Segregated cation flux by TPC2 biases Ca²⁺ signaling through lysosomes.

ABSTRACT: Two-pore channels are endo-lysosomal cation channels with malleable selectivity filters that drive endocytic ion flux and membrane traffic. Here we show that TPC2 can differentially regulate its cation permeability when co-activated by its endogenous ligands, NAADP and PI(3,5)P₂. Whereas NAADP rendered the channel Ca²⁺-permeable and PI(3,5)P₂ rendered the channel Na⁺-selective, a combination of the two increased Ca²⁺ but not Na⁺ flux. Mechanistically, this was due to an increase in Ca²⁺ permeability independent of changes in ion selectivity. Functionally, we show that cell permeable NAADP and PI(3,5)P₂ mimetics synergistically activate native TPC2 channels in live cells, globalizing cytosolic Ca^2+<

SUBMITTER: Yuan Y 

PROVIDER: S-EPMC9346130 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature