Yuan, Yu;
Jaślan, Dawid;
Rahman, Taufiq;
Bolsover, Stephen R;
Arige, Vikas;
Wagner, Larry E;
Abrahamian, Carla;
... Patel, Sandip; + view all
(2022)
Segregated cation flux by TPC2 biases Ca^{2+} signaling through lysosomes.
Nature Communications
, 13
(1)
, Article 4481. 10.1038/s41467-022-31959-0.
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Abstract
Two-pore channels are endo-lysosomal cation channels with malleable selectivity filters that drive endocytic ion flux and membrane traffic. Here we show that TPC2 can differentially regulate its cation permeability when co-activated by its endogenous ligands, NAADP and PI(3,5)P2. Whereas NAADP rendered the channel Ca2+-permeable and PI(3,5)P2 rendered the channel Na+-selective, a combination of the two increased Ca2+ but not Na+ flux. Mechanistically, this was due to an increase in Ca2+ permeability independent of changes in ion selectivity. Functionally, we show that cell permeable NAADP and PI(3,5)P2 mimetics synergistically activate native TPC2 channels in live cells, globalizing cytosolic Ca2+ signals and regulating lysosomal pH and motility. Our data reveal that flux of different ions through the same pore can be independently controlled and identify TPC2 as a likely coincidence detector that optimizes lysosomal Ca2+ signaling.
| Type: | Article |
|---|---|
| Title: | Segregated cation flux by TPC2 biases Ca^{2+} signaling through lysosomes |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-022-31959-0 |
| Publisher version: | https://doi.org/10.1038/s41467-022-31959-0 |
| Language: | English |
| Additional information: | © 2022 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Bias, Calcium, Calcium Channels, Calcium Signaling, Cations, Lysosomes, NADP |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10153629 |
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