NAADP-Dependent TPC Current.

Two-pore channels, TPC1 and TPC2, are Ca2+ - and Na+ -permeable cation channels expressed on the membranes of endosomes and lysosomes in nearly all mammalian cells. These channels have been implicated in Ca2+ signaling initiated from the endolysosomes, vesicular trafficking, cellular metabolism, macropinocytosis, and viral infection. Although TPCs have been shown to mediate Ca2+ release from acidic organelles in response to NAADP (nicotinic acid adenine dinucleotide phosphate), the most potent Ca2+ mobilizing messenger, questions remain whether NAADP is a direct ligand of these channels. In whole-endolysosomal patch clamp recordings, it has been difficult to detect NAADP-evoked currents in vacuoles that expressed TPC1 or TPC2, while PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) activated a highly Na+ -selective current under the same experimental configuration. In this chapter, we summarize recent progress in this area and provide our observations on NAADP-elicited TPC2 currents from enlarged endolysosomes as well as their possible relationships with the currents evoked by PI(3,5)P2 . We propose that TPCs are channels dually regulated by PI(3,5)P2 and NAADP in an interdependent manner and the two endogenous ligands may have both distinguished and cooperative roles.