca2+) influx has long been ascribed mainly to voltage-gated Ca2+ channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca2+ entry (SOCE). SOCE is described as Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer’s disease and Huntington’s disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.
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Collins, Helen E., Lan He, Luyun Zou, Jing Qu, Lufang Zhou, Silvio H. Litovsky, Qinglin Yang, Martin E. Young, Richard B. Marchase i John C. Chatham. "Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function". American Journal of Physiology-Heart and Circulatory Physiology 306, nr 8 (15.04.2014): H1231—H1239. http://dx.doi.org/10.1152/ajpheart.00075.2014.
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The endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca2+ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout (crSTIM1-KO) mouse. In cardiomyocytes isolated from crSTIM1-KO mice, STIM1 expression was reduced by ∼92% with no change in the expression of related store-operated Ca2+ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that crSTIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in crSTIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in crSTIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in crSTIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function.
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Okekpa, Simon Imakwu, Rabiatul Basria S. M. N. Mydin, Chandrarohini Saravanan, Emmanuel Jairaj Moses, Gurjeet Kaur Chatar Singh i Muhammad Yusri Musa. "PRELIMINARY ANALYSIS OF STIM-1 EXPRESSION ON FORMALIN-FIXED PARAFFIN-EMBEDDED NASOPHARYNGEAL CANCER TISSUES". Journal of Health and Translational Medicine sp2023, nr 1 (6.06.2023): 325–30. http://dx.doi.org/10.22452/jummec.sp2023no1.34.
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Nasopharyngeal cancer (NPC) is commonly diagnosed at the advanced stage with a poor prognosis. STIM-1 has become a promising cancer biomarker, especially in early diagnostic applications. There is a limited study on STIM1 expression in NPC, especially in formalin-fixed paraffin-embedded NPC tissues. Thus, the present work provides a preliminary analysis of STIM-1 expression on NPC tissues. This study aims to examine STIM-1 expression in NPC associated with tissue origin and the functional effects of STIM1 expression in NPC. Screening for target genes was using the KEGG PATHWAY database. The target gene analysis was initially done further studied using an immunohistostaining approach on NPC tissue samples. From the bioinformatic resources, STIM-1 has shown significant interaction with molecules network associated with cell migration and metastasis. Differentiated NPC showed moderate STIM-1 IHC staining intensity and undifferentiated NPC presented with strong STIM-1 IHC staining intensity. The present preliminary study suggests that STIM-1 could have a positive correlation with NPC pathogenesis. However, further comprehensive work using larger samples size is needed especially focusing on the STIM-1 expression and other clinicopathological parameters.
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Shen, Wei-Wei, i Nicolas Demaurex. "Morphological and functional aspects of STIM1-dependent assembly and disassembly of store-operated calcium entry complexes". Biochemical Society Transactions 40, nr 1 (19.01.2012): 112–18. http://dx.doi.org/10.1042/bst20110620.
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The SOCE (store-operated Ca2+ entry) pathway is a central component of cell signalling that links the Ca2+-filling state of the ER (endoplasmic reticulum) to the activation of Ca2+-permeable channels at the PM (plasma membrane). SOCE channels maintain a high free Ca2+ concentration within the ER lumen required for the proper processing and folding of proteins, and fuel the long-term cellular Ca2+ signals that drive gene expression in immune cells. SOCE is initiated by the oligomerization on the membrane of the ER of STIMs (stromal interaction molecules) whose luminal EF-hand domain switches from globular to an extended conformation as soon as the free Ca2+ concentration within the ER lumen ([Ca2+]ER) decreases below basal levels of ~500 μM. The conformational changes induced by the unbinding of Ca2+ from the STIM1 luminal domain promote the formation of higher-order STIM1 oligomers that move towards the PM and exposes activating domains in STIM1 cytosolic tail that bind to Ca2+ channels of the Orai family at the PM and induce their activation. Both SOCE and STIM1 oligomerization are reversible events, but whether restoring normal [Ca2+]ER levels is sufficient to initiate the deoligomerization of STIM1 and to control the termination of SOCE is not known. The translocation of STIM1 towards the PM involves the formation of specialized compartments derived from the ER that we have characterized at the ultrastructural level and termed the pre-cortical ER, the cortical ER and the thin cortical ER. Pre-cortical ER structures are thin ER tubules enriched in STIM1 extending along microtubules and located deep inside cells. The cortical ER is located in the cell periphery in very close proximity (8–11 nm) to the plasma membrane. The thin cortical ER consists of thinner sections of the cortical ER enriched in STIM1 and devoid of chaperones that appear to be specialized ER compartments dedicated to Ca2+ signalling.
