title: Lithium-Sensitive Store-Operated Ca2+ Entry in the Regulation of FGF23 Release.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Lithium stimulates FGF23 release at least in part by NF-κB dependent up-regulation of Orai1 transcription and store operated Ca2+ entry.
authors.affiliation: Department of Physiology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Yan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmidt
authors.forename: Madhuri S
authors.initials: MS
authors.lastname: Salker
authors.forename: Dorothea
authors.initials: D
authors.lastname: Alexander
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology
chemical_list: D018692:Antimanic Agents; D004791:Enzyme Inhibitors; C505605:Fgf23 protein, rat; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D054358:Withanolides; D005346:Fibroblast Growth Factors; D019284:Thapsigargin; D008094:Lithium; D000252:Calcium-Transporting ATPases; C009684:withaferin A; D002118:Calcium