Large Store-operated Calcium Selective Currents Due to Co-expression of Orai1 or Orai2 with the Intracellular Calcium Sensor, Stim1

Mercer, Jason C.; DeHaven, Wayne I.; Smyth, Jeremy T.; Wedel, Barbara J.; Boyles, Rebecca; Bird, Gary S.; Putney, James W.

doi:10.1074/jbc.m604589200

Cited by 502 publications

(580 citation statements)

References 36 publications

(42 reference statements)

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“…Using elegant screening approaches including positional cloning from the SCID patients, Feske and colleagues [14] have shown that a member of a new class of proteins, called ORAI (keepers of gates of heaven, from Greek mythology), is part of the CRAC channel complex. A similar conclusion was independently reached by others [15][16][17][18], who in addition showed that ORAI1 increased CRAC currents if expressed with the CRAC activator STIM1. STIM1 has been previously shown to mediate CRAC activation after Ca 2+ store depletion [19][20][21][22].…”

Section: Introductionsupporting

confidence: 81%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca 2+ dependence of proliferation and apoptosis in primary human CD4 + T cells following stimulation with anti-CD3/anti-CD28-coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL-2 production and proliferation than non-focal TCR stimuli. Surprising little Ca 2+ entry through Ca 2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca 2+ ] i ) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4 + T cells. We also show that proliferation was very Ca 2+ sensitive in the range 90-120 nM, whereas apoptosis was basically constant for [Ca 2+ ] i levels of 90-120 nM. We conclude that very small changes in [Ca 2+ ] i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.

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Section: Introductionsupporting

confidence: 81%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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“…First, we compared the fluorescence recovery after photobleaching (FRAP) of STIM1-CFP in unstimulated cells resting on a polylysine surface to that of STIM1-CFP in caps. We studied cells cotransfected with STIM1-CFP and untagged Orai1, because cotransfection of these two proteins is required for increased CRAC channel function (Mercer et al, 2006;Peinelt et al, 2006;Soboloff et al, 2006;Zhang et al, 2006). There was clear recovery of fluorescence from STIM1-CFP in the ER of unstimulated cells resting on polylysine, but little recovery of STIM1-CFP fluorescence when the bleached region was part of a cap structure in stimulated cells (Figure 3, A and C).…”

Section: The Mobility Of Stim1-cfp and Orai1-yfp Decreases In The Capsmentioning

confidence: 99%

“…Initial experiments showed that depletion of Ca 2ϩ stores causes translocation of STIM1 into puncta near the PM with kinetics that precede channel opening (Liou et al, 2005;Roos et al, 2005;Mercer et al, 2006;Wu et al, 2006;Liou et al, 2007), and that these puncta appear to correspond to sites of local Ca 2ϩ entry . STIM1 and Orai1 colocalize in these puncta Xu et al, 2006;Li et al, 2007), and aggregation of STIM1 can induce clustering of Orai1 .…”

Section: Introductionmentioning

confidence: 99%

“…Orai1 is a four-pass integral membrane protein found in the PM that forms the channel. Overexpression of STIM1 with Orai1 results in very large CRAClike currents in Drosophila cell lines, Jurkat T-cells, RBL cells, and HEK293 cells (Mercer et al, 2006;Peinelt et al, 2006;Soboloff et al, 2006;Zhang et al, 2006). Recent studies have shown that Orai1 forms multimers and that targeted mutations in Orai1 alter the conductance properties of the CRAC channel Vig et al, 2006a;Yeromin et al, 2006;Gwack et al, 2007b).…”

mentioning

confidence: 99%

“…Some STIM1 resides in the PM in unstimulated cells (Manji et al, 2000;Williams et al, 2002), and externally applied anti-STIM1 antibodies have been reported to inhibit channel activation , but the relationship between PM STIM1 and the STIM1 that moves to puncta after store depletion is not clear. Many studies on STIM1 localization were performed with YFP-tagged fusion proteins that could not insert into the PM because of the YFP moiety (Hauser and Tsien, 2007) yet these fusion proteins were clearly capable of activating CRAC channels (Liou et al, 2005;Baba et al, 2006;Mercer et al, 2006;Soboloff et al, 2006;Wu et al, 2006). Recent work has shown that STIM1 and Orai1 are in membrane contact points between the ER and PM and that movement of a complex containing the two proteins requires at least 10 nm between the two membranes (Varnai et al, 2007).…”

