Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca signals between lysosomes and the endoplasmic reticulum.

Lysosomes and the endoplasmic reticulum (ER) are Ca stores mobilized by the second messengers NAADP and IP, respectively. Here, we establish Ca signals between the two sources as fundamental building blocks that couple local release to global changes in Ca. Cell-wide Ca signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca despite their lysosomal origin. Knockout of ER IP receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca imaging reveals elementary events upon TPC2 opening and signals coupled to IP receptors. Biasing TPC2 activation to a Ca-permeable state sensitizes local Ca signals to IP. This increases the potency of a physiological agonist to evoke global Ca signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca release from physically separated stores is coordinated.