Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases

Tedeschi, Valentina; Russa, Daniele La; Franco, Cristina; Vinciguerra, Antonio; Amantea, Diana; Secondo, Agnese

doi:10.3390/cells10102518

Cited by 7 publications

(4 citation statements)

References 191 publications

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“…We measured the activity of mechanosensitive channels Piezo1 and TRPV4, as well as SOCC, mainly constituted by STIM1, TRPC1 and Orai1. 34 According to the dose-dependent experiments, 4 μg/mL S-RBD was chosen for subsequent molecular and functional assessments (Supplementary Fig. 1 ).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

Yang

Liu

Han

et al. 2023

Sig Transduct Target Ther

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Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

Yang

Liu

Han

et al. 2023

Sig Transduct Target Ther

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“…STIMs can act as modulators of Ca 2+ signaling between cellular compartments [78][79][80], thereby supporting NMDAR trafficking both to and from the PM. The prediction from this hypothesis is that STIM and NMDARs may form a complex.…”

Section: Discussionmentioning

confidence: 99%

STIM2 regulates NMDA receptor endocytosis that is induced by short-term NMDA receptor overactivation in cortical neurons

Serwach,

Nurowska,

Klukowska

et al. 2023

Cell. Mol. Life Sci.

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Recent findings suggest an important role for the dysregulation of stromal interaction molecule (STIM) proteins, activators of store-operated Ca2+ channels, and the prolonged activation of N-methyl-D-aspartate receptors (NMDARs) in the development of neurodegenerative diseases. We previously demonstrated that STIM silencing increases Ca2+ influx through NMDAR and STIM–NMDAR2 complexes are present in neurons. However, the interplay between NMDAR subunits (GluN1, GluN2A, and GluN2B) and STIM1/STIM2 with regard to intracellular trafficking remains unknown. Here, we found that the activation of NMDAR endocytosis led to an increase in STIM2–GluN2A and STIM2–GluN2B interactions in primary cortical neurons. STIM1 appeared to migrate from synaptic to extrasynaptic sites. STIM2 silencing inhibited post-activation NMDAR translocation from the plasma membrane and synaptic spines and increased NMDAR currents. Our findings reveal a novel molecular mechanism by which STIM2 regulates NMDAR synaptic trafficking by promoting NMDAR endocytosis after receptor overactivation, which may suggest protection against excessive uncontrolled Ca2+ influx through NMDARs.

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“…The two core elements of SOCE have now been well described: the first are stromal interaction molecule (STIM) family members, which are integral ER membrane proteins that sense the lowering of lumenal ER Ca 2+ levels and translocate to ER–plasma membrane (PM) contact sites where they cluster and recruit the second SOCE component, the PM Ca 2+ ‐permeable Orai channel family members that mediate Ca 2+ influx into the cell (Emrich et al., 2022; Lewis, 2020; Prakriya & Lewis, 2015; Putney, 2017). The SOCE machinery is not restricted to a simple STIM/Orai interaction but involves a network of proteins constituting a complex interactome that includes soluble and membrane proteins that regulate SOCE (Berlansky et al., 2021; Tedeschi et al., 2021; Wang & Demaurex, 2021).…”

Section: Introductionmentioning

confidence: 99%

SOCE as a regulator of neuronal activity

Courjaret

Prakriya

Machaca

2023

The Journal of Physiology

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Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases

Cited by 7 publications

References 191 publications

SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells

STIM2 regulates NMDA receptor endocytosis that is induced by short-term NMDA receptor overactivation in cortical neurons

SOCE as a regulator of neuronal activity

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