Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes

  • Nat Commun. 2022 Aug 2;13(1):4481. doi: 10.1038/s41467-022-31959-0.
Yu Yuan  1 ,  Dawid Jaślan  2 ,  Taufiq Rahman  3 ,  Stephen R Bolsover  1 ,  Vikas Arige  4 ,  Larry E Wagner 2nd  4 ,  Carla Abrahamian  2 ,  Rachel Tang  2 ,  Marco Keller  5 ,  Jonas Hartmann  1 ,  Anna S Rosato  2 ,  Eva-Maria Weiden  2 ,  Franz Bracher  5 ,  David I Yule  4 ,  Christian Grimm  6 ,  Sandip Patel  7
Affiliations
  • 1. Department of Cell and Developmental Biology, University College London, London, UK.
  • 2. Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.
  • 3. Department of Pharmacology, University of Cambridge, Cambridge, UK.
  • 4. Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA.
  • 5. Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians University, Munich, Germany.
  • 6. Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany. [email protected].
  • 7. Department of Cell and Developmental Biology, University College London, London, UK. [email protected].
PMID: 35918320 DOI: 10.1038/s41467-022-31959-0
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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