Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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"Köpfe" der aktuellen Meldungen:

Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

Gerhard Pichler

Roland Malli

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid Stoffw Microb

Gerndt, S; Chen, CC; Chao, YK; Yuan, Y; Burgstaller, S; Scotto, Rosato, A; Krogsaeter, E; Urban, N; Jacob, K; Nguyen, ONP; Miller, MT; Keller, M; Vollmar, AM; Gudermann, T; Zierler, S; Schredelseker, J; Schaefer, M; Biel, M; Malli, R; Wahl-Schott, C; Bracher, F; Patel, S; Grimm, C.
Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function.
Elife. 2020; 9: Doi: 10.7554/eLife.54712 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-Autor*innen der Med Uni Graz: Burgstaller Sandra; Malli Roland
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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.
Find related publications in this database (using NLM MeSH Indexing): Animals - administration & dosage; Benzylisoquinolines - pharmacology; Calcium - metabolism; Calcium Channel Agonists - chemistry, pharmacology; Calcium Channels - genetics, metabolism; Fluphenazine - pharmacology; Gene Expression Regulation - drug effects; HEK293 Cells - administration & dosage; HeLa Cells - administration & dosage; Humans - administration & dosage; Ionomycin - pharmacology; Macrophages - drug effects, metabolism; Mice - administration & dosage; NADP - analogs & derivatives, metabolism; Phosphatidylinositol Phosphates - pharmacology; Raloxifene Hydrochloride - pharmacology; Single Molecule Imaging - administration & dosage; Sodium - metabolism