Fig. (3).

ER-derived Ca²⁺ effects on autophagy. A. Under starvation conditions, Ca²⁺ derived from the ER activates autophagy: ER depletion of Ca²⁺ by thapsigargin induces autophagy via the same signalling pathways from fig. 2A, and by a Ca²⁺-dependent phosphorylation of PKCθ that directs this kinase to autophagosomes. Ca²⁺ release from the ER through the IP₃R is inhibited with 2-APB and induced with Cadmium and this inhibits and activates, respectively, autophagy via ERK1/2 signalling. Ca²⁺-dependent phosphorylation of Beclin 1 by DAPK also induces autophagy. B. Under full nutrient conditions, Ca²⁺ derived from the ER restrains autophagy: Thapsigargin inhibits autophagy via ATG5 cleavage by calpains. As regards IP₃R function, inhibitors of inositol monophosphatases (IMPase), such as Lithium and L-690,330, which prevent IP₃ generation and, hence, Ca²⁺ release through IP₃R, induce autophagy. Also the inhibition of IP₃R function with xestospongin B and knockdown/knockout of IP₃R dissociates Beclin 1 from Bcl-2-IP₃R complex and stimulates autophagy. IP: inositol 4 monophosphate; IP₂: inositol 4,5 bisphosphate. See text for further details.