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Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
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Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
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Journal Article
Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes
2022
Overview
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)P
2
. Whereas NAADP rendered the channel Ca
2+
-permeable and PI(3,5)P
2
rendered the channel Na
+
-selective, a combination of the two increased Ca
2+
but not Na
+
flux. Mechanistically, this was due to an increase in Ca
2+
permeability independent of changes in ion selectivity. Functionally, we show that cell permeable NAADP and PI(3,5)P
2
mimetics synergistically activate native TPC2 channels in live cells, globalizing cytosolic Ca
2+
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 Ca
2+
signaling.
TPC2 is a lysosomal ion channel permeable to both calcium and sodium ions. Here, the authors show that TPC2 can selectively increase its calcium permeability when simultaneously challenged by both its natural activators- NAADP and PI(3,5)P
2
.
