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REVIEW ARTICLE
From the Department of Experimental and Diagnostic
Medicine, Section of General Pathology and Medical Genetics, and Center
of Biotechnology, University of Ferrara, Ferrara, Italy.
Nucleotides are emerging as an ubiquitous family of extracellular
signaling molecules. It has been known for many years that adenosine
diphosphate is a potent platelet aggregating factor, but it is now
clear that virtually every circulating cell is responsive to
nucleotides. Effects as different as proliferation or differentiation, chemotaxis, release of cytokines or lysosomal constituents, and generation of reactive oxygen or nitrogen species are elicited upon
stimulation of blood cells with extracellular adenosine triphosphate (ATP). These effects are mediated through a specific class of plasma
membrane receptors called purinergic P2 receptors that, according to
the molecular structure, are further subdivided into 2 subfamilies: P2Y
and P2X. ATP and possibly other nucleotides are released from damaged
cells or secreted via nonlytic mechanisms. Thus, during inflammation or
vascular damage, nucleotides may provide an important mechanism
involved in the activation of leukocytes and platelets. However, the
cell physiology of these receptors is still at its dawn, and the
precise function of the multiple P2X and P2Y receptor subtypes remains
to be understood.
(Blood. 2001;97:587-600) In 1978 the existence of plasma membrane receptors
for extracellular nucleotides, the P2 purinergic receptors, was
formally recognized.1 At that time, this identification
was only based on pharmacologic and functional evidence and on the
prophetic intuition of Geoff Burnstock. To date, 12 mammalian P2
receptors have been cloned, characterized, and recognized as
responsible for the diverse cellular responses to stimulation with
extracellular nucleotides.2,3 The P2 receptor family also
includes receptors for extracellular pyrimidines. The new
classification based on the molecular structure is rapidly replacing
the previous one (P2Y, P2X, P2U, P2T, and P2Z) based on the
pharmacologic profile,4 although doubts remain on whether
functional responses of the native P2Z receptor of immune cells can be
entirely explained by the cloned P2X7 subunit. A similar
uncertainty also concerns the platelet P2T receptor, which is likely to
arise from the combination of P2Y and P2X-dependent
responses.2,5 Extracellular effects of nucleotides were
initially recognized in smooth muscle contraction, neurotransmission,
regulation of cardiac function, and platelet aggregation.6
However, over the last 10 years it has become clear that the
intercellular mediator role of these molecules is widespread, and blood
cells have emerged as one of the most interesting targets.
Contrary to a widely held opinion, adenosine triphosphate (ATP) and
possibly also uridine triphosphate (UTP) are often released into the
extracellular environment via nonlytic mechanisms7-12 and
also more frequently as a consequence of cell damage or acute cell death. Furthermore, platelet-dense granules are a relevant source
of secreted ATP.13,14 Once in the pericellular
environment, ATP can serve as a ligand for P2 receptors or be quickly
hydrolyzed by powerful ubiquitous ecto-ATPases and
ectonucleotidases.15-18 ATP can also be used as a
phosphate donor by poorly characterized ectokinases.19
Thus, ATP possesses all the properties of a bona fide fast-acting
intercellular messenger: (a) it is released in a controlled
fashion, (b) ligates specific plasma membrane receptors coupled to intracellular signal transduction, and (c) is
quickly degraded to terminate its action.
Outside excitable tissues, P2 receptors have an obvious relevance in
platelet aggregation, but immunity and inflammation are providing some
of the most exciting developments in this evolving field. A few
reviews covering different aspects of P2 receptor distribution and
function in hemopoietic cells have appeared and have been an invaluable
source of information for the present work.20-26
According to the International Union of Pharmacology (IUPHAR)
Committee on Receptor Nomenclature and Drug
Classification,27 receptors for extracellular nucleotides
are termed P2 receptors (this nomenclature replaces the older
"P2-purinoceptor"). P2 receptors are divided into 2 subfamilies: G protein-coupled (P2Y) and ligand-gated ion channels
(P2X).3,28-30 Current P2Y/P2X nomenclature is based on the
molecular structure and has replaced the previous one based on
pharmacologic and functional criteria. In mammalian cells, 5 P2Y
(P2Y1, P2Y2, P2Y4,
P2Y6, and P2Y11) and 7 P2X (P2X1-7)
receptors have been cloned and characterized
pharmacologically2 (Table 1).
P2Y5, P2Y7, P2Y9, and
P2Y10 have been purged from this sequence because they are
primarily non-nucleotide receptors (although they may also bind
extracellular nucleotides). A p2y3 (lower case to indicate that it has
not been cloned from mammals) receptor has been cloned from chick brain
and suggested to be a homologue of the mammalian
P2Y6.2 P2Y8 has so far only been
cloned from Xenopus neural plate; thus it is not included in
the list of mammalian receptors. The adenosine diphosphate
(ADP)-activated, G protein-coupled receptor of platelets that triggers
inhibition of stimulated adenylate cyclase has not yet been cloned;
thus it is recommended that this receptor should be given in
italics: P2Y ADP.2
P2Y receptors are 7-membrane-spanning proteins, numbering from
328 to 379 amino acids, for a molecular mass of 41 to 53 kd after
glycosylation.2,31,32 The aminoterminal domain faces the
extracellular environment, and the carboxyterminal is on the cytoplasmic side of the plasma membrane (Figure
1). Signal transduction occurs via the
classical pathways triggered by most 7-membrane-spanning receptors:
activation of phospholipase C and/or stimulation/inhibition of
adenylate cyclase. All of the P2Y receptors are activated by ATP, but
at 2 of them, P2Y4 and P2Y6, UTP is more
potent,33-36 and at P2Y2 ATP and UTP are
equipotent.31 At P2Y1, UTP is inactive and ADP
is reported to be equipotent or even more potent than ATP37,38; at P2Y11 ATP is more potent than ADP
and UTP is inactive.39 With respect to the signal
transduction pathway, P2Y1 and P2Y2 are coupled
to stimulation of phospholipase C-
Investigation of P2Y receptors has been severely hindered by the lack
of specific antibodies, whether polyclonal or monoclonal. Likewise, few
selective agonists, besides naturally occurring nucleotides, or
antagonists are available. A widely used P2Y antagonist is
suramin,41 a drug originally developed for the treatment of tripanosomiasis. However, suramin does not discriminate between P2Y
and P2X and has been reported to inhibit other receptors such as the
nicotinic, glutamate, GABA, and 5-hydroxytryptamine receptors as well
as the activity of diverse growth factors.2 Reactive blue
2, trypan blue, and reactive red have also been used as P2Y antagonists, but they also block P2X-dependent responses.2 Recently Harden and coworkers have introduced a number of nucleotide analogues as competitive P2Y1
antagonists.42,43 Pyridoxal phosphate (P5P) and
pyridoxalphosphate-6-azophenyl 2',4'-disulfonic acid (PPADS) are also
sometimes used to inhibit P2Y-dependent responses, but they are more
widely employed to block P2X receptors.
