Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
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 acti...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/54712 |
| _version_ | 1811181457119379456 |
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| author | Susanne Gerndt Cheng-Chang Chen Yu-Kai Chao Yu Yuan Sandra Burgstaller Anna Scotto Rosato Einar Krogsaeter Nicole Urban Katharina Jacob Ong Nam Phuong Nguyen Meghan T Miller Marco Keller Angelika M Vollmar Thomas Gudermann Susanna Zierler Johann Schredelseker Michael Schaefer Martin Biel Roland Malli Christian Wahl-Schott Franz Bracher Sandip Patel Christian Grimm |
| author_facet | Susanne Gerndt Cheng-Chang Chen Yu-Kai Chao Yu Yuan Sandra Burgstaller Anna Scotto Rosato Einar Krogsaeter Nicole Urban Katharina Jacob Ong Nam Phuong Nguyen Meghan T Miller Marco Keller Angelika M Vollmar Thomas Gudermann Susanna Zierler Johann Schredelseker Michael Schaefer Martin Biel Roland Malli Christian Wahl-Schott Franz Bracher Sandip Patel Christian Grimm |
| author_sort | Susanne Gerndt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:18:03Z |
| format | Article |
| id | doaj.art-64c41b16eef7442a8eaf94088d92df5d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:18:03Z |
| publishDate | 2020-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-64c41b16eef7442a8eaf94088d92df5d2022-12-22T04:32:17ZengeLife Sciences Publications LtdeLife2050-084X2020-03-01910.7554/eLife.54712Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal functionSusanne Gerndt0Cheng-Chang Chen1https://orcid.org/0000-0003-1282-4026Yu-Kai Chao2https://orcid.org/0000-0002-1202-2448Yu Yuan3Sandra Burgstaller4Anna Scotto Rosato5Einar Krogsaeter6https://orcid.org/0000-0001-8232-5498Nicole Urban7Katharina Jacob8Ong Nam Phuong Nguyen9Meghan T Miller10Marco Keller11Angelika M Vollmar12Thomas Gudermann13Susanna Zierler14https://orcid.org/0000-0002-4684-0385Johann Schredelseker15https://orcid.org/0000-0002-6657-0466Michael Schaefer16Martin Biel17Roland Malli18https://orcid.org/0000-0001-6327-8729Christian Wahl-Schott19Franz Bracher20Sandip Patel21Christian Grimm22https://orcid.org/0000-0002-0177-5559Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Cell and Developmental Biology, University College London, London, United KingdomMolecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, AustriaWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyRudolf-Boehm-Institute for Pharmacology and Toxicology, Universität Leipzig, Leipzig, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany; Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, SwitzerlandDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany; Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany; Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universität Leipzig, Leipzig, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyMolecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, AustriaInstitute for Neurophysiology, Hannover Medical School, Hannover, GermanyDepartment of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Cell and Developmental Biology, University College London, London, United KingdomWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, GermanyIon 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.https://elifesciences.org/articles/54712TPC2two-pore channel 2lysosomeNAADPPI(3,5)P2TPC |
| spellingShingle | Susanne Gerndt Cheng-Chang Chen Yu-Kai Chao Yu Yuan Sandra Burgstaller Anna Scotto Rosato Einar Krogsaeter Nicole Urban Katharina Jacob Ong Nam Phuong Nguyen Meghan T Miller Marco Keller Angelika M Vollmar Thomas Gudermann Susanna Zierler Johann Schredelseker Michael Schaefer Martin Biel Roland Malli Christian Wahl-Schott Franz Bracher Sandip Patel Christian Grimm Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function eLife TPC2 two-pore channel 2 lysosome NAADP PI(3,5)P2 TPC |
| title | Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function |
| title_full | Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function |
| title_fullStr | Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function |
| title_full_unstemmed | Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function |
| title_short | Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function |
| title_sort | agonist mediated switching of ion selectivity in tpc2 differentially promotes lysosomal function |
| topic | TPC2 two-pore channel 2 lysosome NAADP PI(3,5)P2 TPC |
| url | https://elifesciences.org/articles/54712 |
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