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Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
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Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
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Journal Article
Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
2020
Overview
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.
Publisher
eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
Subject
/ Agonists
/ Animals
/ Benzylisoquinolines - pharmacology
/ Biochemistry and Chemical Biology
/ Calcium Channel Agonists - chemistry
/ Calcium Channel Agonists - pharmacology
/ Calcium Channels - metabolism
/ Gene Expression Regulation - drug effects
/ Humans
/ lysosome
/ Mice
/ NAADP
/ NADP - analogs & derivatives
/ Phosphatidylinositol Phosphates - pharmacology
/ Plasma
/ Raloxifene Hydrochloride - pharmacology
/ TPC
/ TPC2