P2X receptors are ATP-gated ion channels
Although still on a limited basis, a few anti-P2X antibodies were made
available over the last 2 years by single laboratories or commercial
sources. Polyclonal antibodies against P2X1,
P2X4, and P2X7 can be obtained from at
least 2 companies; in a few laboratories sera against all the members
of the subfamily have been raised.53,46,49,54 One
monoclonal antibody selective for the human P2X7 receptor has been produced and characterized by Buell and
colleagues.55 Interestingly, this monoclonal antibody,
which recognizes an as yet to be identified epitope on the
extracellular domain, inhibits activation of human macrophages by
3'-O-(4-benzoyl)benzoyl-ATP (BzATP), a P2X7
agonist.55
The unique naturally occurring agonist of P2X receptors is ATP, albeit
diadenosine polyphosphates, such as
P,1P4-diadenosine tetraphosphate
(Ap4A) and P,1P6-diadenosine
hexaphosphate (Ap6A), are active at
P2X1 2, and UTP has been reported to be an
agonist at P2X3 as well as
P2X1.56,57 There is an ongoing debate,
initiated by the pioneeristic experiments of Cockcroft and Gomperts in
mast cells,58,59 on whether P2X receptors recognize the
bianionic (ATP2 Better antagonists, with better-characterized activity, are available
at P2X than at P2Y receptors. PPADS is a noncompetitive inhibitor of
most P2X receptors53 and, depending on the experimental conditions, may act irreversibly. Oxidized ATP (oATP) was introduced 7 years ago as a selective P2Z (P2X7)
inhibitor,64 but it is likely to show the same P2X
antagonist selectivity of PPADS, although no detailed investigation has
been carried out. At the effective concentrations (100-300 µM), oATP
shows little or no inhibitory activity at P2Y receptors and at
ectonucleotidases.64 Action of oATP on ectokinases has not
been tested in depth; thus it cannot be excluded that some effects of
this compound may be due to inhibition of
ectophosphorylation.65 PPADS and oATP likely share the
same mechanism of action. Both compounds have aldehyde groups (1 PPADS, 2 oATPs) that can react with unprotonated lysines to form Schiff's bases. It is assumed that they preferentially modify lysine residues in
the vicinity of the ATP binding site, but this assumption is yet to be
proved. Although PPADS has been used as a P2 blocker for some time, it
was only after the introduction of oATP that attention has been paid to
the time-dependent and irreversible inhibitory effect of this P5P
derivative. Time-dependent and irreversible block is extensively
documented for oATP at the P2X7 receptor: A 1- to
2-hour preincubation with this inhibitor, even if followed by
extensive rinsing, makes all cells so far investigated fully refractory
to ATP stimulation via the P2X7
receptor.64,66-69 Refractoriness lasts several hours,
until new receptors are inserted into the plasma membrane.
More recently, Wiley and colleagues have introduced another powerful
blocker of P2X7, compound
1-[N,0-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62).70 This molecule was originally used as an
inhibitor of the calcium calmodulin-dependent kinase71
and made its first appearance in the purinergic field in a study by
Blanchard et al72 aimed at investigating the role of the
P2Z receptor in cell-mediated cytotoxicity. KN-62 acts as a competitive
inhibitor at nanomolar concentrations and shows a striking species
specificity: It is active only at the human and not at the rat or mouse
P2X7 receptor.73 KN-62 is a very useful tool
for short-term studies, but modification of long-term responses should
be interpreted with caution because of concomitant inhibition of
calcium calmodulin kinase. Surprenant and colleagues74
have recently shown that Coomassie Brilliant Blue G selectively blocks
rat P2X7 with nanomolar affinity.
Early studies by Steinberg and Silverstein showed that the J774
mouse macrophage cell line expressed a plasma membrane receptor selectively activated by ATP and a few analogues.60,75
Stimulation of this receptor triggered the same reversible increase in
plasma membrane permeability to low-molecular-mass solutes originally described by Cockcroft and Gomperts in rat mast
cells.58,59 An intriguing finding of these studies was
that stimulation of the ATP-permeabilizing receptor eventually led to
cell death.75 This incidental observation stirred interest
in the possible physiologic meaning of ATP-dependent cytotoxicity and
fostered subsequent studies on the role of P2 receptors in the immune
system. At about the same time, Greenberg et al demonstrated that J774
macrophages also expressed P2Y-like receptors coupled to
Ca++ mobilization via a mechanism other than the
ATP-permeabilizing receptor.76 This was made possible by
the selection by Steinberg and colleagues75 of
ATP-resistant J774 macrophage clones later shown to lack the
P2X7 receptor.77,78
According to the nomenclature proposed by Gordon,4 the
macrophage-permeabilizing receptor was named P2Z, analogously to the
mast cell and lymphocyte ATP receptor. The receptor responsible for
ATP-dependent permeabilization has been referred to as P2Z until very
recently and, even after the cloning of P2X7 and the demonstration that its transfection confers susceptibility to ATP-dependent permeabilization, some investigators prefer the P2Z
nomenclature to indicate the native ATP-permeabilizing receptor, because it is not clear whether P2X7 is the only
constitutive subunit or, rather, the native P2Z receptor is formed by
the assembly of P2X7 in association with other P2X
subtypes. However, because P2X7 reproduces all known
effects of the native P2Z and cells resisting ATP-mediated
permeabilization lack P2X7, we will assume heretofore that
the macrophage P2Z and P2X7 receptors are the same
molecule. As seen below, the picture is more complex in lymphocytes and
other cells that do not undergo the typical ATP-dependent permeabilization, although they may express P2X7.
