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

Published version
Peer-reviewed

Type

Article

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Authors

Yuan, Yu 
Bolsover, Stephen R 
Arige, Vikas 

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.

Description

Keywords

Bias, Calcium, Calcium Channels, Calcium Signaling, Cations, Lysosomes, NADP

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

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