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- Title
Presenilin-1 Established ER-Ca<sup>2+</sup> Leak: a Follow Up on Its Importance for the Initial Insulin Secretion in Pancreatic Islets and β-Cells upon Elevated Glucose.
- Authors
Klec, Christiane; Madreiter-Sokolowski, Corina T.; Ziomek, Gabriela; Stryeck, Sarah; Sachdev, Vinay; Duta-Mare, Madalina; Gottschalk, Benjamin; Depaoli, Maria R.; Rost, Rene; Hay, Jesse; Waldeck-Weiermair, Markus; Kratky, Dagmar; Madl, Tobias; Malli, Roland; Graier, Wolfgang F.
- 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.
- Subjects
PRESENILINS; INSULIN; ISLANDS of Langerhans; PHOSPHORYLATION; TYPE 2 diabetes
- Publication
Cellular Physiology & Biochemistry (Cell Physiol Biochem Press GmbH & Co. KG), 2019, Vol 53, Issue 3, p573
- ISSN
1015-8987
- Publication type
Article
- DOI
10.33594/000000158