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Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
- Source :
- eLife, Vol 9 (2020)
- Publication Year :
- 2020
- Publisher :
- eLife Sciences Publications Ltd, 2020.
-
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.
Details
- Language :
- English
- ISSN :
- 2050084X
- Volume :
- 9
- Database :
- Directory of Open Access Journals
- Journal :
- eLife
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.64c41b16eef7442a8eaf94088d92df5d
- Document Type :
- article
- Full Text :
- https://doi.org/10.7554/eLife.54712