Two pore channel protein 2
ligand-gated sodium channel activity
Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function.
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 Ca<sup>2+</sup>-signals and non-selective cation currents, the other weaker Ca<sup>2+</sup>-signals and Na<sup>+</sup>-selective currents. These properties were mirrored by the Ca<sup>2+</sup>-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P<sub>2</sub>, 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.