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

Gerndt, Susanne; Chen, Cheng-Chang; Chao, Yu-Kai; Yuan, Yu; Burgstaller, Sandra; Rosato, Anna Scotto; Krogsaeter, Einar; Urban, Nicole; Jacob, Katharina; Ong, Nam Phuong Nguyen; Miller, Meghan T.; Keller, Marco; Vollmar, Angelika M.; Gudermann, Thomas; Zierler, Susanna; Schredelseker, Johann; Schaefer, Michael; Biel, Martin; Malli, Roland; Wahl-Schott, Christian; Bracher, Franz; Patel, Sandip und Grimm, Christian (2020): Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. In: eLife, Bd. 9, e54712

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)P-2, 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2050-084X
• Sprache: Englisch