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Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Fran, 2022. "Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31959-0
    DOI: 10.1038/s41467-022-31959-0
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    References listed on IDEAS

    as
    1. Peter J. Calcraft & Margarida Ruas & Zui Pan & Xiaotong Cheng & Abdelilah Arredouani & Xuemei Hao & Jisen Tang & Katja Rietdorf & Lydia Teboul & Kai-Ting Chuang & Peihui Lin & Rui Xiao & Chunbo Wang &, 2009. "NAADP mobilizes calcium from acidic organelles through two-pore channels," Nature, Nature, vol. 459(7246), pages 596-600, May.
    2. Frances M. Platt, 2014. "Sphingolipid lysosomal storage disorders," Nature, Nature, vol. 510(7503), pages 68-75, June.
    3. Stephen K. Dove & Frank T. Cooke & Michael R. Douglas & Lee G. Sayers & Peter J. Parker & Robert H. Michell, 1997. "Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis," Nature, Nature, vol. 390(6656), pages 187-192, November.
    4. Jiyuan Zhang & Xin Guan & Kunal Shah & Jiusheng Yan, 2021. "Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Jose Manuel Cancela & Grant C. Churchill & Antony Galione, 1999. "Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells," Nature, Nature, vol. 398(6722), pages 74-76, March.
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