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Article

Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes

by
Kuo Zhou
1,
Xuexue Zhu
1,
Ke Ma
1,
Jibin Liu
2,
Bernd Nürnberg
1,
Meinrad Gawaz
3 and
Florian Lang
4,*
1
Department of Pharmacology, Experimental Therapy & Toxicology, Eberhard Karls University, 72074 Tübingen, Germany
2
Institute of Preventive Veterinary Medicine, Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
3
Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
4
Department of Vegetative and Clinical Physiology, Eberhard Karls University, 72074 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(7), 3292; https://doi.org/10.3390/ijms22073292
Submission received: 15 February 2021 / Revised: 14 March 2021 / Accepted: 18 March 2021 / Published: 24 March 2021
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 3.0)
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Abstract

In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.
Keywords: SOCE; ORAI1,2,3; STIM1,2; SGK1; NFAT5; Mg2+; Gd3+; calcium-sensing receptor; megakaryocytes SOCE; ORAI1,2,3; STIM1,2; SGK1; NFAT5; Mg2+; Gd3+; calcium-sensing receptor; megakaryocytes

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MDPI and ACS Style

Zhou, K.; Zhu, X.; Ma, K.; Liu, J.; Nürnberg, B.; Gawaz, M.; Lang, F. Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes. Int. J. Mol. Sci. 2021, 22, 3292. https://doi.org/10.3390/ijms22073292

AMA Style

Zhou K, Zhu X, Ma K, Liu J, Nürnberg B, Gawaz M, Lang F. Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes. International Journal of Molecular Sciences. 2021; 22(7):3292. https://doi.org/10.3390/ijms22073292

Chicago/Turabian Style

Zhou, Kuo, Xuexue Zhu, Ke Ma, Jibin Liu, Bernd Nürnberg, Meinrad Gawaz, and Florian Lang. 2021. "Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes" International Journal of Molecular Sciences 22, no. 7: 3292. https://doi.org/10.3390/ijms22073292

APA Style

Zhou, K., Zhu, X., Ma, K., Liu, J., Nürnberg, B., Gawaz, M., & Lang, F. (2021). Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes. International Journal of Molecular Sciences, 22(7), 3292. https://doi.org/10.3390/ijms22073292

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