The STIM-Orai Pathway: Regulation of STIM and Orai by Thiol Modifications

Niemeyer, Barbara A.

doi:10.1007/978-3-319-57732-6_6

Cited by 8 publications

(8 citation statements)

References 107 publications

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“…STIM and Orai proteins present a variable number of reactive cysteines that impart redox sensitivity to SOCE. We refer the readers to a couple of review articles in which the mechanisms and functional consequences of STIM and Orai modulation by the redox state were extensively described [ 184 , 186 ]. Briefly, STIM1 displays two highly conserved thiol groups (Cys49 and Cys56) in the intraluminal NH 2 terminal tail, which are in close proximity to the Ca 2+ -binding site and are responsible for STIM1 regulation by ROS.…”

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

“…Conversely, the intraluminal protein, Erp57, could promote the formation of a disulfide bridge between Cys49 and Cys59 that prevents STIM1 activation and recruitment into submembrane puncta upon a reduction in [Ca 2+ ] ER [ 188 ]. Although some discrepancies between these two studies have been highlighted [ 184 , 186 ], the redox-dependent S-glutathionylation of Cys49 and Cys56 could release STIM1 from Erp57-dependent inhibition and result in SOCE activation. STIM2 protein presents a higher number of cysteine residues as related to STIM1 (15 vs. 4), and most of these (11 vs. 1) are located in the cytosolic COOH-terminal domain [ 184 , 186 ], which underlies STIM oligomerization and gating of Orai channels [ 189 ].…”

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

“…Although some discrepancies between these two studies have been highlighted [ 184 , 186 ], the redox-dependent S-glutathionylation of Cys49 and Cys56 could release STIM1 from Erp57-dependent inhibition and result in SOCE activation. STIM2 protein presents a higher number of cysteine residues as related to STIM1 (15 vs. 4), and most of these (11 vs. 1) are located in the cytosolic COOH-terminal domain [ 184 , 186 ], which underlies STIM oligomerization and gating of Orai channels [ 189 ]. A recent investigation showed that H 2 O 2 -dependent sulfonylation of the cytoplasmic Cys313 hinders STIM2 oligomerization and, therefore, prevents Orai1 activation [ 183 ].…”

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

“…Orai1 and Orai2 share three highly conserved cysteine residues: Cys126 in the second TM domain, Cys143 in the cytosolic loop connecting the second and third TM domains, and Cys195 at the extracellular end of the third TM domain. Orai3 lacks Cys195 but contains two additional cysteine residues in the long extracellular loop connecting the third and fourth TM domains [ 184 , 186 ]. Bogeski et al unveiled that Cys195 represents the major reactive cysteine of Orai1 and is responsible for H 2 O 2 -dependent inhibition of I CRAC and SOCE in HEK293 cells transfected with STIM1 and Orai1, Jurkat T cells, and CD4 + T cells [ 185 , 186 ].…”

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

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Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

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An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

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Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

Section: Ros Modulate Store-operated Ca 2+ Entry In Vascular Endothelial Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

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“…The nucleophilic thiol group on cysteine is a well-known biological target of ebselen (Ref. 7). GSH is a tripeptide that contains glutamate (Glu), glycine (Gly) and cysteine (Cys).…”

Section: Introductionmentioning

confidence: 99%

Ebselen, a multi-target compound: its effects on biological processes and diseases

Cai

Xiang

et al. 2021

Expert Rev. Mol. Med.

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Ebselen is a well-known synthetic compound mimicking glutathione peroxidase (GPx), which catalyses some vital reactions that protect against oxidative damage. Based on a large number of in vivo and in vitro studies, various mechanisms have been proposed to explain its actions on multiple targets. It targets thiol-related compounds, including cysteine, glutathione, and thiol proteins (e.g., thioredoxin and thioredoxin reductase). Owing to this, ebselen is a unique multifunctional agent with important effects on inflammation, apoptosis, oxidative stress, cell differentiation, immune regulation and neurodegenerative disease, with anti-microbial, detoxifying and anti-tumour activity. This review summarises the current understanding of the multiple biological processes and molecules targeted by ebselen, and its pharmacological applications.

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