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

Author:

Gerndt Susanne12,Chen Cheng-Chang1ORCID,Chao Yu-Kai2ORCID,Yuan Yu3,Burgstaller Sandra4,Scotto Rosato Anna2,Krogsaeter Einar2ORCID,Urban Nicole5,Jacob Katharina2,Nguyen Ong Nam Phuong1,Miller Meghan T16,Keller Marco1,Vollmar Angelika M1,Gudermann Thomas2,Zierler Susanna2ORCID,Schredelseker Johann12ORCID,Schaefer Michael15,Biel Martin1,Malli Roland4ORCID,Wahl-Schott Christian7,Bracher Franz1,Patel Sandip3,Grimm Christian2ORCID

Affiliation:

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

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.

Funder

Mucolipidosis IV Foundation

Deutsche Forschungsgemeinschaft

Biotechnology and Biological Sciences Research Council

University of Pennsylvania

NCL Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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