NAADP/TPC2/Ca²⁺ signaling inhibits autophagy

Nicotinic adenine acid dinucleotide phosphate (NAADP) is one of the most potent endogenous Ca²⁺ mobilizing messengers. NAADP mobilizes Ca²⁺ from an acidic lysosome-related store, which can be subsequently amplified into global Ca²⁺ waves by calcium-induced calcium release (CICR) from ER/SR via Ins(1,4,5)P3 receptors or ryanodine receptors. A body of evidence indicates that 2 pore channel 2 (TPC2), a new member of the superfamily of voltage-gated ion channels containing 12 putative transmembrane segments, is the long sought after NAADP receptor. Activation of NAADP/TPC2/Ca²⁺ signaling inhibits the fusion between autophagosome and lysosome by alkalizing the lysosomal pH, thereby arresting autophagic flux. In addition, TPC2 is downregulated during neural differentiation of mouse embryonic stem (ES) cells, and TPC2 downregulation actually facilitates the neural lineage entry of ES cells. Here we propose the mechanism underlying how NAADPinduced Ca²⁺ release increases lysosomal pH and discuss the role of TPC2 in neural differentiation of mouse ES cells.