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The NAADP Receptor: New Receptors or New Regulation?

¹ Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK;
² The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK

SUMMARY

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent calcium mobilizing messenger yet discovered. Its action has now been reported in a large number of cell types from a diverse array of organisms, and in some cases linked to the transduction of specific cellular stimuli. However, what is controversial is the nature of its target calcium release channel, as well as the subcellular localization of its receptor. Some have proposed that NAADP activates a novel calcium release channel distinct from the two major classes of channels known, the inositol trisphosphate receptors and ryanodine receptors. However, others have suggested that it acts in a novel way to regulate a known calcium release channel, the ryanodine receptor.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is structurally related to the well-known coenzyme nicotinamide adenine dinucleotide phosphate (NADP), the only difference being the replacement of the nicotinamide moiety by nicotinic acid. In contrast to NADP, NAADP is a potent activator of Ca²⁺ release from intracellular stores, and in some cases also Ca²⁺ influx. Such effects have been reported in a wide range of cells and preparations across the phylogenic spectrum. We discuss below on the basis of current work whether NAADP acts on a novel Ca²⁺-release mechanism or regulates known Ca²⁺-release channels by novel mechanisms.

The chemical synthesis of NAADP was first described by Bernofsky, who prepared it through an enzymic base-exchange reaction by incubating NADP and nicotinic acid with calf spleen NAD glycohydrolase (1). It was not until 1987, however, that the potent Ca²⁺-releasing activities of NAADP were reported, as an unidentified contaminant of commercially available NADP (2), which released Ca²⁺ from vesicular stores in sea urchin egg homogenates. The amount of this contaminant was increased by treating NADP with alkali. Subsequent analysis by HPLC and high resolution mass spectroscopy identified the Ca²⁺-mobilizing compound as NAADP (3).

The initial studies in sea urchin egg homogenates of alkali-activated NADP-evoked Ca²⁺ release (2) and, once identified, NAADP-induced Ca²⁺ release (3, 4), indicated that the release mechanism did not involve the inositol-1,4,5-trisphosphate (InsP₃) receptor (IP₃R). Indeed, NAADP-, cyclic adenosine diphosphate ribose (cADPR)-, and InsP₃-sensitive Ca²⁺-release mechanisms exhibit specific desensitization, in that, regardless of the order of addition, each agent added at its maximal concentration renders homogenates or microsomes insensitive to further Ca²⁺ release by the same agent, but fully sensitive to the others (3). These results suggested that there were at least three separate Ca²⁺ release mechanisms present in sea urchin homogenates.

Pharmacological experiments using selective inhibitors of IP₃Rs such as heparin, and those of ryanodine receptors (RyRs), for example ryanodine, ruthenium red and procaine (as well as inhibitory structural analogs of cADPR), indicated that whereas cADPR most likely activates RyRs, NAADP activates a Ca²⁺-release mechanism that was most likely distinct from IP₃Rs and RyRs. Similar results were observed in intact sea urchin eggs injected with IP₃Rs or RyR inhibitors in response to photolysis of caged NAADP (5). Although the pharmacology of NAADP-induced Ca²⁺ release has not been extensively studied, NAADP-sensitive Ca²⁺-release channels are blocked, noncompetitively, by concentrations of dihydropyridines, gallopamil (also termed methoxyverapamil or D600), or diltiazem that, although being somewhat higher than those required to block voltage-gated Ca²⁺ channels (Table 1), nevertheless do not affect Ca²⁺ release via either IP₃Rs or RyRs (6).

