Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes

Yu Yuan, Dawid Jaślan, Taufiq Rahman, Stephen R. Bolsover, Vikas Arige, Larry E. Wagner, Carla Abrahamian, Rachel Tang, Marco Keller, Jonas Hartmann, Anna S. Rosato, Eva-Maria Weiden, Franz Bracher, David I. Yule, Christian Grimm () and Sandip Patel ()
Additional contact information
Yu Yuan: University College London
Dawid Jaślan: Ludwig-Maximilians University
Taufiq Rahman: University of Cambridge
Stephen R. Bolsover: University College London
Vikas Arige: University of Rochester
Larry E. Wagner: University of Rochester
Carla Abrahamian: Ludwig-Maximilians University
Rachel Tang: Ludwig-Maximilians University
Marco Keller: Ludwig-Maximilians University
Jonas Hartmann: University College London
Anna S. Rosato: Ludwig-Maximilians University
Eva-Maria Weiden: Ludwig-Maximilians University
Franz Bracher: Ludwig-Maximilians University
David I. Yule: University of Rochester
Christian Grimm: Ludwig-Maximilians University
Sandip Patel: University College London

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31959-0

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