1. Biochemistry and Chemical Biology
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Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

  1. Susanne Gerndt
  2. Cheng-Chang Chen
  3. Yu-Kai Chao
  4. Yu Yuan
  5. Sandra Burgstaller
  6. Anna Scotto Rosato
  7. Einar Krogsaeter
  8. Nicole Urban
  9. Katharina Jacob
  10. Ong Nam Phuong Nguyen
  11. Meghan T Miller
  12. Marco Keller
  13. Angelika M Vollmar
  14. Thomas Gudermann
  15. Susanna Zierler
  16. Johann Schredelseker
  17. Michael Schaefer
  18. Martin Biel
  19. Roland Malli
  20. Christian Wahl-Schott  Is a corresponding author
  21. Franz Bracher  Is a corresponding author
  22. Sandip Patel  Is a corresponding author
  23. Christian Grimm  Is a corresponding author
  1. Ludwig Maximilian University of Munich, Germany
  2. UCL London, United Kingdom
  3. Medical University of Graz, Austria
  4. University of Leipzig, Germany
  5. Roche, Switzerland
  6. MHH Hannover, Germany
  7. University College London, United Kingdom
Research Article
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Cite this article as: eLife 2020;9:e54712 doi: 10.7554/eLife.54712

Abstract

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

Article and author information

Author details

  1. Susanne Gerndt

    Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Cheng-Chang Chen

    Pharmacology, Ludwig Maximilian University of Munich, München, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1282-4026
  3. Yu-Kai Chao

    Walther-Straub-Institute of Pharmacology and Toxicology, LM-University Munich, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1202-2448
  4. Yu Yuan

    Biosciences, UCL London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Sandra Burgstaller

    Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
  6. Anna Scotto Rosato

    Medicine, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Einar Krogsaeter

    Medicine, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8232-5498
  8. Nicole Urban

    Pharmacology/Medicine, University of Leipzig, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Katharina Jacob

    Medicine, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Ong Nam Phuong Nguyen

    Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Meghan T Miller

    HTS, Roche, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Marco Keller

    Pharmacy, Ludwig Maximilian University of Munich, München, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Angelika M Vollmar

    Pharmacy, Ludwig Maximilian University of Munich, München, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Thomas Gudermann

    Medicine, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Susanna Zierler

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4684-0385
  16. Johann Schredelseker

    Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6657-0466
  17. Michael Schaefer

    Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Martin Biel

    Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Roland Malli

    Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6327-8729
  20. Christian Wahl-Schott

    Medicine, MHH Hannover, Hannover, Germany
    For correspondence
    wahl-schott.christian@mh-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
  21. Franz Bracher

    Pharmacy, Ludwig Maximilian University of Munich, München, Germany
    For correspondence
    franz.bracher@cup.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
  22. Sandip Patel

    Cell and Developmental Biology, University College London, London, United Kingdom
    For correspondence
    patel.s@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  23. Christian Grimm

    Department of Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany
    For correspondence
    Christian.Grimm@med.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0177-5559

Funding

Mucolipidosis IV Foundation (MDBR-17-120- ML4)

  • Christian Grimm

Deutsche Forschungsgemeinschaft (SFB/TRR152 P04)

  • Christian Grimm

Deutsche Forschungsgemeinschaft (SFB/TRR152 P06)

  • Christian Wahl-Schott

Deutsche Forschungsgemeinschaft (SFB/TRR152 P12)

  • Martin Biel

Deutsche Forschungsgemeinschaft (BR 1034/7-1)

  • Franz Bracher

Biotechnology and Biological Sciences Research Council (BB/N01524X/1)

  • Sandip Patel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Bavarian Government and the European Union. All of the animals were handled according to approved institutional animal care protocols of the University of Munich. The protocol was approved by the Bavarian Government (AZ55.2-1-54-2532-170-17).

Reviewing Editor

  1. Richard S Lewis, Stanford University School of Medicine, United States

Publication history

  1. Received: December 23, 2019
  2. Accepted: March 12, 2020
  3. Accepted Manuscript published: March 13, 2020 (version 1)
  4. Accepted Manuscript updated: March 16, 2020 (version 2)
  5. Version of Record published: March 31, 2020 (version 3)
  6. Version of Record updated: April 6, 2020 (version 4)

Copyright

© 2020, Gerndt et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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