Journal
ELIFE
Volume 9, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.54712
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Funding
- Mucolipidosis IV Foundation [MDBR-17-120-ML4, 404.510.2577]
- Deutsche Forschungsgemeinschaft [SFB/TRR152, BR 1034/7-1, 239283807, GR 4315/2-1]
- Biotechnology and Biological Sciences Research Council [BB/N01524X/1]
- University of Pennsylvania Orphan Disease Center
- NCL Foundation 2018-Grimm-Paquet
- BBSRC [BB/N01524X/1, BB/T015853/1] Funding Source: UKRI
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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.
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