Calcium signalling by nicotinic acid adenine dinucleotide phosphate NAADP Michiko Yamasaki, Grant C.. Cyclic ADP-ribose cADPR and nicotinic acid adenine dinucleotide phosphate NAADP were
Trang 1Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)
Michiko Yamasaki, Grant C Churchill and Antony Galione
Department of Pharmacology, University of Oxford, UK
Intracellular Ca2+signals are coordinated to elicit
spa-tiotemporal patterns These include repetitive Ca2+
transients, which may be localized or propagated as
regenerative waves that may also pass into
neighbour-ing cells [1–3] d-myo-Inositol 1,4,5-trisphosphate
(InsP3) is a well-established intracellular Ca2+
mobil-izing messenger in many cell types [3], and is a
para-digm for additional molecules that release Ca2+ from
intracellular Ca2+stores Cyclic ADP-ribose (cADPR)
and nicotinic acid adenine dinucleotide phosphate
(NAADP) were first discovered in the sea urchin egg
as novel Ca2+ mobilizing agents [4–6] In this cell,
cADPR was shown to target ryanodine receptors
(RyRs) to release Ca2+ from the endoplasmic
reticu-lum (ER), and now has been established as an
intracel-lular messenger in several cell types [7,8] In contrast,
NAADP was found to activate a Ca2+ release
mech-anism distinct from those activated by InsP3 and
cADPR, based on pharmacology and self-induced
inactivation of the different Ca2+ release mechanisms
It has thus been of great interest to investigate the physiology, enzymology and pharmacology of the NAADP signalling pathway Recent reports have shown increases in NAADP levels in response to cellular stim-uli fulfilling a major criterion for the classification of NAADP as a second messenger not only in sea urchin eggs but also in mammalian cells [9–12] Here we focus
on the Ca2+ mobilizing properties of NAADP and compare them with the actions of InsP3and cADPR
Distinct properties of NAADP Since the discovery of NAADP as a Ca2+ mobilizing molecule in sea urchin egg homogenates, the sea urchin egg has remained an important system in which to study the actions of NAADP NAADP has an ability
to release Ca2+ from intracellular Ca2+ stores and is the most potent Ca2+ mobilizing agent described so
Keywords
acidic stores; cADPR; endoplasmic
reticulum; InsP3; NAADP
Correspondence
A Galione, Department of Pharmacology,
University of Oxford, Mansfield Road,
Oxford OX1 3QT, UK
Fax: +44 1865 271853
Tel: +44 1865 271633
E-mail: antony.galione@pharm.ox.ac.uk
(Received 28 April 2005, accepted 30 June
2005)
doi:10.1111/j.1742-4658.2005.04860.x
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a recently described Ca2+ mobilizing messenger, and probably the most potent We briefly review its unique properties as a Ca2+mobilizing agent We present arguments for its action in targeting acidic calcium stores rather than the endoplasmic reticulum Finally, we discuss possible biosynthetic pathways for NAADP in cells and candidates for its target Ca2+ release channel, which has eluded identification so far
Abbreviations
cADPR, cyclic ADP-ribose; CICR, Ca 2+ -induced Ca 2+ release; ER, endoplasmic reticulum; InsP3, D -myo-inositol 1,4,5-trisphosphate; NAADP, nicotinic acid adenine dinucleotide phosphate; RyR, ryanodine receptor.
