Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca 2+ storage cellular compartments with a central role in intracellular Ca 2+ 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 Ca 2+ ) 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 Ca 2+ and H + across endolysosomal membranes. In particular, we discuss the role of the Ca 2+ -mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca 2+ 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 Ca 2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca 2+ -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 Ca 2+ regulation and signalling.
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Molecular mechanisms of endolysosomal Ca 2+ signalling in health and disease
Anthony J. Morgan* 1 , Frances M. Platt*, Emyr Lloyd‑Evans† and Antony Galione* 1
Follow Biochemical Journal
, Volume 439 (3)
Portland Press – Nov 1, 2011
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