Prof Sandip Patel’s lab publishes paper with collaborators in eLife

Congratulations to Yu (Cara) Yuan, a finishing PhD student in the Patel lab, who has had her joint first author paper with collaborators in Germany published in eLife. This work also formed the basis of a successful project grant funded by the BBSRC in the last round.

Abstract 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.

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