Trang 2far Perhaps the most intriguing property of NAADP
is its profound self-desensitization mechanism that is
unparalleled by any other intracellular messenger
Sub-threshold concentrations of NAADP inactivate the
NAADP evoked Ca2+ release that normally shows a
robust Ca2+release response [13–15] Although similar
effects have been seen in plant cell preparations [16], in
intact mammalian cells only high concentrations of
NAADP cause such self-desensitization [10,11,17–20],
which is also interesting as this occurs in the apparent
absence of any Ca2+release (Fig 1)
In sea urchin eggs and egg homogenates, heparin
(an InsP3 receptor antagonist), ruthenium red,
pro-caine and 8-NH2-cADPR (ryanodine or cADPR
recep-tor antagonists), inhibit InsP3- and cADPR-induced
Ca2+signals, whilst the NAADP-evoked Ca2+ release
persists In these preparations, thapsigargin, an ER
Ca2+-ATPase inhibitor, depletes InsP3 and ryanodine
sensitive Ca2+ stores, resulting in the inhibition of
InsP3 and cADPR responses However,
NAADP-induced Ca2+release remains [21] Similar results were
seen in intact sea urchin eggs when photolysing caged
derivatives of these messengers Both photoreleased
InsP3 and cADPR failed to evoke Ca2+ release in
thapsigargin-treated cells, whilst the response to
photo-released NAADP remained unaffected [22,23] (Fig 2)
Pharmacological analyses extended to mammalian
preparations have also confirmed the distinct nature of
the NAADP-sensitive Ca2+ release mechanism from
those regulated by InsP3 or cADPR, particularly in
brain [24], and cardiac microsomes [25] as well as
in arterial smooth muscle cells [26] Furthermore, in
sea urchin eggs, NAADP-sensitive Ca2+ stores can
be separated physically from thapsigargin-sensitive stores sensitive to InsP3 and cADPR by cell fraction-ation of egg homogenates or intact egg stratificfraction-ation [6,27,28]
The pharmacology of NAADP-induced Ca2+release
in sea urchin egg homogenates has been found to be different from known Ca2+ release channels For example, it is sensitive to l-type Ca2+ channel inhibi-tors, such as dihydropyridines, D600 and diltiazem, and to certain K+ channel blockers, without affecting
Ca2+ release via either InsP3 or ryanodine receptors [14,21,24] Furthermore, NAADP-mediated Ca2+ release is neither potentiated by Ca2+ or Sr2+, nor inhibited by Mg2+[14,21,29] Therefore in contrast to
Fig 1 Inactivation properties of NAADP-induced release (A) Sea urchin eggs: The top panel illustrates the unusual phenomenon whereby in sea urchin egg homogenates, a low concentration of NAADP (1 n M ) that induces no apparent Ca 2+ release (right hand trace), fully desensiti-zes the NAADP receptor mechanism so that a subsequent application of a maximal concentration of NAADP (500 n M , see left hand trace) is now without effect [13,14] (B) Mammalian cells: NAADP-induced Ca 2+ release in MIN6 cells Percentage of the increase in normalized fluor-escence (F⁄ F 0 %) demonstrated for each caged NAADP concentration The inset bar symbolizes the least significant difference (LSD) that was calculated from observed errors The numbers in brackets over the bars present number of replicates Data are means ± SEM The graph shows a bell-shaped concentration-response curve which is typical in mammalian systems Higher concentrations of NAADP inactivate release by this messenger under conditions where little if any release occurs Modified from [10].
Fig 2 NAADP-induced Ca2+release from a thapsigargin-insensitive
Ca 2+ store Effect of thapsigargin on the initial response to photo-release of an InsP3-cADPR mixture and NAADP Eggs were treated with thapsigargin (2 l M ) for > 30 min and then exposed to UV The final intracellular concentrations were (l M ): Oregon green 488 BAPTA Dextran, 10; caged NAADP, 0.5; and both caged cADPR and caged InsP 3 , 5 Modified from [22].
Trang 3Ca2+ release channels modulated by either InsP3 or
cADPR that participate in Ca2+-induced Ca2+release
mechanism (CICR), the NAADP-sensitive Ca2+release
mechanism is unlikely to do so directly The apparent
inability of NAADP to induce regenerative Ca2+
signals itself implies a role in initiating localized Ca2+
signals, which may then be propagated by recruiting
CICR mechanisms Additional interactions of NAADP
signalling pathways with Ca2+ signals may arise since
the metabolism of NAADP to inactive NAAD is
regu-lated by a Ca2+-dependent 2¢-phosphatase [30]
Radioligand binding studies employing [32P]NAADP
support the idea that NAADP acts on a fundamentally
different Ca2+ releasing channel from those gated by
InsP3 or cADPR Binding of radiolabelled NAADP to
sea urchin egg homogenate membranes is highly
speci-fic [13,31,32] and is unaffected by InsP3 or cADPR
[13,31] Binding studies have revealed another peculiar
property of the NAADP receptor where NAADP
binds to its receptor in an essentially irreversible
man-ner in the sea urchin egg homogenates [13,31,32] In
mammalian systems, however, [32P]NAADP binding to
membrane preparations from rat brain [31], rat heart
[25] and MIN-6 cells [10] is reversible The apparent
irreversibility of NAADP binding in sea urchin egg
preparations is dependent on high K+ concentrations
in the binding medium routinely used [15]
Ca2+ mobilizing messengers and
multiple stores
Studies of the Ca2+ mobilizing effects of NAADP in
intact cells have revealed that this Ca2+ release
mech-anism rarely operates in isolation Rather the resultant
Ca2+ signals evoked by this molecule are often
boos-ted by Ca2+ release by RyRs, InsP3Rs or both
Inter-actions between different Ca2+release mechanisms are
critical for shaping Ca2+ signals in response to