All murine macrophage lines so far investigated express P2Y
receptors coupled to release of Ca++ from intracellular
stores and IP3 generation, but the individual subtypes have
not been investigated in detail. Functional and molecular expression of
P2X7 has been shown in some murine cell lines and in mouse
and rat peritoneal macrophages.60,75,79-83 Monocyte-derived human macrophages are susceptible to ATP-mediated permeabilization and express P2X7.66,84,85
Among human macrophage lines, THP-1 and U937 cells express P2Y
receptors (P2Y2, P2Y4, and
P2Y6),5,86-88 but only the THP-1 monocytic
cell line has been reported to express P2X7 to a
significant level.88 However, P2X7 receptor
expression can differ significantly among cell batches propagated in
different laboratories. Monocytes freshly isolated from peripheral
blood express P2Y receptors but lack P2X7, whether investigated at the molecular or at the functional level. Although a
few studies are available, it is generally agreed that, at the most,
15% to 17% of human monocytes undergo the plasma membrane permeability transitions diagnostic of P2X7 expression when
stimulated with ATP.66,84 There appears to be an inverse
correlation between P2Y2 and P2X7 expression
during monocyte to macrophage maturation: P2Y2 messenger
RNA (mRNA) declines while P2X7 mRNA
increases.89 Up-regulation of P2X7 and
acquisition of P2X7-dependent responses are detectable
within 24 hours of seeding human monocytes on plastic dishes.
Up-regulation of P2X7 and down-regulation of
P2Y2 by the inflammatory mediators interferon- The first report on the effect of exogenous nucleotides on
macrophage function was a paper by Cohn and Parks.91 In
this study the authors showed that addition of adenine nucleotides to a
mouse macrophage culture resulted in a dramatic increase in pinocytic
vesicle formation. After this early study, exogenous nucleotides as a
stimulant for macrophages were basically neglected for several years
and resurrected only in 1985 by Silverstein and
coworkers,92 who reported that extracellular ATP inhibited Fc receptor-mediated phagocytosis and at the same time caused influx
of Na+, efflux of K+, and an increase in
[Ca++]i. In this study it was also for the
first time suggested that macrophages expressed receptors specific for
ATP. The possibility that these ATP effects could be due to ATP
hydrolysis by plasma membrane ecto-ATPase was ruled out by subsequent
papers by Steinberg and Silverstein60,75,76 that reported
an in-depth characterization of the macrophage-permeabilizing ATP
receptor. It was also soon clear that the ATP receptor coupled to
release of Ca++ from intracellular stores (P2Y) and the
ATP-permeabilizing (P2Z/P2X7) receptor were 2 separate
entities with widely different nucleotide selectivity and affinity and
likely involved in different responses.76 In J774
macrophages, the concentration of ATP giving one half of the maximal
response (EC50) for Ca++ release from
intracellular stores (and which therefore reflects activation of P2Y)
is in the range of 50 to 70 µM. In microelectrode impalement
experiments, the ATP EC50 for depolarization, presumably reflecting opening of P2X7, was reported to be between 250 and 400 µM,93 but a lower EC50 was reported
for P2X7-triggered Ca++ rise in
thioglycollate-elicited mouse peritoneal macrophages.94 However, determinations based on the measurement of uptake of fluorescent markers give higher EC50 (1.0-1.5 mM ATP) for
the activation of the native mouse P2X7
receptor.76,95 The UTP EC50 for
Ca++ release from intracellular stores is between 300 and
500 nM 76 and thus much lower than the ATP
EC50.76,94 This suggests that macrophages
express P2Y4 or P2Y6 or an endogenous yet to be
identified uridine nucleotide-specific receptor. Therefore, it is
clear that should ATP release occur in a tissue, macrophage P2Y
receptors are likely to be activated more easily and more frequently
than P2X7.
An early and, with hindsight, obvious proposal was that macrophages
and, in general, inflammatory cells, could use P2Y receptors as very
sensitive sensors of cell and tissue damage.76 After all,
mammalian cells contain huge amounts (5-10 mM) of ATP in their cytosol;
thus, any event that causes even a transient break in the plasma
membrane will cause release of ATP into the pericellular environment.
Furthermore, it is becoming apparent that frank cell injury or death
might not even be necessary for ATP release because shear stress forces
and stretching are also powerful stimuli for ATP
leakage.8-12 J774 macrophages chemotact in response to
micromolar concentrations of ADP but, rather intriguingly, not of
UTP.96 Human macrophages in the vicinity of dying K562
cells have been shown in vitro to undergo an increase in
[Ca++]i that can be closely mimicked by the
addition of cell lysate or of ATP at micromolar doses.97
Precedent treatment with the cell lysate made the macrophages
refractory to the subsequent application of ATP, suggesting, although
not proving, that a substance contained in the lysate and ATP might
converge on the same receptor. Thus it can be hypothesized that ATP and
other intracellular nucleotides function as early alarm signals that
alert macrophages of even minor cell and tissue damage (a response
could be elicited with as little as 100 nM ATP) (Figure
3).
