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

Abstract

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.

Keywords: CP: Cell biology; Ca(2+) stores; IP(3); IP(3) receptors; NAADP; endoplasmic reticulum; histamine; lysosomes; puffs; tuffs; two-pore channels.