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

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.

SUBMITTER: Gerndt S

PROVIDER: S-EPMC7108868 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Gerndt Susanne S Chen Cheng-Chang CC Chao Yu-Kai YK Yuan Yu Y Burgstaller Sandra S Scotto Rosato Anna A Krogsaeter Einar E Urban Nicole N Jacob Katharina K Nguyen Ong Nam Phuong ONP Miller Meghan T MT Keller Marco M Vollmar Angelika M AM Gudermann Thomas T Zierler Susanna S Schredelseker Johann J Schaefer Michael M Biel Martin M Malli Roland R Wahl-Schott Christian C Bracher Franz F Patel Sandip S Grimm Christian C

eLife 20200316

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<su ...[more]

PMID: 32167471

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Project description:BackgroundErbB4/HER4 is a unique member of the ErbB family of receptor tyrosine kinases concerning its activation of anti-proliferative JAK2-STAT5 pathway when stimulated by ligand Neuregulin (NRG). Activation of this pathway leads to expression of genes like ?-casein which promote cell differentiation. Recent experimental studies on mouse HC11 mammary epithelial cells stimulated by ligand Neuregulin (NRG) showed a time-dependent switching behavior in the ?-casein expression. This behavior cannot be explained using currently available mechanistic models of the JAK-STAT pathway. We constructed an improved mechanistic model which introduces two crucial modifications to the canonical HER4-JAK2-STAT5 pathway based on literature findings. These modifications include competitive HER4 heterodimerization with other members of the ErbB family and a slower JAK2 independent activation STAT5 through HER4. We also performed global sensitivity analysis on the model to test the robustness of the predictions and parameter combinations that are sensitive to the outcome.ResultsOur model was able to reproduce the time-dependent switching behavior of ?-casein and also establish that the modifications mentioned above to the canonical JAK-STAT pathway are necessary to reproduce this behavior. The sensitivity studies show that the competitive HER4 heterodimerization reactions have a profound impact on the sensitivity of the pathway to NRG stimulation, while the slower JAK2-independent pathway is necessary for the late stage promotion of ?-casein mRNA transcription. The difference in the time scales of the JAK-dependent and JAK-independent pathways was found to be the main contributing factor to the time-dependent switch. The transport rates controlling activated STAT5 dimer nuclear import and ?-casein mRNA export to cytoplasm affected the time delay between NRG stimulation and peak ?-casein mRNA activity.ConclusionThis study highlights the effect of competitive and parallel reaction pathways on both short and long-term dynamics of receptor-mediated signaling. It provides robust and testable predictions of the dynamical behavior of the HER4 mediated JAK-STAT pathway which could be useful in designing treatments for various cancers where this pathway is activated/altered.

Dataset Information

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

Publications

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

Similar Datasets

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