Yuan, Yu; Jaślan, Dawid; Rahman, Taufiq; Bolsover, Stephen R; Arige, Vikas; Wagner, Larry E; Abrahamian, Carla; ... Patel, Sandip; + view all Yuan, Yu; Jaślan, Dawid; Rahman, Taufiq; Bolsover, Stephen R; Arige, Vikas; Wagner, Larry E; Abrahamian, Carla; Tang, Rachel; Keller, Marco; Hartmann, Jonas; Rosato, Anna S; Weiden, Eva-Maria; Bracher, Franz; Yule, David I; Grimm, Christian; Patel, Sandip; - view fewer (2022) Segregated cation flux by TPC2 biases Ca^{2+} signaling through lysosomes. Nature Communications , 13 (1) , Article 4481. 10.1038/s41467-022-31959-0.

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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 Ca2+ signals and regulating lysosomal pH and motility. Our data reveal that flux of different ions through the same pore can be independently controlled and identify TPC2 as a likely coincidence detector that optimizes lysosomal Ca2+ signaling.

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