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

eLife - Tập 9
Susanne Gerndt1,2, Cheng‐Chang Chen1, Yu‐Kai Chao2, Yu Yuan3, Sandra Burgstaller4, Anna Scotto Rosato2, Einar Krogsaeter2, Nicole Urban5, Katharina Jacob2, Ong Nam Phuong Nguyen1, Meghan T. Miller1,6, Marco Keller1, Angelika M. Vollmar1, Thomas Gudermann2, Susanna Zierler2, Johann Schredelseker1,2, Michael Schaefer1,5, Martin Biel1, Roland Malli4, Christian Wahl‐Schott7, Franz Bracher1, Sandip Patel3, Christian Grimm2
1Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany
2Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany
3Department of Cell and Developmental Biology, University College London, London, United Kingdom
4Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
5Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universität Leipzig, Leipzig, Germany
6Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland
7Institute for Neurophysiology, Hannover Medical School, Hannover, Germany

Tóm tắt

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.

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Tập 9

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