Selective modulation of subtype III IP(3)R by Akt regulates ER Ca(2+) release and apoptosis

Ca(2+) 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 (IP(3)R) serve to discharge Ca(2+) from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP(3)R isoforms and protect cells from apoptosis, reducing ER Ca(2+) release. However, it has not been elucidated which IP(3)R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP(3)R I, strongly suppresses IP(3)-mediated Ca(2+) release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca(2+) flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca(2+) release. Moreover, regulating Ca(2+) 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 IP(3)R III, leading to diminished Ca(2+) transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt.