Acidic Ca²⁺ stores and immune-cell function

Acidic organelles act as intracellular Ca²⁺ stores; they actively sequester Ca²⁺ in their lumina and release it to the cytosol upon activation of endo-lysosomal Ca²⁺ channels. Recent data suggest important roles of endo-lysosomal Ca²⁺ channels, the Two-Pore Channels (TPCs) and the TRPML channels (mucolipins), in different aspects of immune-cell function, particularly impacting membrane trafficking, vesicle fusion/fission and secretion. Remarkably, different channels on the same acidic vesicles can couple to different downstream physiology. Endo-lysosomal Ca²⁺ stores can act under different modalities, be they acting alone (via local Ca²⁺ nanodomains around TPCs/TRPMLs) or in conjunction with the ER Ca²⁺ store (to either promote or suppress global ER Ca²⁺ release). These different modalities impinge upon functions as broad as phagocytosis, cell-killing, anaphylaxis, immune memory, thrombostasis, and chemotaxis.