High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

Nikoleta Daskoulidou, Bo Zeng, Lisa M. Berglund, Hongni Jiang, Gui Lan Chen, Olga Kotova, Sunil Bhandari, James Ayoola, Steven Griffin, Stephen Atkin, Maria F. Gomez, Shang Zhong Xu

Research output: Contribution to journalArticle

21 Citations (Scopus)


Abstract: ORAI and stromal interaction molecule (STIM) are store-operated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIM in vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM d-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2Akita/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells co-expressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia. Key message: ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose.Increased expression is confirmed in Akita (Ins2Akita/J) and STZ diabetic mice and patients.Upregulation mechanism is mediated by Ca2+/calcineurin/NFATc3 signalling.High glucose has no direct effects on ORAI1-3 channel activity and channel activation process.

Original languageEnglish
Pages (from-to)511-521
Number of pages11
JournalJournal of Molecular Medicine
Issue number5
Publication statusPublished - 1 May 2015
Externally publishedYes


  • Calcineurin
  • Calcium channels
  • Diabetes mellitus
  • Hyperglycaemia
  • NFATc transcription factors
  • ORAI
  • STIM1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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  • Cite this

    Daskoulidou, N., Zeng, B., Berglund, L. M., Jiang, H., Chen, G. L., Kotova, O., Bhandari, S., Ayoola, J., Griffin, S., Atkin, S., Gomez, M. F., & Xu, S. Z. (2015). High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling. Journal of Molecular Medicine, 93(5), 511-521. https://doi.org/10.1007/s00109-014-1234-2