Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function.
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.
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.