The [Ca++]i rise could also be exploited by
the macrophages for the potentiation of antimicrobial defense
mechanisms. Nucleotides by themselves are unable to activate the
macrophage NADPH oxidase but enhance superoxide generation stimulated
by phagocytosable particles.98 It is conceivable that P2
receptors could also be used as an amplification system to spread the
alarm by generating additional inflammatory mediators. In murine and
human macrophages, extracellular ATP triggers release of TNF- Participation of P2 receptors in IL-1
In human monocytes, ATP is a powerful stimulus not only for caspase-1
activation but also for the externalization of mature caspase-1
subunits.112 The meaning of this novel observation is
elusive, but it may point to a possible function of activated caspase-1
either in the extracellular space or on the outer leaflet of the plasma
membrane. In addition, ATP might trigger IL-1 Participation of P2X7 in LPS-dependent activation of immune
cells might have very interesting and far-reaching practical
applications in the treatment of sepsis caused by gram-negative
bacteria. In 1994 Proctor and colleagues115 showed that
the ATP analogue, 2-methylthio-ATP (2-MeS-ATP), inhibited
endotoxin-stimulated release of toxic mediators such as TNF- Stimulation with extracellular nucleotides also switches on the
inducible nitric oxide synthase (iNOS),116-118 a key
enzyme for the bactericidal activity of macrophages. Nucleotides per se
are ineffective, but coexposure to low doses of ATP (or UTP) and LPS produces a much higher stimulation of iNOS activity compared with LPS
alone. In murine Raw 264.7 macrophages a prolonged (18 hours) incubation was needed to elicit nitrite release, suggesting that P2
stimulation acted by increasing iNOS gene expression rather than by
increasing enzyme activity. Other data suggest that P2 receptors are
involved in NO generation in a rather more complex fashion. Denlinger
and coworkers showed that pretreatment with 2-MeS-ATP prevented iNOS
expression and NO generation due to the subsequent addition of
LPS,117 raising the issue of the possible participation of
P2 receptors in LPS-dependent signaling.116,117 In
addition, it has been recently shown that NO production due to
Mycobacterium tuberculosis infection also occurs in
P2X7 knockout mice and it is inhibited by P2
blockers,119 thus pointing to the participation of other
P2X and P2Y receptors. There are an increasing number of papers
suggesting that P2 receptors (namely P2X7) might have a
role in endotoxin- or parasite-mediated macrophage stimulation. Besides
the studies carried out in our laboratory showing that incubation of
macrophages or microglia with oATP or apyrase inhibited LPS-dependent
IL-1 A common event observed in many reactions involving mononuclear
phagocytes is multinucleation: often during chronic inflammatory reactions macrophages differentiate into epithelioid cells that eventually fuse into large polykarions named multinucleated giant cells
(MGCs).120 Furthermore, in the bone, osteoclast precursors normally fuse to generate large elements with increasing bone resorption activity. MGCs are a common finding of widespread infectious diseases such as tuberculosis, but little is known about the molecular mechanism underlying fusion. In 1995, Falzoni et al66
suggested that the P2X7 receptor could be involved in MGC
formation. Monocyte-derived human macrophages can be induced to fuse in
vitro by incubation with concanavalin A or phytohemagglutinin, provided
that contaminating lymphocytes are also present.121
Pretreatment with oATP fully inhibits this process, although other
responses such as concanavalin A-dependent
[Ca++]i changes, chemotaxis, or expression of
plasma membrane molecules thought to take part in cell fusion (eg,
CD11a, CD18, and CD54) are unaffected.66 We have extended
these studies to J774 macrophages and selected several clones that
either express P2X7 to a very high level
(P2X7plus) or lack it altogether (P2X7less).
P2X7plus cells spontaneously fuse in culture to form MGCs
of different size and shape, containing from a few to 20 or more
nuclei.77 A monoclonal antibody raised against the
P2X7 outer domain prevents fusion of human macrophages in
culture.122,123
The participation in ICE activation and IL-1 That extracellular ATP is a potent cytotoxic factor for macrophages was
immediately apparent as soon as a thorough investigation of ATP
receptors was started in these cells, and P2X7 was quickly identified as the culprit. Initially in Silverstein's and later in our
laboratory, murine macrophage clones were selected that showed an
almost absolute refractoriness to ATP-mediated
cytotoxicity.60,75,76,95 These cells showed a normal
mobilization of Ca++ from intracellular stores in response
to ATP, but no permeabilization of the plasma membrane, and accordingly
lacked reactivity to anti-P2X7 antibodies.77
Blockade of the P2X7 receptor by oATP or KN-62 abrogated
ATP-dependent cytotoxicity. The role of P2 receptors in cytotoxicity is
usually tested in the presence of exogenous ATP, but it cannot be
excluded that ATP spontaneously released by cell monolayers may provide
a chronic cytolytic stimulus by acting as an autocrine/paracrine
factor. We have tested this hypothesis in P2X7plus J774
macrophage cultures grown to confluence. These macrophage clones show
an unusually high rate of spontaneous cell death that can be
significantly reduced by pretreatment with oATP or coincubation with
apyrase or hexokinase.131 In contrast to the
P2X7plus clones, the P2X7less cells have a low
rate of spontaneous death that is not affected by the presence of
P2X7 blockers or ATP-hydrolyzing enzymes. The mechanism of
ATP-dependent death can be either necrosis or apoptosis, depending on
the length of incubation in the presence of the nucleotide and the
dose. In our hands, ATP-pulsed J774 macrophages appear to die mostly by colloido-osmotic lysis; on the contrary, monocyte-derived human macrophages, which incidentally are more resistant to ATP-mediated cytotoxicity, are prone to die by apoptosis.124,125 It is
possible that the propensity of these cells to die by apoptosis is
