STIM2 Regulates Capacitive Ca
            <sup>2+</sup>
            Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death

Berna‐Erro, Alejandro; Braun, Attila; Kraft, Robert A.; Kleinschnitz, Christoph; Schuhmann, Michael K.; Stegner, David; Wultsch, Thomas; Eilers, Jens; Meuth, Sven G.; Stoll, Guido; Nieswandt, Bernhard

doi:10.1126/scisignal.2000522

Cited by 242 publications

(344 citation statements)

References 46 publications

(71 reference statements)

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“…Interestingly, however, our results also show that STIM1 and STIM2 are able to function mostly independently as STIM1 overexpression in STIM2-silenced myoblasts, and, to a certain extent, STIM2 overexpression in STIM1-silenced myoblasts are able to restore both SOCE and myoblast differentiation. This is consistent with a recent work on mice neurons showing that STIM2 regulates SOCE independently of STIM1 (53). A hypothesis would be that STIM2 controls SOCE during small store depletions, whereas STIM1 would be recruited, together with STIM2, during larger store depletions.…”

Section: Discussionsupporting

confidence: 92%

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Darbellay

Arnaudeau

Ceroni

et al. 2010

Journal of Biological Chemistry

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Our recent work identified store-operated Ca 2؉ entry (SOCE) as the critical Ca 2؉ source required for the induction of human myoblast differentiation (Darbellay, B., Arnaudeau, S., König, S., Jousset, H., Bader, C., Demaurex, N., and Bernheim, L. (2009) J. Biol. Chem. 284, 5370 -5380). The present work indicates that STIM2 silencing, similar to STIM1 silencing, reduces myoblast SOCE amplitude and differentiation. Because myoblasts in culture can be induced to differentiate into myotubes, which spontaneously contract in culture, we used the same molecular tools to explore whether the Ca 2؉ mechanism of excitation-contraction coupling also relies on STIM1 and STIM2. Live cell imaging of early differentiating myoblasts revealed a characteristic clustering of activated STIM1 and STIM2 during the first few hours of differentiation. Thapsigargin-induced depletion of endoplasmic reticulum Ca 2؉ content caused STIM1 and STIM2 redistribution into clusters, and co-localization of both STIM proteins. Interaction of STIM1 and STIM2 was revealed by a rapid increase in fluorescence resonance energy transfer between CFP-STIM1 and YFP-STIM2 after SOCE activation and confirmed by co-immunoprecipitation of endogenous STIM1 and STIM2. Although both STIM proteins clearly contribute to SOCE and are required during the differentiation process, STIM1 and STIM2 are functionally largely redundant as overexpression of either STIM1 or STIM2 corrected most of the impact of STIM2 or STIM1 silencing on SOCE and differentiation. With respect to excitation-contraction, we observed that human myotubes rely also on STIM1 and STIM2 to refill their endoplasmic reticulum Ca 2؉ -content during repeated KCl-induced Ca 2؉ releases. This indicates that STIM2 is a necessary partner of STIM1 for excitation-contraction coupling. Thus, both STIM proteins are required and interact to control SOCE during human myoblast differentiation and human myotube excitationcontraction coupling. STIM1 and STIM2 are endoplasmic reticulum (ER)2 transmembrane proteins that are activated by a drop in Ca 2ϩ content in the ER (2-5). Once activated, STIM1 and STIM2 trigger a Ca 2ϩ influx (also called store-operated Ca 2ϩ entry (SOCE)) through Ca 2ϩ -selective Orai channels located at the plasma membrane (6 -13). This Ca 2ϩ influx restores the ER Ca 2ϩ content (2-4, 10, 12, 14 -26).Several studies examined whether STIM2 had a specific role, distinct from STIM1, but no clear answer has emerged yet. A lower Ca 2ϩ -activation threshold of STIM2 as compared with STIM1 has been suggested (2), although N-terminal Ca 2ϩ -binding affinity seems to be similar for STIM1 and STIM2 (27-29). In STIM2 knock-out mice, and also in several cell types in which STIM2 has been silenced, SOCE amplitude is only slightly reduced. This could reflect either a smaller activation of Orai1 by the N-terminal part of STIM2 or a lower expression of STIM2 as compared with STIM1 (3,4,24,30). In other studies, overexpression of STIM2 has been reported to inhibit SOCE (31) or, on the contrary, to restore SOCE i...

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Section: Discussionsupporting

confidence: 92%

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Darbellay

Arnaudeau

Ceroni

et al. 2010

Journal of Biological Chemistry

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“…arterial thrombosis in ischemic brain infraction (59) and hypoxic damage to neurons (60). In contrast, STIM1/Orai1-dependent SOCe is required for T and B cell activation (61), and mutations in STIM1 result in immunodeficiency and autoimmune syndromes (62).…”

Section: Discussionmentioning

confidence: 99%

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca 2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPSmediated Ca 2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca 2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca 2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1 -/-mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca 2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

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“…Hyperactive SOCE may contribute to the motor deficiencies in σ1R-knockout mice (Maurice and Su, 2009;Sabino et al, 2009;Mavlyutov et al, 2010) and to neurodegeneration in Alzheimer's (Mishina et al, 2008;Ishikawa and Hashimoto, 2009;Hyrskyluoto et al, 2013) and Parkinson's diseases (Mishina et al, 2005;Hyrskyluoto et al, 2013;Francardo et al, 2014), where expression of σ1R is reduced. These suggestions prompt consideration of whether σ1R also interacts with STIM2 because it appears to play the major role in regulating SOCE in central neurons (Berna-Erro et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1

Srivats¹,

Balasuriya²,

Pasche³

et al. 2016

J Gen Physiol

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STIM2 Regulates Capacitive Ca ²⁺ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death

Cited by 242 publications

References 46 publications

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1

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STIM2 Regulates Capacitive Ca 2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death

Cited by 242 publications

References 46 publications

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Human Muscle Economy Myoblast Differentiation and Excitation-Contraction Coupling Use the Same Molecular Partners, STIM1 and STIM2

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1

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Resources

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STIM2 Regulates Capacitive Ca ²⁺ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death

Sigma1 receptors inhibit store-operated Ca²⁺ entry by attenuating coupling of STIM1 to Orai1