Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Klec, C; Madreiter-Sokolowski, CT; Ziomek, G; Stryeck, S; Sachdev, V; Duta-Mare, M; Gottschalk, B; Depaoli, MR; Rost, R; Hay, J; Waldeck-Weiermair, M; Kratky, D; Madl, T; Malli, R; Graier, WF.
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.
Cell Physiol Biochem. 2019; 53(3): 573-586.
Doi: 10.33594/000000158
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Graier Wolfgang
- Klec Christiane
- Co-Autor*innen der Med Uni Graz
- Depaoli Maria Rosa
- Duta-Mare Madalina-Cristina
- Gottschalk Benjamin
- Hay Jesse
- Kratky Dagmar
- Madl Tobias
- Madreiter-Sokolowski Corina
- Malli Roland
- Rost René
- Sachdev Vinay
- Stryeck Sarah
- Waldeck-Weiermair Markus
- Ziomek Gabriela
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- Abstract:
- 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. 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. 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. 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. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.