related to their lower susceptibility to ATP because we have previously observed132 that, to set in motion the complex machinery
involved in apoptosis, a certain amount of time is needed that is
clearly unavailable in those cells that are so sensitive to ATP as to decease quickly. An in-depth investigation of the apoptotic
pathways triggered by ATP in macrophages has not been yet carried out, but we know from work in microglial cells that caspase-1, -3, and -8 are activated with the subsequent cleavage of the caspase substrates
PARP (poly [ADP-ribose] polymerase) and lamin B.106,133 In addition, the crucial transcription factors, NF- Dendritic cells are a newcomer in the purinergic field. It has
been known for a while that epidermal Langerhans' cells posses a
powerful plasma membrane formalin-resistant ecto-ATPase that has been
used as a histochemical marker,135 but their physiologic function was never understood. In 1993 Girolomoni and
coworkers136 demonstrated that human epidermal Langerhans'
cells can be permeabilized by ATP, albeit to a lesser degree than human
keratinocytes or J774 macrophages. However, inhibition of ecto-ATPase
greatly enhanced sensitivity to ATP, and this led these authors to
suggest that one of the possible physiologic functions of this
ectoenzyme was protection of Langerhans' cells against the noxious
effects of extracellular ATP. Scattered reports have then followed
suggesting that phagocytic cells of the thymus reticulum express a
P2X7-like ATP-permeabilizing receptor,137 but
only during the last few years has a systematic study of these
receptors been carried out in human and mouse dendritic
cells.138-143
Human dendritic cells were found to express mRNA for P2X1,
P2X4, P2X5, and P2X7 as well as for
P2Y1, P2Y2, P2Y4, P2Y6,
and P2Y11 receptors.140 Immunohistochemistry
with an anti-P2X7 monoclonal antibody performed in human
tonsils shows that a cell population of the marginal zone identified as
dendritic cells heavily expresses P2X7.55
Scanty pharmacologic data suggest that at least P2Y1, P2Y2, and P2Y4 are functional and mediate a
Ca++ signal in these cells.139
P2X7 functions have been investigated in detail in human
and mouse dendritic cells, and available evidence suggests that this
receptor mediates cytokine release and might also particpate in antigen
presentation.141-142 During their investigation of P2Y
receptors in human dendritic cells, Liu et al139 observed that dendritic cells redirect their dendrites toward a nearby patch
pipette leaking ATP, an incidental finding that might suggest that
dendritic cells, like other mononuclear phagocytes, exhibit a
P2Y-mediated chemotactic response to ATP. In addition, it has been
shown that stimulation with UTP or uridine diphosphate (but surprisingly not with ATP) provided a potent stimulus for the cytokine
gene transcription and secretion.144 Given the high expression of P2X7, it is not surprising that dendritic
cells are exceedingly sensitive to the cytotoxic activity of ATP and readily die by apoptosis.141,145 Whether this may have
relevance in the overall process of modulation of the immune response
is presently unknown.
Lymphocyte responsivity to nucleotides has been known for many
years: In 1978 Gregory and Kern reported that extracellular ATP
stimulated proliferation of mouse thymocytes146; Fishman et
al in 1980 observed that in human peripheral lymphocytes ATP suppressed
proliferation,147 presumably via generation of adenosine. In 1981 Ikehara et al148 in some way reconcilied these
contrasting observations by showing that ATP stimulation of DNA
synthesis was observed in lymphoid cells from the thymus and inhibition in cells from spleen, lymph nodes, and peripheral blood. These early
observations were followed by a few other studies that overall were of
little help in building a coherent picture of the responses of lymphoid
cells to extracellular nucleotides, and they remained basically
anecdotal.149,150 It was not until the end of the 1980s that a systematic approach to the study of purinergic receptor expression and function in lymphocytes was
started.151-157
Human B lymphocytes express P2Y receptors, as indicated by the ability
of ATP and many other nucleotides (UTP, GTP, CTP, ITP, ADP, adenosine
5'-O-(3'-thiotriphosphate), ATP Expression of P2 receptors in mouse lymphocytes has been more
thoroughly investigated. RT-PCR data show that murine thymocytes express the message for P2X1, P2Y1, and
P2Y2 receptors and accordingly undergo Ca++
release from intracellular stores and an increase in plasma membrane permeability to external cations when challenged with
ATP.164-166 Steroid hormones or cross-linking of T-cell
receptor (TCR) by anti-TCR monoclonal antibody causes a transient
enhancement of P2Y2 mRNA, suggesting that this could be an
early event in response to a variety of activatory
stimuli.167 Sensitivity to ATP in thymocytes changes
depending on the stage of maturation:
CD4+CD8 The role of P2X receptors in the control of lymphocyte proliferation
could be more complex than just being effectors of cell death. We have
recently examined the effect of transduction of P2X7less
human B-lymphoid cells with the P2X7 receptor complementary DNA and have surprisingly found that its expression confers a proliferation advantage in the absence of serum.172 We
have not yet dissected the biochemical mechanism underlying the
enhanced growth rate of the P2X7 transfectants, but we
believe that it involves autocrine stimulation by ATP, because
incubation with apyrase or hexokinase or pretreatment with oATP
abrogated proliferation of P2X7 transfectants in the
absence of serum.172 Whether these observations are
relevant for tumors arising from hemopoietic cells is under investigation.
Stimulation with extracellular ATP causes shedding of the cell adhesion
molecule L-selectin (CD62L) and the low-affinity receptor for IgE
(CD23) from B chronic lymphocytic leukemic cells.173,174 These cells express P2X7, and agonist/antagonist studies
suggest that the receptor involved is P2X7.162
CD23 and L-selectin are normally found in high amounts in sera from
patients with B chronic lymphocytic leukemia, and this could be due to
ATP-dependent shedding via P2X7 stimulation.
