Department of Cell and Developmental Biology, University College London, London, UK.
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.
Nat Commun. 2022 Aug 2;13(1):4481. doi: 10.1038/s41467-022-31959-0.
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. Whereas NAADP rendered the channel Ca-permeable and PI(3,5)P rendered the channel Na-selective, a combination of the two increased Ca but not Na flux. Mechanistically, this was due to an increase in Ca permeability independent of changes in ion selectivity. Functionally, we show that cell permeable NAADP and PI(3,5)P mimetics synergistically activate native TPC2 channels in live cells, globalizing cytosolic Ca 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 signaling.
双孔通道是内体溶酶体阳离子通道，具有可塑的选择性过滤器，可驱动内吞离子流和膜运输。在这里，我们表明 TPC2 可以在其内源性配体 NAADP 和 PI(3,5)P 共同激活时，对其阳离子通透性进行差异调节。虽然 NAADP 使通道对 Ca 具有通透性，而 PI(3,5)P 使通道对 Na 具有选择性，但两者的组合增加了 Ca 但不是 Na 通量。从机制上讲，这是由于 Ca 通透性的增加独立于离子选择性的变化。在功能上，我们表明，细胞通透性的 NAADP 和 PI(3,5)P 模拟物在活细胞中协同激活天然 TPC2 通道，使细胞质 Ca 信号全域化，并调节溶酶体 pH 值和运动性。我们的数据表明，通过相同孔的不同离子通量可以独立控制，并确定 TPC2 作为一种可能的巧合检测器，优化溶酶体 Ca 信号。
