Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli.

In their landmark 1987 paper,[1] Hon Cheung Lee and colleagues discovered not one but two Ca2+-mobilizing second messengers, cADPR and NAADP from the effects of nucleotides on Ca2+ release in sea urchin egg homogenates.

[3] Subsequently, NAADP has been detected in sources as diverse as human sperm, red and white blood cells, liver, and pancreas, to name but a few.

The transduction mechanisms that couple cell stimuli to such NAADP increases are ill-defined, with some suggestions of cyclic AMP[7] or cytosolic Ca2+ itself[8] stimulating synthesis.

Regardless of the details, an outstanding issue is that the physiological route of NAADP synthesis has still not been unequivocally identified — neither the reaction(s) nor the enzyme(s).

To date, the most favoured hypothesis is the so-called base-exchange reaction (nicotinic acid + NADP → NAADP + nicotinamide; catalyzed by ADP-ribosyl cyclases) which are a family of enzymes that include CD38 and CD157 in mammals (and orthologs in sea urchin and Aplysia ovotestis).

A 2'-3'-phosphatase stimulated by Ca2+ has been proposed in brain[12] and, possibly in pancreatic acinar cells, that catabolises NAADP to inactive NAAD.

The physiological consequences of Ca2+ release by each messenger may be different i.e. NAADP couples to downstream responses that cannot be mimicked by IP3 and cADPR.

[17] They are a highly dynamic continuum of vesicles with a rich variety of established biochemical roles in cells, to which Ca2+ storage can now be added.

Whether this has consequences for vesicle (or NAADP) function remains to be seen, but luminal pH is usually crucial for resident protein activity.

[citation needed] In other Ca2+-storing organelles such as the endoplasmic reticulum or Golgi, stores are filled by calcium ATPase pumps, typified by the ubiquitous members of the SERCA or the SPCA (secretory pathway Ca2+-ATPase) families respectively.

Acidic vesicles in some cell types may well take a leaf out of the yeasts'/plants' book and host two uptake pathways, but whether this is a widespread template is unclear.

[22] Appropriately, these channels reside on acidic organelles (including different classes of endosomes and lysosomes) likely due to the presence of endolysomal targeting sequences.

[23] The effect of genetic manipulation of TPC levels (i.e. over-expression, knock-down or knock-out) is consistent with TPCs being the NAADP-gated channel.

Moreover, the TPC isoforms exhibit different organellar distributions, with TPC1 being found throughout the endo-lysosomal system (although predominantly in recycling and early endosomes) whereas TPC2 shows a more restricted late-endosomal/lysosomal localization.

The surprising conclusion in 2012 that TPCs are not involved in NAADP signalling was due to two technical difficulties that have since been overcome or explained.

However, others have questioned whether these mice are true DKO when they are predicted to retain >90% of the TPC protein sequences (i.e. they express only mildly truncated TPCs which are still functional and NAADP-sensitive [27]).

In sea urchin egg homogenate and T-cells, the binding protein(s) may be smaller than TPCs themselves, judging by photoaffinity labelling with [32P]azido-NAADP.

[37] This domain binds NAADP with appropriate nanomolar affinity and selectivity over NADP, and appears to be needed for activation of either TPC1 or TPC2 (contrasting with the isoform-selectivity of JPT2).

[40][41] Back in 2009, a selective cell-permeant NAADP antagonist, trans-Ned-19 was discovered[42] which blocks Ca2+ signals and downstream Ca2+-dependent processes such as differentiation.

[43] Prior to that, only high concentrations of blockers of L-type Ca2+ channels (e.g. diltiazem, dihydropyridines) could be used (with obvious concerns over non-NAADP effects).

Therefore, an inactive, lipophilic ester precursor (NAADP/AM) has been synthesised which crosses membranes and rapidly regenerates NAADP in the cytosol following the action of endogenous esterases.

[citation needed] The two paralogous enzymes- transmembrane CD38 and GPI anchored CD157, that produce NAADP (and cADPR) in humans both have their active synthesis site in the ectodomain.

Considering the fact that the substrate of NAADP synthesis (NADP) itself is very sparse in the extracellular medium, a purse diffusion based mechanism has been suspected to be less likely than a transporter mediated path.

In bacterial infection, however, NAADP induction of lysosomal Ca2+ efflux and TFEB activation leads to enhanced expression of inflammatory cytokines.

[52] Similarly, phagocytosis via the Fc receptor in the macrophage is driven only by highly local Ca2+ domains generated by NAADP/TPCs (whereas the global ER Ca2+ signals play no role).