Scattered evidence for a role of extracellular nucleotides in
granulocyte responses has been present for a while,175,176 but a systematic investigation was only started at the end of the
1980s.177-181 Most studies concentrated on neutrophils,
showing that ATP was able to trigger an increase in
[Ca++]i, stimulation of phosphoinositide
breakdown, superoxide anion generation, and granule exocytosis (both
specific and azurophilic).182,183 In human neutrophils,
ATP and UTP were reported to be equipotent for both the
[Ca++]i increase and superoxide anion
formation,178,179 and ATP was also shown to stimulate
phospholipase C and diacylglycerol generation as well as protein kinase
C activity.183,184 It is of great interest in the light of
the proposed proinflammatory role of extracellular ATP that this
nucleotide also increases membrane expression of CD11b/CD18 and
adhesion to albumin-coated latex beads.185 Because ATP is
released by the endothelium and its local concentration is likely to
increase during inflammation as a consequence of inactivation of
ecto-ATPases by oxygen radicals,186 up-regulation of
adhesion molecules by this nucleotide could be of relevance for
leukocyte migration across the vessel wall. ATP also enhances the
adhesion between neutrophils and pulmonary endothelial cells, a
mechanism that might be relevant in syndromes such as adult respiratory
distress syndrome and septic shock.187,188 Of course, it
cannot be excluded that the ATP effect could be at least in part
mediated by its hydrolysis to adenosine,189 but recent
data suggest that ecto-ATPase activity has an inhibitory rather than stimulatory effect on granulocyte-endothelium
interaction.190 Dubyak and coworkers reported that chronic
stimulation with ATP P2 subtype expression has not been thoroughly investigated in
neutrophils, mainly because of the lack of selective antibodies. RT-PCR
data show that human polymorphonuclear granulocytes express P2Y4 and P2Y6 but not P2Y1 or
P2Y2 receptors.5 Among P2X receptors, the
presence of P2X7 was shown by Northern blotting and
immunocytochemistry.49 It has been suggested that human
neutrophils might express receptors for diadenosine
polyphosphates,193 but evidence for this is
preliminary. Besides neutrophils, eosinophils also express P2 receptors
coupled to [Ca++]i increases, actin
reorganization, and stimulation of the NADPH oxidase.194,195 Interestingly, eosinophils show locomotive
activity in response to ATP, ADP, and GTP.194 No data are
available as to the P2 subtypes expressed.
ADP is one of the best-known activators of platelet
aggregation,25,196-198 but the receptors involved
have been, at least partially, identified only during the last 5 years. Stimulation with ADP causes release of Ca++
from intracellular stores, Ca++ influx, phospholipase C
activation, inhibition of stimulated adenylate cyclase, shape change,
activation of fibrinogen receptors, and
aggregation.199-201 ATP and ATP analogues are potent
inhibitors of these responses. It has also been shown that ADP causes
granule release and thromboxane A2
production.202,203 It was initially thought that these
effects were mediated by only one receptor named P2T; however,
later studies led to the molecular and pharmacologic characterization
in platelets of at least 2 of the known members of the P2 family:
P2X1 204-207 and
P2Y1.208,209 With the availability of more
selective platelet P2Y1 and P2X1 agonists and
antagonist, it is becoming evident that the view that these are the P2
receptors solely responsible of ADP-mediated platelet activation is an
oversimplification. It is clear that it is possible to block
ADP-mediated inhibition of stimulated adenylate cyclase activity
without decreasing the ADP-dependent [Ca++]i
rise. Thus it is postulated that ADP-triggered platelet activation is
mediated by 3 receptors: One not yet cloned receptor
(P2TAC) is coupled to inhibition of stimulated
adenylate cyclase activity; a second (P2Y1) to
phospholipase C activation, InsP3 formation, and
Ca++ release from intracellular stores; and a third one
(P2X1) to fast Ca++ influx across the plasma
membrane.210,211 According to this proposal, the
P2TAC receptor would coincide with the platelet P2YADP (written in italics to signify that it is
not yet cloned) receptor of the nomenclature established by
IUPHAR.2,27 Development of selective platelet P2 receptor
antagonists has progressed further than in other cell types, and some
have already reached clinical applications. Two thienopyridine
compounds, ticlopidine and clopidogrel, inhibit ADP-triggered platelet
aggregation presumably by selectively blocking
P2YADP. The limited structure-relationship
analysis so far carried out suggests that 2-alkylthio-substituted
analogues of ATP and AMP (eg, 2-MeS-ATP; 2-methylthioadenylyl
5'-( Effects of extracellular ATP on erythrocytes were initially
reported in 1972 by Parker and Snow,221 who showed that
this nucleotide caused Na+ influx and K+ efflux
paralleled by an increase in water content. As later demonstrated in
other cell types, ion fluxes were prevented by Mg2+ or
hexokinase plus glucose and potentiated by ethylenediaminetetraacetic acid. All other nucleotides tested were ineffective. An increase in
plasma membrane permeability of erythrocytes was also reported by
Trams,222 who showed a dramatic accumulation of
extracellular adenylates in the presence of extracellular ATP. These
authors concluded that ATP caused a permeability change in erythrocyte plasma membrane that allowed for leakage of cytoplasmic ATP
("ATP-induced ATP release"). These data would suggest the
expression by erythrocytes of a P2X7-like receptor, but no
further characterization of this phenomenon was carried out. Release of
ATP under hypoxic conditions has also been reported,223
but the pathway involved was not elucidated. At variance with P2X,
erythrocyte P2Y receptors are more thoroughly characterized. Avian red
blood cells express a typical P2Y1 receptor coupled to
phospholipase According to the few available studies, all hemopoietic precursors
isolated from mouse bone marrow, as opposed to stromal cells, are
highly sensitive to the cytotoxic effect of ATP.228,229 This phenotypic property has made available a very efficient procedure for the isolation of highly purified marrow stromal cells or the deletion of hemopoietic cell precursors. The cytotoxic mechanisms appear to be dependent on the known pore-forming ability of ATP mediated by P2X7 activation and can be
significantly enhanced by including in the reaction medium a
low-molecular-weight nonpermeant poisonous agent such as potassium
thiocyanate.228,229 This procedure might turn out helpful
for the local treatment of tumors of hemopoietic origin.
