Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.
- calcium store
- nicotinic acid adenine dinucleotide phosphate (NAADP)
- two-pore channel (TPC)
Abbreviations: ACA, autoinhibited Ca2+-ATPase; AtTPC1, Arabidopsis thaliana TPC1; cADPR, cyclic adenosine diphosphate ribose; CaM, calmodulin; CAX, Ca2+/H+ exchanger; CICR, Ca2+-induced Ca2+ release; ClC, Cl− channel; ER, endoplasmic reticulum; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HEK, human embryonic kidney; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; LAMP, lysosomal-associated membrane protein; MLIV, mucolipidosis type IV; NAADP, nicotinic acid adenine dinucleotide phosphate; NAADP-AM, NAADP-acetoxymethyl ester; NCKX, Na+/Ca2+-K+ exchanger; NCX, Na+/Ca2+ exchanger; NHE, Na+/H+ exchanger; NPC, Niemann–Pick type C; pHL, luminal pH; PKC, protein kinase C; PIP2, PI(3,5)P2; PMCA, plasma membrane Ca2+-ATPase; Po, mean open probability; RNAi, RNA interference; RyR, ryanodine receptor; SERCA, sarco-endoplasmic reticulum Ca2+-ATPase; shRNA, short hairpin RNA; siRNA, small interfering RNA; SPCA, secretory pathway Ca2+-ATPase; SR, sarcoplasmic reticulum; tBHQ, tert-butylhydroquinone; TMD, transmembrane domain; TPC, two-pore channel; HsTPC2, human TPC2; Trp, transient receptor potential; TRPML1, mucolipin 1; SpTPC, sea urchin TPC; V-ATPase, vacuolar-type H+-ATPase
- © The Authors Journal compilation © 2011 Biochemical Society