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Ramanagoudr-Bhojappa, Ramanagouda, Yong Miao i Monika Vig. "High affinity associations with α-SNAP enable calcium entry via Orai1 channels". PLOS ONE 16, nr 10 (15.10.2021): e0258670. http://dx.doi.org/10.1371/journal.pone.0258670.
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Molecular steps that activate store-operated calcium entry (SOCE) via Orai channel supramolecular complex remain incompletely defined. We have earlier shown that α-SNAP regulates the on-site functional assembly and calcium selectivity of Orai1 channels. Here we investigate the molecular basis of its association with Orai, Stim and find that the affinity of α-SNAP for Orai and Stim is substantially higher than previously reported affinities between Stim and Orai sub-domains. α-SNAP binds the coiled-coil 3 (CC3) sub-domain of Stim1. Mutations of Tryptophan 430 in Stim1-CC3 disrupted α-SNAP association and SOCE, demonstrating a novel α-SNAP dependent function for this crucial subdomain. Further, α-SNAP binds the hinge region near the C-terminus of Orai1 and an additional broad region near the N-terminus and Valine 262 and Leucine 74 were necessary for these respective interactions, but not Orai, Stim co-clustering. Thus, high affinity interactions with α-SNAP are necessary for imparting functionality to Stim, Orai clusters and induction of SOCE.
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Li, Li-Sha, Yun-Peng Zhu, Qi-Dong Xia, Shao-Gang Wang i Deng He. "High-Calcium Microenvironment during the Development of Kidney Calculi Can Promote Phenotypic Transformation of NRK-52E Cells by Inhibiting the Expression of Stromal Interaction Molecule-1". BioMed Research International 2022 (1.03.2022): 1–10. http://dx.doi.org/10.1155/2022/2350198.
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Objective. To explore whether Stromal Interaction Molecule-1 (STIM1) participates in the phenotypic transformation of NRK-52E cells under high-calcium microenvironment. Materials and Methods. NRK-52E cells were treated with high concentration of calcium. The viability and apoptosis of cells were detected by CCK-8 (cell counting kit-8) and flow cytometry, respectively. The expression changes of phenotypic marker proteins (E-cadherin and OPN) and calcium channel proteins (STIMl and Orai1) in high-calcium environment were detected by western blotting and real-time quantitative polymerase chain reaction. The expression of STIMl protein in NRK-52E cells was upregulated and downregulated by plasmid-STIM1 and plasmid-shRNA-STIMl, respectively. The expressions of phenotypic marker proteins after upregulation or downregulation of STIMl were detected again. Besides, the intracellular calcium concentrations of NRK-52E cells in different treatments were detected by flow cytometry. Results. High-calcium microenvironment can promote the phenotypic transformation and the adhesion of calcium salts in NRK-52E cells and simultaneously suppress the expression of STIMl protein in NRK-52E cells. Downregulation of STIMl protein could also promote the phenotype transformation, while both the gene silence of matrix gla protein (MGP) and overexpression of STIMl showed reverse results. Conclusion. STIMl protein plays an important role in promoting phenotypic transformation of NRK-52E cells in high-calcium microenvironment.
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Kume, Kohei, Liting Chen, Jae-Woong Lee i Markus Muschen. "Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation". Blood 132, Supplement 1 (29.11.2018): 1373. http://dx.doi.org/10.1182/blood-2018-99-117315.