agon-ists in many different cell types [33] The effects of
NAADP on Ca2+ release are often abolished or
attenuated by both heparin and 8-NH2-cADPR,
anta-gonists for InsP3and cADPR receptors, indicating that
the different Ca2+release channels are tightly coupled
functionally In sea urchin eggs, ascidian oocytes, and
arterial smooth muscle, antagonists of InsP3Rs or
RyRs reduce responses to NAADP [26,34,35], whereas
in T-lymphocytes, starfish oocytes and pancreatic
aci-nar cells, little effect of NAADP is seen in the presence
of these inhibitors [18,36–39] To explain these
phe-nomena two models have currently been proposed
The first describes a single pool, the ER, expressing
InsP3Rs and RyRs Here NAADP interacts either
directly with RyRs or via a separate protein that may
indirectly activate RyRs [40,41] This model accounts for the apparent complete abolition of NAADP evoked release by either RyR blockers or thapsigargin
A direct action of NAADP on RyRs is also supported
by the findings that NAADP was shown to activate isolated RyRs reconstituted in lipid bilayers from rabbit skeletal muscle (RyR1) [42] and cardiac micro-somes (RyR2) [43] A second model, the two pool or trigger hypothesis, is based on the idea that there is a distinct NAADP-sensitive storage organelle, possibly
an thapsigargin-insensitive acidic store [28], that is responsible for a localized signal which is amplified
by InsP3Rs and RyRs the on the ER by CICR [22,34,36,38] This model accounts for the finding in some cells that localized NAADP-induced signals per-sist in the presence of InsP3Rs and RyR antagonists or thapsigargin, but are abolished by agents that dissipate storage of by acidic organelles, such as the vacuolar
H+ pump inhibitor, bafilomycin A1 This has been most clearly demonstrated in the sea urchin egg [28], but also extended to several mammalian cell types [11,44–46] Two types of pharmacological manipula-tion of acidic stores have been investigated with regard
to NAADP-evoked release Glycyl-phenylalanyl-naph-thylamide (GPN) is an agent that penetrates cellu-lar membranes but is a substrate for the luminal lysosomal enzyme cathepsin C trapping membrane impermeant products within lysosomes resulting in disruption of lysosomal-related organelles by osmotic lysis [47] The other approach is aimed at collapsing proton gradients thought to power Ca2+ uptake into acidic stores by Ca2+⁄ H+ exchange, such as bafilo-mycin A1, FCCP and NH3 [48] These agents selec-tively inhibit NAADP-induced Ca2+ release, whilst having little effect on the effects of either InsP3 or cADPR [11,28,45,46]
Changes in endogenous levels of NAADP
Only recently have NAADP levels been measured directly by using a radioreceptor assay with the NAADP binding protein from sea urchin eggs [9– 12,49] and shown to change in response to extracellu-lar stimuli [9–12] This provided the final piece of evidence required to classify NAADP as a second mes-senger NAADP levels have been shown to change in sea urchin sperm during activation before fertilization [9], in pancreatic beta cells in response to glucose [10],
in smooth muscle cells in response to endothelin [11], and in pancreatic acinar cells in response to gut-peptide cholecystokinin [12], which has been the most detailed study so far As outlined above, mouse
Trang 4pancreatic acinar cells have been an important system
in which investigate mechanisms for the generation of
intracellular Ca2+ signals It has been suggested that
interactions between a subset and all three messengers
are used to generate specific Ca2+ signatures in
response to extracellular agonists such as
cholecysto-kinin and neurotransmitter acetylcholine [20,38,39,50–
52] In this cell type, it has been proposed that an
initial increase in NAADP in response to
cholecysto-kinin triggers a primary Ca2+ release, followed by
recruitment of InsP3Rs and RyRs by CICR Although
there is much circumstantial evidence from
physiologi-cal and pharmacologiphysiologi-cal studies that cholecystokinin
increases NAADP and cADPR levels, changes in the levels of NAADP or cADPR had not been character-ized in response to this agonist until recently We have recently provided the strong evidence to establish NAADP as a second messenger in pancreatic acinar cells [12] Significant elevations of both NAADP and cADPR levels in response to a specific agonist, chole-cystokinin, in a concentration-dependent manner were reported (Fig 3) Cholecystokinin A receptors, expres-sed on mouse pancreatic acinar cells, possess two bind-ing sites for cholecystokinin, high and low-affinity binding sites [53–55] Concentration-response data sug-gest that production of NAADP and cADPR can be
Fig 3 Effects of cholecystokinin on NAADP and cADPR production in pancreatic acinar cells (A) Time course of cholecystokinin induced NAADP (r) Data were normalized to the maximum obtained with each individual time-course experiment The NAADP levels reach a maxi-mum within 10 s and return to resting levels in about 60 s (n ¼ 12) (B) Concentration-response curve for cholecystokinin-induced NAADP increases (d) The data were filled to the Hill equation with two-sites (EC50s of 11.0 ± 3.0 p M and 830 ± 6.6 p M ) Lorglumide, a cholecysto-kinin A receptor agonist, was present at 10 l M (n ¼ 3–6) (open triangles) (C) The time course of cADPR production (d) was determined in the presence of physiological concentration of cholecystokinin (10 p M ) The production of cAPDR showed prolonged elevations comparing that of NAADP Lorglumide inhibited cADPR production (m) (D) Cholecystokinin-induced cADPR elevations (j) occur in a concentration-dependent manner Data are mean ± SEM Modified from [12].
