NAADP Receptors

Abstract

Of the established Ca²⁺-mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations, and its receptors undergo dramatic desensitization. Recent studies have identified a new class of calcium-release channel, the two-pore channels (TPCs), as the likely targets for NAADP regulation, even though the effect may be indirect. These channels localized at endolysosomes, where they mediate local Ca²⁺ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca²⁺ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca²⁺ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca²⁺-induced Ca²⁺-release (CICR) channels at lysosomal–endoplasmic reticulum (ER) junctions. The third is to regulate plasma membrane excitability by the targeting of Ca²⁺ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca²⁺-activated channels. In this review, I discuss the role of nicotinic acid adenine nucleotide diphosphate (NAADP)-mediated Ca²⁺ 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 Ca²⁺ signaling.