Year: 2022
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: Membrane contact sites between endolysosomes and the ER as novel hubs in Ca2+ signalling., G1579701519, G2144867290, G3221862683, G3245588637, Improving recycling to reduce brain cell death, Understanding polymodal gating of a lysosomal ion channel, G3916100709, G40717403, G5515288158, Switching the ion selectivity of an ion channel on demand, G6534012216, G6911590788, G7552089987, G7649446995, G9000150953
OpenAlex ID: W4289521109