For many years it was thought that receptors for extracellular
nucleotides had a physiologic role only in excitable tissues; however,
it is now increasingly clear that they are widespread and involved in
signal transduction in several other tissues, including blood cells
(Table 2). Drugs based on
P2YADP antagonism are already in use as
antithrombotic agents, and P2Y1 blockers are being
developed for this same purpose. Besides thrombosis, another promising
field of application of P2 agonist/antagonist is inflammation. Ability
of P2 receptors to mediate chemotaxis (via P2Y), or cytotoxic responses
and cytokine secretion (via P2X7), opens an entirely new
perspective for the development of anti-inflammatory drugs. Chronic
inflammatory diseases might be one of the first targets for the
clinical application of selective P2X7 antagonists. These
compounds might prove beneficial to reduce IL-1
Two recent papers suggest that circulating human monocytes
express a functional P2X7 receptor coupled to IL-1
Submitted May 8, 2000; accepted October 5, 2000.
Supported by grants by the Italian Ministry of Scientific Research (Cofin and 60%), the National Research Council of Italy (Target Project on Biotechnology), the Italian Association for Cancer Research, and Telethon of Italy. J.M.S. supported by a fellowship from the European Community (training grant BMH4-98-5146).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Francesco Di Virgilio, Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Via Borsari, 46, I-44100 Ferrara, Italy; e-mail: fdv{at}dns.unife.it.
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E. Adinolfi, M. G. Callegari, M. Cirillo, P. Pinton, C. Giorgi, D. Cavagna, R. Rizzuto, and F. Di Virgilio Expression of the P2X7 Receptor Increases the Ca2+ Content of the Endoplasmic Reticulum, Activates NFATc1, and Protects from Apoptosis J. Biol. Chem., April 10, 2009; 284(15): 10120 - 10128. [Abstract] [Full Text] [PDF]
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F. Scheuplein, N. Schwarz, S. Adriouch, C. Krebs, P. Bannas, B. Rissiek, M. Seman, F. Haag, and F. Koch-Nolte NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells J. Immunol., March 1, 2009; 182(5): 2898 - 2908. [Abstract] [Full Text] [PDF]
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J. K. Ramalingam, C. Hunke, X. Gao, G. Gruber, and P. R. Preiser ATP/ADP Binding to a Novel Nucleotide Binding Domain of the Reticulocyte-binding Protein Py235 of Plasmodium yoelii J. Biol. Chem., December 26, 2008; 283(52): 36386 - 36396. [Abstract] [Full Text] [PDF]
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E. J. Paredes-Gamero, C. M. M. P. Leon, R. Borojevic, M. E. M. Oshiro, and A. T. Ferreira Changes in Intracellular Ca2+ Levels Induced by Cytokines and P2 Agonists Differentially Modulate Proliferation or Commitment with Macrophage Differentiation in Murine Hematopoietic Cells J. Biol. Chem., November 14, 2008; 283(46): 31909 - 31919. [Abstract] [Full Text] [PDF]
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D. Myrtek, T. Muller, V. Geyer, N. Derr, D. Ferrari, G. Zissel, T. Durk, S. Sorichter, W. Luttmann, M. Kuepper, et al. Activation of Human Alveolar Macrophages via P2 Receptors: Coupling to Intracellular Ca2+ Increases and Cytokine Secretion J. Immunol., August 1, 2008; 181(3): 2181 - 2188. [Abstract] [Full Text] [PDF]
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T. I. A. Roach, R. A. Rebres, I. D. C. Fraser, D. L. DeCamp, K.-M. Lin, P. C. Sternweis, M. I. Simon, and W. E. Seaman Signaling and Cross-talk by C5a and UDP in Macrophages Selectively Use PLC{beta}3 to Regulate Intracellular Free Calcium J. Biol. Chem., June 20, 2008; 283(25): 17351 - 17361. [Abstract] [Full Text] [PDF]
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T. Noguchi, K. Ishii, H. Fukutomi, I. Naguro, A. Matsuzawa, K. Takeda, and H. Ichijo Requirement of Reactive Oxygen Species-dependent Activation of ASK1-p38 MAPK Pathway for Extracellular ATP-induced Apoptosis in Macrophage J. Biol. Chem., March 21, 2008; 283(12): 7657 - 7665. [Abstract] [Full Text] [PDF]
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S. Adriouch, P. Bannas, N. Schwarz, R. Fliegert, A. H. Guse, M. Seman, F. Haag, and F. Koch-Nolte ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site FASEB J, March 1, 2008; 22(3): 861 - 869. [Abstract] [Full Text] [PDF]
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D. M. Grbic, E. Degagne, C. Langlois, A.-A. Dupuis, and F.-P. Gendron Intestinal Inflammation Increases the Expression of the P2Y6 Receptor on Epithelial Cells and the Release of CXC Chemokine Ligand 8 by UDP J. Immunol., February 15, 2008; 180(4): 2659 - 2668. [Abstract] [Full Text] [PDF]
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D.-J. Jun, J. Kim, S.-Y. Jung, R. Song, J.-H. Noh, Y.-S. Park, S.-H. Ryu, J.-H. Kim, Y.-Y. Kong, J.-M. Chung, et al. Extracellular ATP Mediates Necrotic Cell Swelling in SN4741 Dopaminergic Neurons through P2X7 Receptors J. Biol. Chem., December 28, 2007; 282(52): 37350 - 37358. [Abstract] [Full Text] [PDF]
