| First Author | Gerndt S | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32167471 | Mgi Jnum | J:306599 |
| Mgi Id | MGI:6716973 | Doi | 10.7554/eLife.54712 |
| Citation | Gerndt S, et al. (2020) Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. Elife 9:e54712 |
| abstractText | 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(2+)-signals and non-selective cation currents, the other weaker Ca(2+)-signals and Na(+)-selective currents. These properties were mirrored by the Ca(2+)-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. |
