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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Klec, C; Madreiter-Sokolowski, CT; 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.
Glycogen Synthase Kinase 3 Beta Controls Presenilin-1-Mediated Endoplasmic Reticulum Ca²⁺ Leak Directed to Mitochondria in Pancreatic Islets and β-Cells.
Cell Physiol Biochem. 2019; 52(1): 57-75.
Doi: 10.33594/000000005
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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
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- Abstract:
- In pancreatic β-cells, the intracellular Ca²⁺ homeostasis is an essential regulator of the cells major functions. The endoplasmic reticulum (ER) as interactive intracellular Ca²⁺ store balances cellular Ca²⁺. In this study basal ER Ca²⁺ homeostasis was evaluated in order to reveal potential β-cell-specificity of ER Ca²⁺ handling and its consequences for mitochondrial Ca²⁺, ATP and respiration. The two pancreatic cell lines INS-1 and MIN-6, freshly isolated pancreatic islets, and the two non-pancreatic cell lines HeLA and EA.hy926 were used. Cytosolic, ER and mitochondrial Ca²⁺ and ATP measurements were performed using single cell fluorescence microscopy and respective (genetically-encoded) sensors/dyes. Mitochondrial respiration was monitored by respirometry. GSK3β activity was measured with ELISA. An atypical ER Ca²⁺ leak was observed exclusively in pancreatic islets and β-cells. This continuous ER Ca²⁺ efflux is directed to mitochondria and increases basal respiration and organellar ATP levels, is established by GSK3β-mediated phosphorylation of presenilin-1, and is prevented by either knockdown of presenilin-1 or an inhibition/knockdown of GSK3β. Expression of a presenlin-1 mutant that mimics GSK3β-mediated phosphorylation established a β-cell-like ER Ca²⁺ leak in HeLa and EA.hy926 cells. The ER Ca²⁺ loss in β-cells was compensated at steady state by Ca²⁺ entry that is linked to the activity of TRPC3. Pancreatic β-cells establish a cell-specific ER Ca²⁺ leak that is under the control of GSK3β and directed to mitochondria, thus, reflecting a cell-specific intracellular Ca²⁺ handling for basal mitochondrial activity. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.