Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes

Yuan, Yu; Jaslan, Dawid; Rahman, Taufiq; Bolsover, Stephen R.; Arige, Vikas; Wagner, Larry E.; Abrahamian, Carla; Tang, Rachel; Keller, Marco; Hartmann, Jonas; Rosato, Anna S.; Weiden, Eva-Maria; Bracher, Franz; Yule, David I.; Grimm, Christian and Patel, Sandip (2022): Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes. In: Nature Communications, Vol. 13, No. 1, 4481

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)P-2. Whereas NAADP rendered the channel Ca2+-permeable and PI(3,5)P-2 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)P-2 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. 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.

• Item Type: Journal article
• Faculties: Medicine; Chemistry and Pharmacy > Department of Pharmacy
• Subjects: 600 Technology > 610 Medicine and health; 500 Science > 540 Chemistry
• Language: English