Extracellular stimuli evoke the synthesis of intracellular second messengers, several of which couple to the release of Ca2+ from Ca2+-storing organelles via activation of cognate organellar Ca2+-channel complexes. The archetype is the inositol 1,4,5-trisphosphate (IP3) and IP3 receptor (IP3R) on the endoplasmic reticulum (ER). A less understood, parallel Ca2+ signalling cascade is that involving the messenger nicotinic acid adenine dinucleotide phosphate (NAADP) that couples to Ca2+ release from acidic Ca2+ stores [e.g. endo-lysosomes, secretory vesicles, lysosome-related organelles (LROs)]. NAADP-induced Ca2+ release absolutely requires organellar TPCs (two-pore channels). This review discusses how ER and acidic Ca2+ stores physically and functionally interact to generate and shape global and local Ca2+ signals, with particular emphasis on the two-way dialogue between these two organelles.

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