Preferential Coupling of the NAADP Pathway to Exocytosis in T-Cells.

A cytotoxic T-lymphocyte (CTL) kills an infected or tumorigenic cell by Ca²⁺-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. However, these granules are more than reservoirs of secretory cytolytic proteins but may also serve as unique Ca²⁺ signaling hubs that autonomously generate their own signals for exocytosis. This review discusses a selective role for the Ca²⁺-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP) and its molecular targets, two-pore channels (TPCs), in stimulating exocytosis. Given that TPCs reside on the exocytotic granules themselves, these vesicles generate as well as respond to NAADP-dependent Ca²⁺ signals, which may have wider implications for stimulus-secretion coupling, vesicular fusion, and patho-physiology.