FIGURE 2.

Possible sites of regulation of the canonical pathway of autophagy by IP₃ receptors and Ca²⁺. The middle box shows several of the molecular complexes that participate in autophagy. The pathways by which physiological factors such as nutrient availability and growth factors (indicated in red) modulate autophagy are shown schematically. Possible sites at which IP₃Rs or elevated cytosolic Ca²⁺ could also modulate this pathway are indicated in blue. The specific mechanisms are as follows: 1, transfer of Ca²⁺ from the ER to the mitochondria mediated by IP₃Rs could contribute to the maintenance of an elevated “energy state” (high ATP/AMP ratio); 2, Ca²⁺ acting through calmodulin-dependent kinase kinase-β (CaMKK-β) can activate AMPK (15); 3, Vps34 has also been suggested to be a CaM-dependent enzyme (46); 4, Bcl-2, by binding IP₃Rs, can influence the amount bound to the Beclin-1-Vps34 complex (37) ; and 5, activation of calpains has been proposed to inhibit autophagy (16). The only target of calpains in the autophagic pathway that has been described is Atg5 (63). Abbreviations used: FIP200, focal adhesion kinase-interacting protein; Ulk, Unc51-like kinase; TSC, tuberous sclerosis complex protein; Rheb, Ras homology enriched in brain protein; S6K-1, p70 ribosomal protein S6 kinase-1; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1.