| 11354088 | The neglected CRAC proteins: Orai2, Orai3, and STIM2. | Hoth M and Niemeyer BA, Curr Top Membr. 2013;71:237-71. doi: 10.1016/B978-0-12-407870-3.00010-X. | Plasma-membrane-localized Orai1 ion channel subunits interacting with ER-localized STIM1 molecules comprise the major subunit composition responsible for calcium release-activated calcium channels. STIM1 "translates" the Ca(2+) store content into Orai1 activity, making it a store-operated channel. S urprisingly, in addition to being the physical activator, STIM1 also modulates Orai1 properties, including its inactivation and permeation (see Chapter 1). STIM1 is thus more than a pure Orai1 activator. Within the past 7 years following the discovery of STIM and Orai proteins, the molecular mechanisms of STIM1/Orai1 activity and their functional importance have been studied in great detail. Much less is currently known about the other isoforms STIM2, Orai2, and Orai3. In this chapter, we summarize the current knowledge about STIM2, Orai2, and Orai3 properties and function. Are these homologues mainly modulators of predominantly STIM1/Orai1-mediated complexes or do store-dependent or -independent functions such as regulation of basal Ca(2+) concentration and activation of Orai3-containing complexes by arachidonic acid or by estrogen receptors point toward their "true" physiological function? Is Orai2 the Orai1 of neurons? A major focus of the review is on the functional relevance of STIM2, Orai2, and Orai3, some of which still remains speculative. | 23890118 | 1000-07-01 |
| 11056026 | STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. | Popugaeva E, etal., Mol Neurodegener. 2015 Aug 15;10:37. doi: 10.1186/s13024-015-0034-7. | BACKGROUND: Alzheimer disease (AD) is a disease of lost memories. Mushroom postsynaptic spines play a key role in memory storage, and loss of mushroom spines has been proposed to be linked to memory loss in AD. Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pa thological hallmarks of AD. It is important to evaluate effects of amyloid on stability of mushroom spines. RESULTS: In this study we used in vitro and in vivo models of amyloid synaptotoxicity to investigate effects of amyloid peptides on hippocampal mushroom spines. We discovered that application of Abeta42 oligomers to hippocampal cultures or injection of Abeta42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII). We further discovered that expression of STIM2 protein rescued CaMKII activity and protected mushroom spines from amyloid toxicity in vitro and in vivo. CONCLUSIONS: Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD. | 26275606 | 1000-04-01 |
| 7175076 | Differential roles for STIM1 and STIM2 in store-operated calcium entry in rat neurons. | Gruszczynska-Biegala J, etal., PLoS One. 2011 Apr 26;6(4):e19285. | The interaction between Ca(2+) sensors STIM1 and STIM2 and Ca(2+) channel-forming protein ORAI1 is a crucial element of store-operated calcium entry (SOCE) in non-excitable cells. However, the molecular mechanism of SOCE in neurons remains unclear. We addressed this issue by establishing the presence and function of STIM proteins. Real-time polymerase chain reaction from cortical neurons showed that these cells contain significant amounts of Stim1 and Stim2 mRNA. Thapsigargin (TG) treatment increased the amount of both endogenous STIM proteins in neuronal membrane fractions. The number of YFP-STIM1/ORAI1 and YFP-STIM2/ORAI1 complexes was also enhanced by such treatment. The differences observed in the number of STIM1 and STIM2 complexes under SOCE conditions and the differential sensitivity to SOCE inhibitors suggest their distinct roles. Endoplasmic reticulum (ER) store depletion by TG enhanced intracellular Ca(2+) levels in loaded with Fura-2 neurons transfected with YFP-STIM1 and ORAI1, but not with YFP-STIM2 and ORAI1, which correlated well with the number of complexes formed. Moreover, the SOCE inhibitors ML-9 and 2-APB reduced Ca(2+) influx in neurons expressing YFP-STIM1/ORAI1 but produced no effect in cells transfected with YFP-STIM2/ORAI1. Moreover, in neurons transfected with YFP-STIM2/ORAI1, the increase in constitutive calcium entry was greater than with YFP-STIM1/ORAI1. Our data indicate that both STIM proteins are involved in calcium homeostasis in neurons. STIM1 mainly activates SOCE, whereas STIM2 regulates resting Ca(2+) levels in the ER and Ca(2+) leakage with the additional involvement of STIM1. | 21541286 | 1000-11-01 |
| 152995403 | STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells. | Weidinger C, etal., EMBO Mol Med. 2013 Sep;5(9):1311-21. doi: 10.1002/emmm.201302989. Epub 2013 Aug 6. | Store-operated calcium entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels regulates the function of many immune cells. Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. This and t he reported role of Ca(2+) signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF-α and IFN-γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy. | 23922331 | 2013-09-01 |
| 10047297 | Native STIM2 and ORAI1 proteins form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons. | Gruszczynska-Biegala J and Kuznicki J, J Neurochem. 2013 Sep;126(6):727-38. doi: 10.1111/jnc.12320. Epub 2013 Jun 12. | In non-excitatory cells, stromal interaction molecule 1 (STIM1) and STIM2 mediate store-operated calcium entry via an interaction with ORAI1 calcium channels. However, in neurons, STIM2 over-expression appears to play a role in calcium homeostasis that is different from STIM1 over-expression. The aim of this study was to establish the role and localization of native STIM2 in the neuronal cell. Co-immunoprecipitation experiments revealed that the interaction between endogenous STIM2 and ORAI1 was greater in a low-calcium medium than in a high-calcium medium. Using a Proximity Ligation Assay (PLA), the number of apparent complexes of endogenous STIM2 with ORAI1 was quantified. No change in the number of PLA signals was observed in the presence of thapsigargin, which depletes calcium from the endoplasmic reticulum (ER). However, the number of apparent STIM2-ORAI1 complexes increased when intracellular and subsequently ER calcium concentrations were decreased by BAPTA-AM or a low-calcium medium. Both Fura-2 acetoxymethyl ester calcium imaging and PLA in the same neuronal cell indicated that the calcium responses correlated strongly with the number of endogenous STIM2-ORAI1 complexes. The small drop in calcium levels in the ER caused by decreased intracellular calcium levels appeared to initiate the calcium-sensitive and thapsigargin-insensitive interaction between STIM2 and ORAI1. We show in neuronal somata the formation of endogenous complexes of stromal interaction molecule 2 (STIM2) with ORAI1 calcium channels. Their number increased when intracellular Ca(2)(+) concentrations were decreased by the Ca(2)(+) chelator BAPTA-AM or a low-calcium medium (EGTA), but did not in the presence of thapsigargin (TG). We conclude that the small drop of Ca(2)(+) level in endoplasmic reticulum, due to the decreased level of intracellular Ca(2)(+), is sufficient to trigger STIM2-ORAI1 complex formation in a thapsigargin-insensitive manner. | 23711249 | 2013-07-01 |
| 11341413 | The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. | Matsumoto M, etal., Immunity. 2011 May 27;34(5):703-14. doi: 10.1016/j.immuni.2011.03.016. Epub 2011 Apr 28. | A chief Ca(2+) entry pathway in immune cells is store-operated Ca(2+) (SOC) influx, which is triggered by depletion of Ca(2+) from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2 0;'>STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity. | 21530328 | 2011-06-01 |
