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

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Yuan, Yu 
Bolsover, Stephen R 
Arige, Vikas 


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.



Article, /631/80/86/1999, /631/1647/1453/1970, /631/80/642/1624, /631/80/86/2372, /9/74, /13/106, /13/109, /14, /14/34, /14/35, /14/63, /45/41, /45/70, article

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Nat Commun

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Springer Science and Business Media LLC
RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/T015853/1, BB/W01551X/1)