Early studies of Percoll-gradient fractionation of alkali-activated NADP-induced Ca²⁺ release showed that this mechanism regulated release from a nonmitochondrial store devoid of cytochrome c activity, which was separate from those activated by InsP₃ or cADPR (generated from NAD⁺) (2). IP₃Rs and RyRs are well-characterized as mainly residing in (sarco-) endoplasmic reticulum (ER) Ca²⁺ stores, the site of Ca²⁺ sequestration by thapsigargin-sensitive sarco-endoplasmic reticulum Ca²⁺ ATPases (SERCA pumps). Whereas thapsigargin, as expected, depletes InsP₃-sensitive and cADPR-sensitive Ca²⁺ stores in both sea urchin egg homogenates (6) and intact eggs (9), NAADP-sensitive stores remain largely unaffected by this treatment. Further evidence for NAADP-sensitive stores being discrete from the ER comes from elegant experiments using stratified sea urchin eggs. Centrifugation of eggs results in the formation of elongated structures in which organelles are stratified in distinct regions. Fluorescence-tagged thapsigargin labels structures at the nuclear pole, which is also the site of both InsP₃- and cADPR-induced Ca²⁺ release. In contrast, NAADP-sensitivity, functionally visualized by Ca²⁺ imaging, is located at the opposite pole enriched in mitochondria (10) and acidic compartments (11). NAADP-sensitive stores are unlikely to be mitochondria because they express a paucity of mitochondrial markers, thus, acidic organelles emerged as plausible candidates. More-detailed Percoll fractionations of sea urchin egg homogenate allowed the purification of NAADP-sensitive Ca²⁺ stores with minimal InsP₃ or cADPR sensitivity. These stores colocalized with egg reserve granules—functionally equivalent to secretory lysosomes—which are also involved in plasma membrane repair following mechanical wounding (12, 13), providing one explanation for the presence of NAADP-sensitive Ca²⁺ influx pathways in the plasma membrane (14–16). These stores are enriched in [³²P]-NAADP binding sites and lysosomal markers, and sequester Ca²⁺ which may be discharged by NAADP (11). The vacuolar proton pump inhibitor bafilomycin and various protonophores abrogate this Ca²⁺ sequestration, and the lysomotropic agent glycyl-L-phenylalanine-ß-naphthylamide (GPN) abolishes NAADP-induced Ca²⁺ release. In intact eggs, as well as in egg homogenates, GPN and bafilomycin selectively abolish NAADP- but not InsP₃- or cADPRevoked Ca²⁺ release (Table 1). Taken together, these data are consistent with a mechanism whereby NAADP-sensitive release is located in thapsigargin-insensitive acidic Ca²⁺ stores (11).

The nature of the NAADP receptor in sea urchin egg homogenates has been probed by characterizing [³²P]-NAADP–binding proteins. Binding is essentially irreversible in this preparation, and, together with the high binding capacity, make it a system of choice for the purification and molecular characterization of these proteins. [³²P]-NAADP binds to a single population of high affinity binding sites (Kd ~ 0.3 nM, B_max ~ 125 fmol/mg protein) on sea urchin egg homogenate membranes (17, 18). Detergent-solubilized [³²P]- NAADP–binding proteins display similar binding characteristics to those found in native membranes, indicating that they are intrinsic membrane proteins, and gel-filtration molecular size analysis indicates that they are substantially smaller than either native IP₃Rs or RyRs (19).

NAADP-induced Ca²⁺ release is also widespread in mammalian systems. The exocrine pancreatic acinar cell was the first intact mammalian cell type in which NAADP-induced Ca²⁺ release was reported (20), but studies on mammalian exocrine cells, in general, have also been crucial for developing our current view of intracellular Ca²⁺ signaling events. Experiments on the perfused cat submandibular gland provided the earliest evidence for agonist-elicited release of Ca²⁺ from non-mitochondrial intracellular stores, also demonstrating cellular extrusion of Ca²⁺ by active transport and, after a delay, activation of Ca²⁺ entry (21). Studies on permeabilized pancreatic acinar cells demonstrated for the first time that InsP₃ releases Ca²⁺ from a non-mitochondrial store (22).

Combining patch-clamp whole-cell recording of Ca²⁺-activated Cl^– current with fluorescence measurement of the cytosolic Ca²⁺ concentration (23, 24) has made it possible to probe directly the action of various intracellular messengers in pancreatic acinar cells (23–26). In this way, InsP₃ (25, 27), cADPR (26), and NAADP (20, 24, 28) were shown to elicit repetitive local cytosolic Ca²⁺ spikes in the apical granular pole. The local apical Ca²⁺ spiking depends on concerted activity of RyRs and IP₃Rs (28, 29).

The two physiological activators of pancreatic acinar secretion, acetylcholine (ACh) and cholecystokinin (CCK), initiate Ca²⁺ spiking via different messenger pathways. Inactivation of NAADP-evoked Ca²⁺ release in mammalian cells occurs at high concentrations of NAADP (20). This is in contrast to the situation in sea urchin eggs, where concentrations that are below the threshold for inducing Ca²⁺ release fully desensitize the release mechanism (14). Inactivation of NAADP receptors by intracellular application of NAADP at a high concentration (µM) blocks Ca²⁺ spiking elicited by physiological CCK concentrations (1–10 pM) (20, 28), but has no effect on Ca²⁺ spiking responses elicited by ACh (28) or bombesin (30). Physiological Ca²⁺ signaling elicited by CCK, therefore, has a unique requirement for functional intracellular NAADP receptors.

