Gerndt, S; Chen, C-C; Chao, Y-K; Yuan, Y; Burgstaller, S; Scotto Rosato, A; Krogsaeter, E; ... Grimm, C; + view all Gerndt, S; Chen, C-C; Chao, Y-K; 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; - view fewer (2020) Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. eLife , 2020 (9) , Article e54712. 10.7554/eLife.54712.

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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.

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