Modulation of Calcium Entry by the Endo-lysosomal System

Endo-lysosomes are acidic organelles that besides the role in macromolecules degradation, act as intracellular Ca2+ stores. Nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca2+-mobilizing second messenger, produced in response to agonist stimulation, activates Ca2+-releasing channels on endo-lysosomes and modulates a variety of cellular functions. NAADP-evoked signals are amplified by Ca2+ release from endoplasmic reticulum, via the recruitment of inositol 1,4,5-trisphosphate and/or ryanodine receptors through a Ca2+-induced Ca2+- release (CICR) mechanism. The endo-lysosomal Ca2+ channels activated by NAADP were recently identified as the two-pore channels (TPCs). In addition to TPCs, endo-lysosomes express another distinct family of Ca2+- permeable channels, namely the transient receptor potential mucolipin (TRPML) channels, functionally distinct from TPCs. TPCs belong to the voltage-gated channels, resembling voltage-gated Na+ and Ca2+ channels. TPCs have important roles in vesicular fusion and trafficking, in triggering a global Ca2+ signal and in modulation of the membrane excitability. Depletion of acidic Ca2+ stores has been shown to activate store-operated Ca2+ entry in human platelets and mouse pancreatic β-cells. In human platelets, Ca2+ influx in response to acidic stores depletion is facilitated by the tubulin-cytoskeleton and occurs through non-selective cation channels and transient receptor potential canonical (TRPC) channels. Emerging evidence indicates that activation of intracellular receptors, situated on endo-lysosomes, elicits canonical and non-canonical signaling mechanisms that involve CICR and activation of non-selective cation channels in plasma membrane. The ability of endo-lysosomal Ca2+ stores to modulate the Ca2+ release from other organelles and the Ca2+ entry increases the diversity and complexity of cellular signaling mechanisms.