How and from which intracellular store does NAADP elicit Ca²⁺ release in the acinar cells? This is difficult to answer on the basis of studies in intact acinar cells, because the apical granular pole, where the NAADP-induced Ca²⁺ spiking occurs, contains two major Ca²⁺ pools located in the endoplasmic reticulum (ER) and the zymogen granules (ZGs) (31). The ER is generally considered to be the main Ca²⁺ store from which cytosolic Ca²⁺ signals are generated (32), therefore, it would seem desirable to test the action of NAADP on a pure ER preparation. The nucleus may, in practice, constitute such a preparation. The outer nuclear membrane is continuous with the ER membrane and the lumen of the nuclear envelope is continuous with the ER lumen (33). Studies on isolated liver nuclei have demonstrated active, ATP-dependent and thapsigargin-sensitive Ca²⁺ uptake into the nuclear envelope, and InsP₃ and cADPR liberate Ca²⁺ from this store (34). More recent studies on isolated nuclei from pancreatic acinar cells, which also contain several layers of surrounding ER, demonstrate that the thapsigarginsensitive Ca²⁺ store can release Ca²⁺ in response to stimulation, not only with InsP₃ or cADPR, but also with NAADP (35). Data obtained from this preparation show that the Ca²⁺ liberation elicited by NAADP (and also by cADPR) can be blocked by ryanodine or ruthenium red, but not by caffeine. Alternately, the Ca²⁺ release evoked by InsP₃ is blocked by caffeine (acting as an IP₃R antagonist), but not by ryanodine or ruthenium red (35). Therefore, the simplest hypothesis to account for these data is that NAADP, like cADPR, causes Ca²⁺ release from the ER by opening RyRs. NAADP and cADPR act on separate receptor sites, because inactivation of NAADP receptors by a high NAADP concentration (µM) does not prevent cADPR-elicited Ca²⁺ release (35).

In pancreatic acinar cells, CCK and NAADP can also release Ca²⁺ from an acidic, bafilomycin-sensitive, but thapsigargin-insensitive, Ca²⁺ store located in the apical granular pole (36) that new, as yet unpublished results suggest, does not have characteristics of the ER. Ca²⁺ can be released from this acidic granular store by either InsP₃, cADPR, or NAADP. As is the case for the ER, the actions of NAADP and cADPR on the acidic store can be abolished by RyR inhibitors, whereas the action of InsP₃ can only be blocked by IP₃R antagonists. It has been proposed that the acid pool from which NAADP releases Ca²⁺ could be in lysosome-related organelles, including ZGs (36). The ZGs have an extraordinarily high total Ca²⁺ concentration (>10 mM) (37) and isolated single ZGs can release Ca²⁺ in response to both InsP₃ or cADPR (37). So far, the action of NAADP has not been tested on ZGs. Because cytosolic Ca²⁺ signals generated by stimulation with InsP₃, cADPR, or NAADP are remarkably similar (24), it seems possible, even likely, that NAADP could also liberate Ca²⁺ from isolated ZGs.

Apical Ca²⁺ signals are of strategic importance for the control of pancreatic enzyme and fluid secretion (38, 39). It appears that the reason for the particular sensitivity of the apical region of pancreatic acinar cells to Ca²⁺-releasing stimuli is the close proximity, in this part of the cell, of two separate Ca²⁺ stores, both having a full complement of Ca²⁺-releasing channels. Given the fact that CICR only initiates in the apical pole and depends on the dual function of both RyRs and IP₃Rs (29), it does not seem unreasonable to propose that the apical Ca²⁺ spikes arise from CICR interactions between these receptors on both types of Ca²⁺ stores.