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Abstract Background: Nuclear factor of activated T cells (NFAT) factors regulate activation and Ca2+ signaling in B-cells. Store-operated Ca2+ entry (SOCE) is regulated by Orai1 and Stim1 and upstream of NFAT. We previously reported on the observation of autonomous oscillatory Ca2+ signal activity in BCR-ABL1-driven B-ALL. Autonomous Ca2+ oscillations may provide oncogenic survival signals to B-ALL cells, however their significance and mechanism remained unclear. Results: Here we found that autonomous Ca2+ oscillations are common across multiple subtypes of B-cell lineage ALL and mature B-cell lymphoma and reflect downstream survival and proliferation signals from oncogenic BCR-signaling or oncogenes that mimic active BCR-signaling (e.g. ABL1-kinase fusions, CD79B mutation, EBV-encoded oncoprotein LMP2A, RAS-pathway lesions). By contrast, multiple myeloma and Hodgkin's lymphoma that lack BCR-expression and function also lack Ca2+ oscillations (Figure, top panel). As Orai1 and Stim1/2 are essential SOCE-effector genes, we performed genetic experiments to test the impact of Cre-mediated deletion of Orai1 and Stim1/2 in BCR-ABL1 and NRASG12D-dependent models of B-ALL. Inducible deletion of Orai1 or Stim1/2 not only abrogated SOCE but also autonomous Ca2+ oscillations. Signal amplitudes of residual autonomous Ca2+ oscillations were significantly reduced (P < 0.0001; Figure, bottom panel). Further, deletion of either Orai1 or Stim1/2 induced cell death and abrogated colony-forming capacity in both models of B-ALL. In agreement with these findings, NFATc1 no longer translocated to the nucleus upon Cre-mediated ablation of Orai1 or Stim1/2 induced, which reflected functional inactivation of NFATc1. These results demonstrated that Orai1- and Stim1/2-mediated SOCE signaling and autonomous Ca2+ oscillations are critical in BCR-ABL1 and NRASG12D-dependent B-ALL. A NFAT-calcineurin association inhibitor, INCA-6, was tested for its ability to suppress NFATc1 and autonomous Ca2+ signaling in patient-derived xenograft (PDX) models of B-ALL, mantle cell lymphoma and DLBCL. Treatment with INCA-6 suppressed survival and proliferation signals in all six PDX of B-ALL, mantle cell lymphoma and DLBCL but not multiple myeloma cells. Unlike myeloma cells, B-ALL, mantle cell and DLBCL cells expressed a functional (pre-)BCR. These findings suggest that the SOCE-NFAT pathway is linked to Ca2+ signaling downstream of a functional BCR- or oncogenic BCR-mimics. Furthermore, to determine whether high expression levels of ORAI1, STIM1, STIM2 and NFATC1 represents a biomarker of clinical outcome for patients with B-ALL, we segregated patients from two clinical trials (Children's Oncology Group P9906 (n=207) and Eastern Cooperative Oncology Group (E2993; n=215)) into two groups on the basis of higher or lower than median expression levels of ORAI1, STIM1, STIM2 and NFATC1 at the time of diagnosis. Higher than median expression levels of each of these four genes at the time of diagnosis predicted shorter overall and relapse-free survival (P < 0.02 or lower for each of these genes). These findings identify SOCE-NFAT signal as a novel biomarker with potential use in risk stratification of children and adults with B-ALL. Conclusions: We identified Orai1 and Stim1 as central mediators of SOCE. Most BCR-dependent B-cell malignancies are driven by oncogenic BCR-signals, which result in autonomous Ca2+ oscillations. While the significance of autonomous Ca2+-oscillations remains unclear, deletion of Orai1 and Stim1/2 resulted in a complete loss of Ca2+ oscillations, loss of NFATc1-activation and cell death. We conclude that previously unrecognized Ca2+-oscillations downstream of oncogenic BCR-signaling are required for survival and proliferation of B-ALL and B-cell lymphoma cells. Pharmacological inhibition of SOCE (Orai1 and Stim1/2) or NFATC1 (e.g. INCA-6) represents a selective strategy to disrupt autonomous Ca2+ oscillations and oncogenic BCR-signaling in a broad range of B-cell malignancies. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Quintana, Ariel, Vangipurapu Rajanikanth, Suzette Farber-Katz, Aparna Gudlur, Chen Zhang, Ji Jing, Yubin Zhou, Anjana Rao i Patrick G. Hogan. "TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling". Proceedings of the National Academy of Sciences 112, nr 51 (7.12.2015): E7083—E7092. http://dx.doi.org/10.1073/pnas.1521924112.
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The stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM–ORAI function. However, little is known about proteins that organize ER–plasma membrane junctions for STIM–ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER–plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.
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Hooper, Robert, Xuexin Zhang, Marie Webster, Christina Go, Joseph Kedra, Katie Marchbank, Donald L. Gill, Ashani T. Weeraratna, Mohamed Trebak i Jonathan Soboloff. "Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma". Molecular and Cellular Biology 35, nr 16 (8.06.2015): 2790–98. http://dx.doi.org/10.1128/mcb.01500-14.
