A primer of NAADP-mediated Ca2+ signalling: From sea urchin eggs to mammalian cells

• NAADP has satisfied all the criteria laid down for a second messenger.
• NAADP mobilizes Ca2+ from acidic Ca2+ stores.
• Target channels for NAADP in the endolysosomal system have been identified including two-pore channels.
• Organellar communication may occur to generate Ca2+ signals.
• NAADP-mediated Ca2+ release occurs in a wide range of cells and mediates key physiological processes.
• Defects in the NAADP signalling pathway may be associated with a number of important human diseases.

Since the discovery of the Ca2+ mobilizing effects of the pyridine nucleotide metabolite, nicotinic acid adenine dinucleotide phosphate (NAADP), this molecule has been demonstrated to function as a Ca2+ mobilizing intracellular messenger in a wide range of cell types. In this review, I will briefly summarize the distinct principles behind NAADP-mediated Ca2+ signalling before going on to outline the role of this messenger in the physiology of specific cell types. Central to the discussion here is the finding that NAADP principally mobilizes Ca2+ from acidic organelles such as lysosomes and it is this property that allows NAADP to play a unique role in intracellular Ca2+ signalling. Lysosomes and related organelles are small Ca2+ stores but importantly may also initiate a two-way dialogue with other Ca2+ storage organelles to amplify Ca2+ release, and may be strategically localized to influence localized Ca2+ signalling microdomains. The study of NAADP signalling has created a new and fruitful focus on the lysosome and endolysosomal system as major players in calcium signalling and pathophysiology.

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