Physiological and pathophysiological functions of SOCE in the immune system

Feske, Stefan

doi:10.2741/e540

Cited by 72 publications

(6 citation statements)

References 128 publications

(215 reference statements)

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“…In non-excitable cells, change in intracellular Ca 2+ ([Ca 2+ ] i ) levels directly related to the release of Ca 2+ stores from the ER, is due to activation of the store-operated Ca 2+ entry (SOCE) mechanism (Tojyo et al, 2014). Once ER Ca 2+ stores are depleted, stromal interaction molecule 1 (STIM1), which acts as an ER sensor, interacts with proteins at the plasma membrane Ca 2+ influx channels (Liao et al, 2008;Shaw and Feske, 2012a). SOCE in immune cells is mediated by the highly Ca 2+ -selective Ca 2+ release-activated Ca 2+ (CRAC) channel and is essential for the proper immune response (Shaw and Feske, 2012a;Vaeth et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Once ER Ca 2+ stores are depleted, stromal interaction molecule 1 (STIM1), which acts as an ER sensor, interacts with proteins at the plasma membrane Ca 2+ influx channels (Liao et al, 2008;Shaw and Feske, 2012a). SOCE in immune cells is mediated by the highly Ca 2+ -selective Ca 2+ release-activated Ca 2+ (CRAC) channel and is essential for the proper immune response (Shaw and Feske, 2012a;Vaeth et al, 2015). An increase in [Ca 2+ ] i is initiated by agonist binding to cellsurface receptors, which generates second messenger IP 3 , leading to the release of Ca 2+ stored in the ER.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Ca2+ entry via Orai–TRPC1 induces ER stress, initiating immune activation in macrophages

Conceicao

Sun

Zboril

et al. 2019

Journal of Cell Science

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Activation of cellular stresses is associated with inflammation; however, the mechanisms are not well identified. Here, we provide evidence that loss of Ca 2+ influx induces endoplasmic reticulum (ER) stress in primary macrophages and in murine macrophage cell line Raw 264.7, in which the unfolded protein response is initiated to modulate cytokine production, thereby activating the immune response. Stressors that initiate the ER stress response block storedependent Ca 2+ entry in macrophages prior to the activation of the unfolded protein response. The endogenous Ca 2+ entry channel is dependent on the Orai1-TRPC1-STIM1 complex, and the presence of ER stressors decreased expression of TRPC1, Orai1 and STIM1. Additionally, blocking Ca 2+ entry with SKF96365 also induced ER stress, promoted cytokine production, activation of autophagy, increased caspase activation and induced apoptosis. Furthermore, ER stress inducers inhibited cell cycle progression, promoted the inflammatory M1 phenotype, and increased phagocytosis. Mechanistically, restoration of Orai1-STIM1 expression inhibited the ER stress-mediated loss of Ca 2+ entry that prevents ER stress and inhibits cytokine production, and thus induced cell survival. These results suggest an unequivocal role of Ca 2+ entry in modulating ER stress and in the induction of inflammation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of Ca2+ entry via Orai–TRPC1 induces ER stress, initiating immune activation in macrophages

Conceicao

Sun

Zboril

et al. 2019

Journal of Cell Science

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“…The CRAC channel is composed of the pore-forming calcium release-activated calcium channel modulator 1 (Orai1) subunit at the plasma membrane (PM) and the endoplasmic reticulum (ER)-resident stromal interaction molecule-1 (STIM1) auxiliary subunit, and it plays a crucial role in the calcium mobilization of immune cells 18 . ER Ca 2+ release is mediated by the calcium-releasing channel IP3R in non-muscle cells 19 .…”

Section: Introductionmentioning

confidence: 99%

Multi-walled carbon nanotubes act as a chemokine and recruit macrophages by activating the PLC/IP3/CRAC channel signaling pathway

Tan

et al. 2017

Sci Rep

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The impact of nanomaterials on immune cells is gaining attention but is not well documented. Here, we report a novel stimulating effect of carboxylated multi-walled carbon nanotubes (c-MWCNTs) on the migration of macrophages and uncover the underlying mechanisms, especially the upstream signaling, using a series of techniques including transwell migration assay, patch clamp, ELISA and confocal microscopy. c-MWCNTs dramatically stimulated the migration of RAW264.7 macrophages when endocytosed, and this effect was abolished by inhibiting phospholipase C (PLC) with U-73122, antagonizing the IP3 receptor with 2-APB, and blocking calcium release-activated calcium (CRAC) channels with SK&F96365. c-MWCNTs directly activated PLC and increased the IP3 level and [Ca2+]i level in RAW264.7 cells, promoted the translocation of the ER-resident stromal interaction molecule 1 (STIM1) towards the membranous calcium release-activated calcium channel modulator 1 (Orai1), and increased CRAC current densities in both RAW264.7 cells and HEK293 cells stably expressing the CRAC channel subunits Orai1 and STIM1. c-MWCNTs also induced dramatic spatial polarization of KCa3.1 channels in the RAW264.7 cells. We conclude that c-MWCNT is an activator of PLC and strongly recruits macrophages via the PLC/IP3/CRAC channel signaling cascade. These novel findings may provide a fundamental basis for the impact of MWCNTs on the immune system.

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“…Orai1, suggested to be part of the "classical" CRAC channel, exhibits a pervasive expression in many cell types including immune cells, cardiomyocytes, vascular smooth muscle cells, endothelial cells, melanocytes and airways [62,153,154]. In particular, Orai1 controls a broad variety of immune system functions [155][156][157]. The most prominent example for the essential role of Orai1 in the immune system is exemplified by a single point mutant (Orai1 R91W), leading to severe combined immune deficiency [19] (Table 6).…”

Section: Physiology and Pathophysiology Of Orai Isoformsmentioning

confidence: 99%

Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

Tiffner

Derler

2021

IJMS

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Ca2+ ion channels are critical in a variety of physiological events, including cell growth, differentiation, gene transcription and apoptosis. One such essential entry pathway for calcium into the cell is the Ca2+ release-activated Ca2+ (CRAC) channel. It consists of the Ca2+ sensing protein, stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum (ER) and a Ca2+ ion channel Orai in the plasma membrane. The Orai channel family includes three homologues Orai1, Orai2 and Orai3. While Orai1 is the “classical” Ca2+ ion channel within the CRAC channel complex and plays a universal role in the human body, there is increasing evidence that Orai2 and Orai3 are important in specific physiological and pathophysiological processes. This makes them an attractive target in drug discovery, but requires a detailed understanding of the three Orai channels and, in particular, their differences. Orai channel activation is initiated via Ca2+ store depletion, which is sensed by STIM1 proteins, and induces their conformational change and oligomerization. Upon STIM1 coupling, Orai channels activate to allow Ca2+ permeation into the cell. While this activation mechanism is comparable among the isoforms, they differ by a number of functional and structural properties due to non-conserved regions in their sequences. In this review, we summarize the knowledge as well as open questions in our current understanding of the three isoforms in terms of their structure/function relationship, downstream signaling and physiology as well as pathophysiology.

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Physiological and pathophysiological functions of SOCE in the immune system

Cited by 72 publications

References 128 publications

Loss of Ca2+ entry via Orai–TRPC1 induces ER stress, initiating immune activation in macrophages

Loss of Ca2+ entry via Orai–TRPC1 induces ER stress, initiating immune activation in macrophages

Multi-walled carbon nanotubes act as a chemokine and recruit macrophages by activating the PLC/IP3/CRAC channel signaling pathway

Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

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