The Molecular Basis for Ca²⁺ Signalling by NAADP: Two-Pore Channels in a Complex?

NAADP is a potent Ca²⁺ mobilizing messenger in a variety of cells but its molecular mechanism of action is incompletely understood. Accumulating evidence indicates that the poorly characterized two-pore channels (TPCs) in animals are NAADP sensitive Ca²⁺-permeable channels. TPCs localize to the endo-lysosomal system but are functionally coupled to the better characterized endoplasmic reticulum Ca²⁺ channels to generate physiologically relevant complex Ca²⁺ signals. Whether TPCs directly bind NAADP is not clear. Here we discuss the idea based on recent studies that TPCs are the pore-forming subunits of a protein complex that includes tightly associated, low molecular weight NAADP-binding proteins.