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The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. Wnt5A, a key driver of melanoma invasiveness, induces Ca2+signals. To understand how store-operated calcium entry (SOCE) contributes to Wnt5A-induced malignancy in melanoma models, we examined the expression and function of STIM1 and Orai1 in patient-derived malignant melanoma cells, previously characterized as either highly invasive (metastatic) or noninvasive. Using both fluorescence microscopy and electrophysiological approaches, we show that SOCE is greatly diminished in invasive melanoma compared to its level in noninvasive cell types. However, no loss of expression of any members of the STIM and Orai families was observed in invasive melanoma cells. Moreover, overexpressed wild-type STIM1 and Orai1 failed to restore SOCE in invasive melanoma cells, and we observed no defects in their localization before or after store depletion in any of the invasive cell lines. Importantly, however, we determined that SOCE was restored by inhibition of protein kinase C, a known downstream target of Wnt5A. Furthermore, coexpression of STIM1 with an Orai1 mutant insensitive to protein kinase C-mediated phosphorylation fully restored SOCE in invasive melanoma. These findings reveal a level of control for STIM/Orai function in invasive melanoma not previously reported.
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Niemeyer, Barbara A. "Tuning the Taps: STIM1 and STIM2 Regulatory Mechanisms". Biophysical Journal 108, nr 2 (styczeń 2015): 11a. http://dx.doi.org/10.1016/j.bpj.2014.11.084.
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Subedi, Krishna, Hwei Ling Ong i Indu Ambudkar. "STIM1-STIM2 Interactions Modulate Store-Operated Calcium Entry". Biophysical Journal 108, nr 2 (styczeń 2015): 566a. http://dx.doi.org/10.1016/j.bpj.2014.11.3097.
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Jeong, Seung Yeon, Mi Ri Oh, Jun Hee Choi, Jin Seok Woo i Eun Hui Lee. "Calsequestrin 1 Is an Active Partner of Stromal Interaction Molecule 2 in Skeletal Muscle". Cells 10, nr 11 (20.10.2021): 2821. http://dx.doi.org/10.3390/cells10112821.
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Calsequestrin 1 (CASQ1) in skeletal muscle buffers and senses Ca2+ in the sarcoplasmic reticulum (SR). CASQ1 also regulates store-operated Ca2+ entry (SOCE) by binding to stromal interaction molecule 1 (STIM1). Abnormal SOCE and/or abnormal expression or mutations in CASQ1, STIM1, or STIM2 are associated with human skeletal, cardiac, or smooth muscle diseases. However, the functional relevance of CASQ1 along with STIM2 has not been studied in any tissue, including skeletal muscle. First, in the present study, it was found by biochemical approaches that CASQ1 is bound to STIM2 via its 92 N-terminal amino acids (C1 region). Next, to examine the functional relevance of the CASQ1-STIM2 interaction in skeletal muscle, the full-length wild-type CASQ1 or the C1 region was expressed in mouse primary skeletal myotubes, and the myotubes were examined using single-myotube Ca2+ imaging experiments and transmission electron microscopy observations. The CASQ1-STIM2 interaction via the C1 region decreased SOCE, increased intracellular Ca2+ release for skeletal muscle contraction, and changed intracellular Ca2+ distributions (high Ca2+ in the SR and low Ca2+ in the cytosol were observed). Furthermore, the C1 region itself (which lacks Ca2+-buffering ability but has STIM2-binding ability) decreased the expression of Ca2+-related proteins (canonical-type transient receptor potential cation channel type 6 and calmodulin 1) and induced mitochondrial shape abnormalities. Therefore, in skeletal muscle, CASQ1 plays active roles in Ca2+ movement and distribution by interacting with STIM2 as well as Ca2+ sensing and buffering.
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Derler, Isabella, Isaac Jardin i Christoph Romanin. "Molecular mechanisms of STIM/Orai communication". American Journal of Physiology-Cell Physiology 310, nr 8 (15.04.2016): C643—C662. http://dx.doi.org/10.1152/ajpcell.00007.2016.
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Ca2+entry into the cell via store-operated Ca2+release-activated Ca2+(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+channels open after depletion of intracellular Ca2+stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+permeation into the cell.