Relation between IP3R and autophagy. IP3-induced Ca2+ release towards the mitochondria promotes ATP production, inhibition of AMPK and thus stimulation of mTOR activity. mTOR can stimulate the IP3Rs by direct phosphorylation. Inhibition of mTOR leads to the formation of the ULK1-Atg13-FIP200 complex and autophagy. In addition, the IP3R might act as scaffold for Bcl-2 and Beclin 1, thereby promoting the inhibition of Beclin 1 by Bcl-2. Beclin 1 promotes the formation of the PtdIns3K Complex III. Both complexes are necessary for the formation of the phagophore and subsequent autophagy. Ca2+ (and calmodulin) can activate multiple systems in the cell including CaMKKβ, ERK, CaMKI, PKCθ, DAPK, which phosphorylates Beclin 1, thereby mediating its dissociation from Bcl-2, and putatively also Vps34, a component of the PtdIns3K Complex III. The blue box indicates the mitochondrial (Mit.) compartment. Arrows indicate the flow of the signals; a green arrow indicates stimulation; a red arrow indicates inhibition; a double arrow indicates an interaction; a broken arrow indicates a mechanism that remains to be further defined. For more detailed explanation, see text.
Parys et al. Cell Communication and Signaling 2012 10:17 doi:10.1186/1478-811X-10-17