Endo-lysosomes are acidic organelles that besides the role in macromolecules degradation, act as intracellular Ca(2+) stores. Nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca(2+)-mobilizing second messenger, produced in response to agonist stimulation, activates Ca(2+)-releasing channels on endo-lysosomes and modulates a variety of cellular functions. NAADP-evoked signals are amplified by Ca(2+) release from endoplasmic reticulum, via the recruitment of inositol 1,4,5-trisphosphate and/or ryanodine receptors through a Ca(2+)-induced Ca(2+)- release (CICR) mechanism. The endo-lysosomal Ca(2+) channels activated by NAADP were recently identified as the two-pore channels (TPCs). In addition to TPCs, endo-lysosomes express another distinct family of Ca(2+)- 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 Ca(2+) channels. TPCs have important roles in vesicular fusion and trafficking, in triggering a global Ca(2+) signal and in modulation of the membrane excitability. Depletion of acidic Ca(2+) stores has been shown to activate store-operated Ca(2+) entry in human platelets and mouse pancreatic β-cells. In human platelets, Ca(2+) 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 Ca(2+) stores to modulate the Ca(2+) release from other organelles and the Ca(2+) entry increases the diversity and complexity of cellular signaling mechanisms.
Keywords: Acidic calcium stores; Intracellular GPCR; NAADP; Store-operated calcium entry; Two-pore channels (TPCs).