Trang 5activated through both high and low-affinity sites on
cholecystokinin A receptor This same study also
dem-onstrated receptor specificity for the production of
NAADP and cADPR, whereby increases in cADPR
levels via stimulation of acetylcholine muscarinic
recep-tors as well as cholecystokinin A receprecep-tors, whereas
NAADP increased only through the activation of
chol-ecystokinin A Intriguingly, the striking difference seen
in time courses between NAADP and cADPR
pro-duction, where the increase in NAADP was rapid
and transient, whereas the increase in cADPR was
much prolonged, strongly supports the proposed
hypothesis that NAADP provides a localized Ca2+
trigger signal at the apical region where InsP3Rs, RyRs
and NAADP-sensitive Ca2+ stores coexist [45,56–62]
(Fig 4), and subsequently this localized Ca2+ signal is
amplified by a CICR mechanism via sensitization of
RyRs throughout of the cell [20,38,39,50–52,60–63]
Cell surface receptors are predominantly located in the
basolateral membrane, however, agonist-induced Ca2+
signals initiate at the apical pole before propagating
into the basolateral domain by the CICR mechanism
The abundance of RyRs in the basolateral region
together with the slow rise in the cADPR levels
dem-onstrated in our recent report [12] may also contribute
greatly to such spatiotemporal heterogeneities of Ca2+
signals
Although there are few reports of direct NAADP
measurements, an interesting correlation is emerging
Inhibition of agonist-evoked signalling by inactivating NAADP concentrations or bafilomycin A1 correlates well with receptors whose stimulation leads to eleva-tions in NAADP levels, whereas those that are not sensitive to these pharmacological manipulations are not [11,12,45]
Outstanding questions in NAADP signalling pathways
There are still several important aspects of the NAADP signalling pathway that are unclear Foremost is the nature of the NAADP receptor Studies from the sea urchin egg system have suggested that NAADP probably acts on a distinct protein that is pharmacolo-gically different from IsnP3Rs of RyRs [64], although direct activation of RyRs has also been proposed [64] The kinetics of Ca2+ release evoked by NAADP are consistent with the gating of a Ca2+ release channel rather than a transporter protein [65] Preliminary biochemical characterization of [32P]NAADP binding proteins from sea urchin eggs have shown that such proteins are likely to be integral membrane proteins, and probably smaller than either InsP3Rs or RyRs [30] However, it is possible that the NAADP binding pro-teins may not form a pore themselves but rather inter-act with and modulate other channels Further, in line with the multiplicity of InsP3Rs and RyR isoforms, it is also possible that multiple isoforms of NAADP ‘recep-tors’ exist which may go some way in reconciling con-flicting pharmacological data from different systems [64] Perhaps the most detailed study of the functional properties of NAADP receptors, in the absence of their molecular isolation, has come from the study of NAADP signalling in starfish oocytes [37,66] Here much emphasis has been placed on the ability of NAADP to gate a cation influx in addition to release from internal stores In contrast to the situation in sea urchin eggs where NAADP induces a brief Ca2+influx (the ‘cortical flash’), followed by a more substantial mobilization [9], the starfish oocytes exhibits a pro-found Ca2+ influx of in response to NAADP It has been proposed that NAADP receptors may be expressed at the plasma membrane of these cells, and thus electrophysiological analyses have been employed
to characterize such NAADP-induced currents [67] An interesting question is whether these currents arise from direct activation of NAADP receptors on the plasma membrane or activation of a plasma membrane channel via calcium released from cortical NAADP-sensitive stores Taken together these observations imply the widespread distribution of NAADP receptors and multiple roles of NAADP However, the ultimate
Fig 4 Localization of NAADP-induced Ca 2+ signals in mouse
pan-creatic acinar cells Panpan-creatic acinar cells were injected with
Ore-gon Green 488 BAPTA Dextran and caged NAADP (estimated final
concentration: 100 n M ) In response photoreleased NAADP, the
local Ca 2+ spikes were confined to the apical pole (blue trace), but
not to the basal pole (red trace) (n ¼ 8) These localized Ca 2+
spikes become progressively amplified Modified from [45].
