2. Academic Validation
  3. Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

  • Elife. 2020 Mar 16;9:e54712. doi: 10.7554/eLife.54712.
Susanne Gerndt  # 1 2,  Cheng-Chang Chen  # 1,  Yu-Kai Chao  # 2,  Yu Yuan  # 3,  Sandra Burgstaller 4,  Anna Scotto Rosato 2,  Einar Krogsaeter 2,  Nicole Urban 5,  Katharina Jacob 2,  Ong Nam Phuong Nguyen 1,  Meghan T Miller 1 6,  Marco Keller 1,  Angelika M Vollmar 1,  Thomas Gudermann 2,  Susanna Zierler 2,  Johann Schredelseker 1 2,  Michael Schaefer 1 5,  Martin Biel 1,  Roland Malli 4,  Christian Wahl-Schott 7,  Franz Bracher 1,  Sandip Patel 3,  Christian Grimm 2
Affiliations

Affiliations

  • 1 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany.
  • 2 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
  • 3 Department of Cell and Developmental Biology, University College London, London, United Kingdom.
  • 4 Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria.
  • 5 Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universität Leipzig, Leipzig, Germany.
  • 6 Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
  • 7 Institute for Neurophysiology, Hannover Medical School, Hannover, Germany.
  • # Contributed equally.
PMID: 32167471 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.

Keywords

NAADP; PI(3,5)P2; TPC; TPC2; biochemistry; chemical biology; human; lysosome; mouse; two-pore channel 2.

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