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- Title
Lithium- Sensitive Store-Operated Ca Entry in the Regulation of FGF23 Release.
- Authors
Zhang, Bingbing; Yan, Jing; Schmidt, Sebastian; Salker, Madhuri S.; alexander, Dorothea; Föller, Michael; Lang, Florian
- Abstract
Background/Aims: Lithium, a widely used drug for the treatment of mood disorders, has previously been shown to stimulate the release of fibroblast growth factor FGF23, a powerful regulator of 1,25(OH)2D3 formation and mineral metabolism. The cellular mechanisms involved have remained elusive. Lithium has been shown to modify Ca2+ signaling. In a wide variety of cells, Ca2+ entry is accomplished by the pore-forming Ca2+ channel subunit Orai1 and its regulator STIM, which stimulates Orai following Ca2+ depletion of intracellular stores. Transcription factors promoting Orai1 expression include NF-κB. The present study thus explored whether the effect of lithium on FGF23 involves and requires Ca2+ entry. Methods: Experiments were performed in UMR106 osteoblastic cells and immortalized primary osteoblasts (IPO). FGF23 and Orai1 transcript levels were estimated from qRT-PCR, cytosolic Ca2+ concentration ([Ca2+]i) from Fura2 fluorescence and store-operated Ca2+ entry (SOCE) from an increase in [Ca2+]i following store depletion by inhibition of the sarcoendoplasmatic Ca2+ ATPase (SERCA) with thapsigargin (1 µM). Results: SOCE in UMR106 cells was enhanced by lithium treatment, an effect abrogated by Orai1 inhibitor 2-APB (50 µM). FGF23 transcript levels were increased by lithium and inhibited by Orai1 inhibitors 2-APB (50 µM) and YM58483 (100 nM) as well as NF-κB inhibitors wogonin (100 µM) and withaferin A (500 nM). Moreover, Orai1 transcript levels were up-regulated by lithium, an effect attenuated by wogonin and withaferin A. Conclusion: Lithium stimulates FGF23 release at least in part by NF-κB dependent up-regulation of Orai1 transcription and store operated Ca2+ entry. © 2015 The Author(s) Published by S. Karger AG, Basel
- Subjects
THERAPEUTIC use of lithium; AFFECTIVE disorders; MENTAL health services; FIBROBLAST growth factors
- Publication
NeuroSignals (Karger AG), 2015, Vol 23, Issue 1, p34
- ISSN
1424-862X
- Publication type
Article
- DOI
10.1159/000442602