Fig. 1.

A mechanism for activation of autophagy by elevated cytoplasmic [Ca²⁺] in the canonical mTOR pathway. Various Ca²⁺ mobilizing agents have been shown to induce autophagy. Activation of calmodulin (CaM) by Ca²⁺ activates CaMKKβ, which phosphorylates and activates AMPK. Activated AMPK phosphorylates the TSC1/TSC1 complex, enhancing its GTPase activity to maintain Rheb in its GDP-bound inhibited state. Absence of Rheb-GTP activity inactivates mTORC1, releasing its break on autophagy. Inhibition of elevated [Ca²⁺]_i by buffering it with BAPTA prevents activation of CaMKKβ and AMPK, enabling Rheb to maintain mTORC1 activity, suppressing autophagy.