Trang 6resolution of many these questions will require isolation
of NAADP-binding proteins
It may come as some surprise that the biosynthetic
pathway for NAADP synthesis is still unknown
Endogenous levels have been reported in several cell
types and in some of these changes in levels in
response to agonists have been reported A favoured
pathway for synthesis involves enzymes known as
ADP-ribosyl cyclases (Fig 5) As the name suggests
these where first described as activities and then
char-acterized as membrane proteins that cyclized NAD to
form cADPR In mammalian systems the
best-charac-terized cyclases so far are CD38 and CD157 (BST-1)
(Fig 5), although other membrane-bound and soluble
forms have been reported [68] However, in vitro, these
multifunctional enzymes can utilize NADP as an
alter-native substrate, and at acidic pH and in the presence
of nicotinic acid, they can catalyse NAADP synthesis
by a mechanism involving base exchange (Fig 5)
Whether CD38 or CD157 are responsible for
agonist-promoted NAADP synthesis in mammalian cells
remains to be demonstrated Two potential problems
may confound this possibility The first is that both
CD38 and CD157 are largely ectoenzymes, although
several reports suggest intracellular localizations as
well The second is that large, and perhaps
nonphysio-logical, concentrations of nicotinic acid are required
for any appreciable NAADP production by these
enzymes, although high localized concentrations may
be postulated One possibility that has not been
explored is that synthesis of NAADP may occur inside
intracellular vesicles, or even extracellularly (as has
been proposed for cADPR [69]), with the products
then being transported back into the cytoplasm where
it can interact with its putative targets If these vesicles
were also the acidic stores proposed as major sites for
NAADP-evoked release [28], then the pH of the
lumi-nal environment would also promote NAADP
synthe-sis, and could also be a site for the accumulation
of nicotinic acid However, endogenous changes in
NAADP levels have been reported in several systems, and we are now in a position to elucidate the mecha-nisms of NAADP production For example, an investi-gation of agonist-induced NAADP changes in cells and tissues from CD38⁄ CD157 knockout mice may be informative Other possibilities for NAADP synthetic pathways also deserving investigation are phosphory-lation of NAAD, better known as a biosynthetic pre-cursor of NAD, or a direct deamination reaction of NADP
The identification of the enzymes involved in NAADP synthesis with the recent identification of various agonists that stimulate increases in cellular NAADP levels may also lead to an understanding of the coupling mechanisms between cell surface receptors and NAADP production Both activation of the chole-cystokinin A receptor and the ET-1 receptor have been shown to couple to NAADP synthesis As these recep-tors are G protein coupled it is possible that G protein subunits may directly regulate enzymes catalysing NAADP production In addition, the finding that cAMP stimulates the NAADP synthesis in the pres-ence of sea urchin membranes [70] may indicate an involvement of downstream regulators (Fig 5)
Summary NAADP has been reported to be an endogenous and potent Ca2+ mobilizing agent in several cell types of many different organisms NAADP evokes localized signals, which may be amplified by recruiting InsP3Rs and RyRs through CICR mechanisms Changes in NAADP levels are linked to the activation of several cell surface receptors All the criteria have now been satisfied for its recognition as an intracellular messen-ger, however, further studies required in the future are
to establish the cellular mechanisms for the regulation
of NAADP synthesis and metabolism as well as the molecular mechanisms mediating NAADP-induced
Ca2+release
Fig 5 Putative synthesis pathway for
NAADP In the presence of b-NADP,
ADP-ribosyl cyclase catalyses the synthesis of
NAADP by a base exchange reaction with
an optimum pH of 4 [71] CD38 and CD157
have been shown to be capable of forming
NAADP under the same condition [71–73].
cAMP is a stimulator of NAADP synthesis
via ADP-ribosyl cyclase [70].
Trang 7AG is a Wellcome Trust Senior Fellow in Basic
Bio-medical Science; MY is a Wellcome Trust Prize
Stu-dent Work in AG and GCC’s laboratories is funded
by the Wellcome Trust
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