Although sea urchin eggs and pancreatic acinar cells are the most intensely studied systems in which the actions and role of NAADP in Ca²⁺ signaling have been investigated, there is a growing list of other cell types in which NAADP participates as an important Ca²⁺-releasing messenger. Rat brain microsomes were the first mammalian preparation in which NAADP-induced Ca²⁺ release was demonstrated (40). In this preparation, the NAADP-regulated Ca²⁺ release mechanism, as in sea urchin eggs, was independent of extravesicular Ca²⁺ concentrations, was unaffected by IP₃R and RyR inhibitors, but was inhibited by micromolar concentrations of dihyropyridines or diltiazem. These findings were mirrored in studies on cholinergic motoneurons from Aplysia, where NAADP-evoked Ca²⁺ release was not blocked by heparin or by ryanodine either alone or together (41). Similarly in frog neuromuscular preparations, NAADP-induced increases in transmitter release from prejunctional neurons were not affected by either ryanodine or thapsigargin (42, 43). In rat cortical neurons, NAADP-evoked increases in Ca²⁺ were thapsigargin- insensitive but again blocked by bafilomycin (44); however, NAADP-induced Ca²⁺ transients were reduced but not abolished by ryanodine or heparin treatments. These data are consistent with the suggestion that NAADP activates a distinct Ca²⁺ release mechanism on acidic compartments, that can, in turn, be amplified by recruiting IP₃Rs and RyRs, presumably by CICR.

Pancreatic beta cells also express an NAADP-sensitive Ca²⁺-release mechanism. In human pancreatic beta cells, NAADP mobilizes Ca²⁺ from a pool that is insensitive to either ryanodine or the IP₃R antagonist, xestospongin C, and might mediate the autocrine inhibitory effects of insulin on further release of this hormone (45). In this study, and in a report of the pancreatic beta MIN6 cell line (46), nanomolar concentrations of NAADP induced Ca²⁺ release, whereas micromolar concentrations inactivated the release mechanism. Because micromolar concentrations of NAADP blocked glucose-induced Ca²⁺ spiking and because glucose administration increased NAADP levels, a messenger role was proposed for NAADP in stimulus-secretion coupling in pancreatic beta cells (46, 47). These findings were extended in MIN6 cells to show that NAADP mobilizes Ca²⁺ through a thapsigargin- and ryanodine-insensitive mechanism in secretory granules (SGs) rather than in the ER (48). These results were complemented by a study in intact MIN6 cells, in which NAADP-evoked Ca²⁺ release was blocked by bafilomycin but not thapsigargin (36).

Smooth muscle is another system in which NAADP-evoked Ca²⁺ release has been observed. In intact pulmonary arterial myocytes, NAADP mobilizes Ca²⁺ from a bafilomycin-sensitive store. Whereas xestospongin C had little effect on NAADP-induced Ca²⁺ release, both ryanodine or thapsigargin reduced but did not abolish NAADP’s effects (49, 50). Thus, as in other systems, local NAADP-induced Ca²⁺ release from acidic stores might be amplified by CICR through the recruitment of RYRs on the ER located proximal to NAADP-activated receptors (50). In rat aortic microsomes, NAADP released Ca²⁺ by a mechanism insensitive to IP₃R or RyR blockers but which was inhibited by dihydropyridines (51). In striated muscle, NAADP released Ca²⁺ from rat heart microsomes, which was unaffected by ryanodine and divalent cations, but blocked by dihydropyridines (52); however, it should be noted that direct interactions of NAADP with purified RyRs from both skeletal (53) and cardiac muscle (54) have been reported by some but not others (55).

Interactions between Ca²⁺-release mechanisms are important in T-cell activation. NAADP evokes Ca²⁺ release with a concentration- dependence similar to that evinced in both pancreatic acinar and beta cells: nanomolar concentrations activated, but micromolar concentrations inhibited Ca²⁺ release (56). Through the use of high, inactivating NAADP concentrations, T cell receptor–mediated activation was inhibited as was, perhaps more puzzlingly, Ca²⁺ release by InsP₃ or cADPR. A follow-up study showed that knock-down studies of RyRs (by utilizing antisense mRNA technology) in Jurkat cells— and experiments that inhibited RyRs with ruthenium red—reduced but did not totally abolish NAADP-induced Ca²⁺ release (16). Based on these studies, it is difficult to distinguish between a direct effect of NAADP on RyRs or an indirect effect involving amplification of NAADP-induced Ca²⁺ release by RyRs. There is a single report that NAADP may also operate as a Ca²⁺-mobilizing messenger in plants. In both red beet and cauliflower, it appears that NAADP releases Ca²⁺ from the ER rather than vacuolar membranes (57) through a mechanism insensitive to either heparin or 8-NH₂-cADPR or dihydropyridines, but blocked by ruthenium red, suggesting that it activates a novel Ca²⁺-release mechanism.

