Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
- Ludwig Maximilian University of Munich, Germany
- UCL London, United Kingdom
- Medical University of Graz, Austria
- University of Leipzig, Germany
- Roche, Switzerland
- MHH Hannover, Germany
- University College London, United Kingdom
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Johann Schredelseker
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
- Richard S Lewis, Stanford University School of Medicine, United States
Version history
- Received: December 23, 2019
- Accepted: March 12, 2020
- Accepted Manuscript published: March 13, 2020 (version 1)
- Accepted Manuscript updated: March 16, 2020 (version 2)
- Version of Record published: March 31, 2020 (version 3)
- 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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Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
eLife 9:e54712.
https://doi.org/10.7554/eLife.54712
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