Figure 1.

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.