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confidence: 99%

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Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

129

142

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The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca 2؉ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca 2؉ channel components to existing and newly forming immunological synapses. INTRODUCTIONT-cell activation in response to antigen induces and requires the elevation of intracellular Ca 2ϩ (Hogan et al., 2003;Quintana et al., 2005;Feske, 2007). T-cell receptor (TCR) engagement leads to activation of well-documented signal transduction pathways that cause a rapid release of Ca 2ϩ from the endoplasmic reticulum (ER; Samelson, 2002;Panyi et al., 2004;Gwack et al., 2007a). The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al., 2007;Hewavitharana et al., 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al., 1998;Lewis, 2001;Hogan et al., 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS). Increased Ca 2ϩ levels are also required for the activation of transcription factors. In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al., 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al., 2002;Hogan et al., 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been ident...

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Postbiotics of Lacticaseibacillus paracaseiCECT 9610 and Lactiplantibacillus plantarumCECT 9608 attenuates store‐operated calcium entry and FAK phosphorylation in colorectal cancer cells

Macias‐Diaz,

Lopez,

Bravo

et al. 2024

Molecular Oncology

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Store‐operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in colorectal cancer (CRC) cells. This mechanism, regulated by the filling state of the intracellular Ca2+ stores, is mediated by the endoplasmic reticulum Ca2+ sensors of the stromal interaction molecules (STIM) family [stromal interaction molecule 1 (STIM1) and STIM2] and the Ca2+‐release‐activated Ca2+ channels constituted by Orai family members, with predominance of calcium release‐activated calcium channel protein 1 (Orai1). CRC cells exhibit enhanced SOCE due to remodeling of the expression of the key SOCE molecular components. The enhanced SOCE supports a variety of cancer hallmarks. Here, we show that treatment of the colorectal adenocarcinoma cell lines HT‐29 and Caco‐2 with inanimate Lacticaseibacillus paracasei (CECT9610) and Lactiplantibacillus plantarum (CECT9608) attenuates SOCE, although no detectable effect is seen on SOCE in normal colon mucosa cells. The effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics was mediated by downregulation of Orai1 and STIM1, while the expression levels of Orai3 and STIM2 remained unaltered. Treatment of HT‐29 and Caco‐2 cells with inanimate Lacticaseibacillus paracasei and Lactiplantibacillus plantarum impairs in vitro migration by a mechanism likely involving attenuation of focal adhesion kinase (FAK) tyrosine phosphorylation. Cell treatment with the Orai1 inhibitor synta‐66 attenuates SOCE and prevents any further effect of Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics. Together, our results indicate for the first time that Lacticaseibacillus paracasei and Lactiplantibacillus plantarum postbiotics selectively exert negative effects on Ca2+ influx through SOCE in colorectal adenocarcinoma cell lines, providing evidence for an attractive strategy against CRC.

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Large Store-operated Calcium Selective Currents Due to Co-expression of Orai1 or Orai2 with the Intracellular Calcium Sensor, Stim1

Cited by 502 publications

References 36 publications

Calcium dependence of T cell proliferation following focal stimulation

Calcium dependence of T cell proliferation following focal stimulation

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Postbiotics of Lacticaseibacillus paracaseiCECT 9610 and Lactiplantibacillus plantarumCECT 9608 attenuates store‐operated calcium entry and FAK phosphorylation in colorectal cancer cells

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