Lithium- Sensitive Store-Operated Ca&lt;sup&gt;2+&lt;/sup&gt; Entry in the Regulation of FGF23 Release

Zhang, Bingbing; Yan, Jing; Schmidt, Sebastian; Salker, Madhuri S.; Alexander, Dorothea; Föller, Michael; Läng, Florian

doi:10.1159/000442602

Cited by 21 publications

(18 citation statements)

References 119 publications

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“…Orai1 and SOCE are up-regulated by PI3K dependent signaling and thus sensitive to chorein [24]. Stimulators of Orai1 expression and SOCE include lithium [25][26][27], which may slow neurodegeneration [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

Sukkar¹,

Hauser²,

Pelzl³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The neurodegenerative disease Chorea-Acanthocytosis (ChAc) is caused by loss-of-function-mutations of the chorein-encoding gene VPS13A. In ChAc neurons transcript levels and protein abundance of Ca²⁺ release activated channel moiety (CRAC) Orai1 as well as its regulator STIM1/2 are decreased, resulting in blunted store operated Ca²⁺-entry (SOCE) and enhanced suicidal cell death. SOCE is up-regulated and cell death decreased by lithium. The effects of lithium are paralleled by upregulation of serum & glucocorticoid inducible kinase SGK1 and abrogated by pharmacological SGK1 inhibition. In other cell types SGK1 has been shown to be partially effective by upregulation of NFκB, a transcription factor stimulating the expression of Orai1 and STIM. The present study explored whether pharmacological inhibition of NFκB interferes with Orai1/STIM1/2 expression and SOCE and their upregulation by lithium in ChAc neurons. Methods: Cortical neurons were differentiated from induced pluripotent stem cells generated from fibroblasts of ChAc patients and healthy volunteers. Orai1 and STIM1 transcript levels and protein abundance were estimated from qRT-PCR and Western blotting, respectively, cytosolic Ca²⁺-activity ([Ca²⁺]_i) from Fura-2-fluorescence, SOCE from increase of [Ca²⁺]_i following Ca²⁺ re-addition after Ca²⁺-store depletion with sarco-endoplasmatic Ca²⁺-ATPase inhibitor thapsigargin (1µM), as well as CRAC current utilizing whole cell patch clamp recording. Results: Orai1 and STIM1 transcript levels and protein abundance as well as SOCE and CRAC current were significantly enhanced by lithium treatment (2 mM, 24 hours). These effects were reversed by NFκB inhibitor wogonin (50 µM). Conclusion: The stimulation of expression and function of Orai1/STIM1/2 by lithium in ChAc neurons are disrupted by pharmacological NFκB inhibition.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

Sukkar¹,

Hauser²,

Pelzl³

et al. 2018

Cell Physiol Biochem

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“…Increases of cytosolic Ca 2+ activity ([Ca 2+ ] i ) are powerful regulators of cell survival and cell death [29-33]. In bone cells, Orai1 and thus SOCE is up-regulated by lithium [34], which favorably influences the course of neurodegenerative disease [35-42]. …”

Section: Introductionmentioning

confidence: 99%

Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients

Pelzl

Elsir

Sahu

et al. 2017

Cell Physiol Biochem

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Background: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca²⁺ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment. Methods: Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca²⁺ activity ([Ca²⁺]_i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca²⁺]_i following Ca²⁺ re-addition after Ca²⁺-store depletion with sarcoendoplasmatic Ca²⁺-ATPase (SERCA) inhibitor thapsigargin (1 µM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry. Results: SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 µM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB. Conclusions: In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment.

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“…serum & glucocorticoid inducible kinase (SGK1), a kinase participating in the regulation of FGF23 formation [45]. SGK1 is in turn at least in part effective by increasing store operated Ca 2+ entry [45][46][47].…”

Section: Resultsmentioning

confidence: 99%

“…Cellular mechanisms governing FGF23 release include increase of cytosolic Ca 2+ activity following stimulation of store operated Ca 2+ entry (SOCE) [45][46][47]. Orai1, the pore forming channel protein accomplishing SOCE is upregulated by the serum & glucocorticoid inducible kinase SGK1 [48][49][50][51].…”

Section: Introductionmentioning

confidence: 99%

Impact of Annexin A 7 Deficiency on FGF23 Plasma Concentrations

Umbach

El-Attar

Luo

et al. 2016

Kidney Blood Press Res

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Background/Aims: The release of fibroblast growth factor FGF23, a powerful regulator of 1,25(OH)₂D₃ formation and mineral metabolism, is stimulated by store-operated Ca²⁺ entry (SOCE), which is accomplished by the pore forming Ca²⁺ release activated channel protein Orai1. Regulators of Orai1 and thus FGF23 release include serum & glucocorticoid inducible kinase SGK1, a kinase up-regulated by glucocorticosteroids. Some effects of glucocorticoids require the presence of annexin A7, such as suppression of prostaglandin E2 in gastric glands. The present study thus explored whether annexin A7 impacts on FGF23 plasma levels. Methods: Comparisons were made between gene targeted mice lacking functional annexin A7 (Anx7^-/-) and their wild type littermates (Anx7^+/+). Serum C-terminal-FGF23, intact FGF23, 1,25(OH)₂D₃ and PTH concentrations were measured by ELISA or EIA. The serum and urinary phosphate concentrations were measured by colorimetry, the serum Ca²⁺ concentration and the urinary Ca²⁺ concentration by flame photometry. Results: Serum C-terminal FGF23 levels and corticosterone levels were significantly higher and serum 1,25(OH)₂ D₃ and PTH levels were significantly lower in Anx7^-/- than in Anx7^+/+ mice. Water intake was slightly but significantly higher in Anx7^-/- mice than in Anx7^+/+ mice. No significant difference was observed between Anx7^-/- and Anx7^+/+ mice in urinary fluid excretion, plasma Ca²⁺ concentration, plasma phosphate concentration and urinary Ca²⁺ output. The urinary phosphate output was significantly lower in Anx7^-/- mice than in Anx7^+/+ mice. Conclusion: Annexin A7 deficiency upregulates FGF23 plasma levels, an effect paralleled by increased corticosterone plasma levels, as well as decreased 1,25(OH)₂ D₃ and PTH plasma levels.

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Lithium- Sensitive Store-Operated Ca<sup>2+</sup> Entry in the Regulation of FGF23 Release

Cited by 21 publications

References 119 publications

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients

Impact of Annexin A 7 Deficiency on FGF23 Plasma Concentrations

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