Presenilin-1 established ER-Ca2+ leak: A follow up on its importance for the initial insulin secretion in pancreatic islets and β-cells upon elevated glucose

Wolfgang F. Graier, Christiane Klec, Corina T. Madreiter-Sokolowski, Gabriela Ziomek, Sarah Stryeck, Vinay Sachdev, Madalina Duta-Mare, Benjamin Gottschalk, Maria R. Depaoli, Rene Rost, Jesse Hay, Markus Waldeck-Weiermair, Dagmar Kratky, Tobias Madl, Roland Malli

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background/Aims: In our recent work, the importance of GSK3β-mediated phosphorylation of presenilin-1 as crucial process to establish a Ca2+ leak in the endoplasmic reticulum and, subsequently, the pre-activation of resting mitochondrial activity in β-cells was demonstrated. The present work is a follow-up and reveals the importance of GSK3β-phosphorylated presenilin-1 for responsiveness of pancreatic islets and β-cells to elevated glucose in terms of cytosolic Ca2+ spiking and insulin secretion. Methods: Freshly isolated pancreatic islets and the two pancreatic β-cell lines INS-1 and MIN-6 were used. Cytosolic Ca2+ was fluorometrically monitored using Fura-2/AM and cellular insulin content and secretion were measured by ELISA. Results: Our data strengthened our previous findings of the existence of a presenilin-1-mediated ER-Ca2+ leak in β-cells, since a reduction of presenilin-1 expression strongly counteracted the ER Ca2+ leak. Furthermore, our data revealed that cytosolic Ca2+ spiking upon administration of high D-glucose was delayed in onset time and strongly reduced in amplitude and frequency upon siRNA-mediated knock-down of presenilin-1 or the inhibition of GSK3β in the pancreatic β-cells. Moreover, glucose-triggered initial insulin secretion disappeared by depletion from presenilin-1 and inhibition of GSK3β in the pancreatic β-cells and isolated pancreatic islets, respectively. Conclusion: These data complement our previous work and demonstrate that the sensitivity of pancreatic islets and β-cells to glucose illustrated as glucose-triggered cytosolic Ca2+ spiking and initial but not long-lasting insulin secretion crucially depends on a strong ER Ca2+ leak that is due to the phosphorylation of presenilin-1 by GSK3β, a phenomenon that might be involved in the development of type 2 diabetes.

Original languageEnglish
Pages (from-to)573-586
Number of pages14
JournalCellular Physiology and Biochemistry
Volume53
Issue number3
DOIs
StatePublished - 2019

Keywords

  • Ca spiking
  • Endoplasmic reticulum
  • Insulin secretion
  • Mitochondria

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