There are now numerous studies showing that NAADP is an extremely potent Ca²⁺-mobilizing messenger as well as a regulator of Ca²⁺ influx in a wide range of cell types from a variety of organisms including mammals and humans (Table 1). NAADP was initially implicated as a Ca²⁺-mobilizing messenger for different agonists in several cell types through the use of protocols that inactivated NAADP-mediated Ca²⁺ release; these findings have now been confirmed by direct NAADP measurements (14, 46, 50). The precise biosynthetic pathway for NAADP is unclear, although CD38 can catalyze synthesis by a base-exchange mechanism in vitro (58). Another major uncertainty is the nature and cellular location of NAADP-sensitive Ca²⁺-release channels. Although in many studies, NAADP-evoked Ca²⁺ release may be insensitive to IP₃R and RyR blockers but inhibited by agents such as dihydropyridines, more often than not RyR inhibitors reduce NAADP-mediated Ca²⁺ release. However, because different Ca²⁺-release channels often interact to shape Ca²⁺ signaling patterns (29, 59), it is not trivial to distinguish between a direct action of NAADP at RyRs or an action at a distinct and novel Ca²⁺-release channel followed by amplification by RyR-mediated CICR (Figure 1). If a direct action is the case, then there is a certain degree of novelty and selectivity as to the mechanism of regulation. If the latter scenario proves correct, then it is likely that we have been confounded by variations in the tightness of coupling between the separate mechanisms in different cells. Another possibility is that NAADP-binding proteins, although likely to be intrinsic membrane proteins (19), are promiscuous and are not intrinsic Ca²⁺-release channels, but regulators of known Ca²⁺ channels such as RyRs, and dihydropyridine-sensitive Ca²⁺ channels, among others. This hypothesis may also explain the apparent heterogeneity of Ca²⁺ stores that NAADP apparently discharges, with NAADP modulating the Ca²⁺ channels found in these different subcellular locations. These scenarios will only be unequivocally resolved by the purification and characterization of NAADP-binding proteins.

View larger version (31K): [in this window] [in a new window]   Figure 1. Possible mechanisms for NAADP-induced calcium release. Direct model: NAADP binds directly to the RyR on Ca2+ stores (ER or acidic compartments) increasing the probability of the channel being open (53, 54). NAADP may also bind and directly regulate plasma membrane (pm) Ca2+ channels (PMCC). Trigger CICR model: This model assumes that there is a discrete NAADP receptor/Ca2+-release channel that is located in a discrete Ca2+-storage organelle (probably an acidic store) (store 1). Localized Ca2+ release from this pool then recruits IP3Rs and RyRs located in a second store [the ER (store 2)] by CICR and globalizes the Ca2+ signals (5, 20). Promiscuous coupling model: In this model, the NAADP-binding protein is not a Ca2+ channel per se, but rather is an integral membrane protein that can associate and regulate Ca2+-release channels such as RyRs (35), in the ER or acidic stores (including secretory granules), or calcium influx channels in the plasma membrane. Conformational coupling model: This model assumes that NAADP interacts directly with a distinct NAADP-regulated Ca2+-release channel in a discrete store. This channel can release Ca2+ in response to NAADP, but the channel may also directly interact with other Ca2+-release channels (IP3Rs or RyRs) or with plasma membrane Ca2+-influx channels. This model provides one explanation for how desensitizing concentrations of NAADP apparently render IP3Rs or RyRs insensitive to their respective agonists (56) or desensitize Ca2+ influx (14), even in the apparent absence of Ca2+ release. Permutations of any of the four models above are also possible. Another possibility is that distinct subtypes of NAADP receptors exist with different localizations, pharmacology, and functions.

Antony Galione, PhD, is a Professor of Pharmacology and a Wellcome Senior Fellow in Basic Biomedical Science at The University of Oxford, UK. E-mail antony.galione{at}pharm.ox.ac.uk; fax +44 1865 271 853.

Ole H. Petersen, FRS, is Medical Research Council Professor in Physiology, at The University of Liverpool, UK. E-mail o.h.petersen{at}liv.ac.uk; fax +44 151 794 5323.

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