Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis
Open Access
- 3 May 2012
- journal article
- research article
- Published by Springer Nature in Cell Death & Disease
- Vol. 3 (5), e304
- https://doi.org/10.1038/cddis.2012.45
Abstract
Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP3R) serve to discharge Ca2+ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP3R isoforms and protect cells from apoptosis, reducing ER Ca2+ release. However, it has not been elucidated which IP3R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP3R I, strongly suppresses IP3-mediated Ca2+ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca2+ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca2+ release. Moreover, regulating Ca2+ flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP3R III, leading to diminished Ca2+ transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt.Keywords
This publication has 42 references indexed in Scilit:
- Endoplasmic reticulum is a main localization site of mTORC2Biochemical and Biophysical Research Communications, 2011
- The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinomaCell Calcium, 2010
- Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylationBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008
- Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosisOncogene, 2008
- Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuliBiochemical and Biophysical Research Communications, 2008
- Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca 2+ release and apoptosisProceedings of the National Academy of Sciences, 2008
- Apoptosis regulation by Bcl-x L modulation of mammalian inositol 1,4,5-trisphosphate receptor channel isoform gatingProceedings of the National Academy of Sciences, 2007
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- Mitochondrial‐targeted active Akt protects SH‐SY5Y neuroblastoma cells from staurosporine‐induced apoptotic cell deathJournal of Cellular Biochemistry, 2007
- Calcium signalling: dynamics, homeostasis and remodellingNature Reviews Molecular Cell Biology, 2003