Lysosomes and the endoplasmic reticulum (ER) are Ca2+ stores mobilized by the second messengers NAADP and IP3, respectively. Here, we establish Ca2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca2+. Cell-wide Ca2+ signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca2+ despite their lysosomal origin. Knockout of ER IP3 receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca2+ imaging reveals elementary events upon TPC2 opening and signals coupled to IP3 receptors. Biasing TPC2 activation to a Ca2+-permeable state sensitizes local Ca2+ signals to IP3. This increases the potency of a physiological agonist to evoke global Ca2+ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca2+ release from physically separated stores is coordinated.
Yuan, Yu; Arige, Vikas; Saito, Ryo; Mu, Qianru; Brailoiu, Gabriela C.; Pereira, Gustavo J.S.; Bolsover, Stephen R.; Keller, Marco; Bracher, Franz; Grimm, Christian; Brailoiu, Eugen; Marchant, Jonathan S.; Yule, David I.; and Patel, Sandip, "Two-Pore Channel-2 and Inositol Trisphosphate Receptors Coordinate CA2+ Signals Between Lysosomes and the Endoplasmic Reticulum" (2023). College of Pharmacy Faculty Papers. Paper 54.
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