Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca2+ signals between lysosomes and the endoplasmic reticulum

Le résumé fourni par la source

Lysosomes and the endoplasmic reticulum (ER) are Ca 2+ stores mobilized by the second messengers NAADP and IP 3 , respectively. Here, we establish Ca 2+ signals between the two sources as fundamental building blocks that couple local release to global changes in Ca 2+ . Cell-wide Ca 2+ 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 2+ despite their lysosomal origin. Knockout of ER IP 3 receptor channels delays these signals, whereas expression of lysosomal TPC2 channels accelerates them. High-resolution Ca 2+ imaging reveals elementary events upon TPC2 opening and signals coupled to IP 3 receptors. Biasing TPC2 activation to a Ca 2+ -permeable state sensitizes local Ca 2+ signals to IP 3 . This increases the potency of a physiological agonist to evoke global Ca 2+ signals and activate a downstream target. Our data provide a conceptual framework to understand how Ca 2+ release from physically separated stores is coordinated.

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