NAADP receptors.
Of the established Ca(2+) mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations. Recent studies have identified a new class of calcium release channel, the two-pore channels (TPCs), as the likely targets for NAADP. These channels are endolysosomal in localization where they mediate local Ca(2+) release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca(2+) mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca(2+) release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca(2+)-induced Ca(2+) release (CICR) channels at lysosomal-ER junctions. The third is to regulate plasma membrane excitability by the targeting of Ca(2+) release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca(2+)-activated channels. In this review, I discuss the role of NAADP-mediated Ca(2+) release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca(2+) signaling.
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom. antony.galione@pharm.ox.ac.uk
Antony
A
Galione
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D010063:Ovum / Q000378:metabolism; D012617:Sea Urchins
D015220:Calcium Channels; D009249:NADP; C024376:NAADP; D002118:Calcium