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K. R. Vaughan, L. Stokes, L. R. Prince, H. M. Marriott, S. Meis, M. U. Kassack, C. D. Bingle, I. Sabroe, A. Surprenant, and M. K. B. Whyte Inhibition of Neutrophil Apoptosis by ATP Is Mediated by the P2Y11 Receptor J. Immunol., December 15, 2007; 179(12): 8544 - 8553. [Abstract] [Full Text] [PDF]
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L. Stokes and A. Surprenant Purinergic P2Y2 Receptors Induce Increased MCP-1/CCL2 Synthesis and Release from Rat Alveolar and Peritoneal Macrophages J. Immunol., November 1, 2007; 179(9): 6016 - 6023. [Abstract] [Full Text] [PDF]
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F. Koch-Nolte, J. Reyelt, B. Schossow, N. Schwarz, F. Scheuplein, S. Rothenburg, F. Haag, V. Alzogaray, A. Cauerhff, and F. A. Goldbaum Single domain antibodies from llama effectively and specifically block T cell ecto-ADP-ribosyltransferase ART2.2 in vivo FASEB J, November 1, 2007; 21(13): 3490 - 3498. [Abstract] [Full Text] [PDF]
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O. S. Qureshi, A. Paramasivam, J. C. H. Yu, and R. D. Murrell-Lagnado Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis J. Cell Sci., November 1, 2007; 120(21): 3838 - 3849. [Abstract] [Full Text] [PDF]
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H. Bendz, S. C. Ruhland, M. J. Pandya, O. Hainzl, S. Riegelsberger, C. Brauchle, M. P. Mayer, J. Buchner, R. D. Issels, and E. Noessner Human Heat Shock Protein 70 Enhances Tumor Antigen Presentation through Complex Formation and Intracellular Antigen Delivery without Innate Immune Signaling J. Biol. Chem., October 26, 2007; 282(43): 31688 - 31702. [Abstract] [Full Text] [PDF]
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T. Darville, L. Welter-Stahl, C. Cruz, A. A. Sater, C. W. Andrews Jr., and D. M. Ojcius Effect of the Purinergic Receptor P2X7 on Chlamydia Infection in Cervical Epithelial Cells and Vaginally Infected Mice J. Immunol., September 15, 2007; 179(6): 3707 - 3714. [Abstract] [Full Text] [PDF]
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G. Borsellino, M. Kleinewietfeld, D. Di Mitri, A. Sternjak, A. Diamantini, R. Giometto, S. Hopner, D. Centonze, G. Bernardi, M. L. Dell'Acqua, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression Blood, August 15, 2007; 110(4): 1225 - 1232. [Abstract] [Full Text] [PDF]
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M. W. Buczynski, D. L. Stephens, R. C. Bowers-Gentry, A. Grkovich, R. A. Deems, and E. A. Dennis TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells J. Biol. Chem., August 3, 2007; 282(31): 22834 - 22847. [Abstract] [Full Text] [PDF]
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S. Adriouch, S. Hubert, S. Pechberty, F. Koch-Nolte, F. Haag, and M. Seman NAD+ Released during Inflammation Participates in T Cell Homeostasis by Inducing ART2-Mediated Death of Naive T Cells In Vivo J. Immunol., July 1, 2007; 179(1): 186 - 194. [Abstract] [Full Text] [PDF]
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M. Baroni, C. Pizzirani, M. Pinotti, D. Ferrari, E. Adinolfi, S. Calzavarini, P. Caruso, F. Bernardi, and F. Di Virgilio Stimulation of P2 (P2X7) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles FASEB J, June 1, 2007; 21(8): 1926 - 1933. [Abstract] [Full Text] [PDF]
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F. Kukulski, F. Ben Yebdri, J. Lefebvre, M. Warny, P. A. Tessier, and J. Sevigny Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo J. Leukoc. Biol., May 1, 2007; 81(5): 1269 - 1275. [Abstract] [Full Text] [PDF]
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C. Pizzirani, D. Ferrari, P. Chiozzi, E. Adinolfi, D. Sandona, E. Savaglio, and F. Di Virgilio Stimulation of P2 receptors causes release of IL-1{beta}-loaded microvesicles from human dendritic cells Blood, May 1, 2007; 109(9): 3856 - 3864. [Abstract] [Full Text] [PDF]
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L. Rossi, R. Manfredini, F. Bertolini, D. Ferrari, M. Fogli, R. Zini, S. Salati, V. Salvestrini, S. Gulinelli, E. Adinolfi, et al. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration Blood, January 15, 2007; 109(2): 533 - 542. [Abstract] [Full Text] [PDF]
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A. del Rey, V. Renigunta, A. H. Dalpke, J. Leipziger, J. E. Matos, B. Robaye, M. Zuzarte, A. Kavelaars, and P. J. Hanley Knock-out Mice Reveal the Contributions of P2Y and P2X Receptors to Nucleotide-induced Ca2+ Signaling in Macrophages J. Biol. Chem., November 17, 2006; 281(46): 35147 - 35155. [Abstract] [Full Text] [PDF]
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I. Lemaire, S. Falzoni, N. Leduc, B. Zhang, P. Pellegatti, E. Adinolfi, P. Chiozzi, and F. Di Virgilio Involvement of the Purinergic P2X7 Receptor in the Formation of Multinucleated Giant Cells J. Immunol., November 15, 2006; 177(10): 7257 - 7265. [Abstract] [Full Text] [PDF]
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F. O. Martinez, S. Gordon, M. Locati, and A. Mantovani Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression J. Immunol., November 15, 2006; 177(10): 7303 - 7311. [Abstract] [Full Text] [PDF]
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G. Caljon, J. Van Den Abbeele, B. Stijlemans, M. Coosemans, P. De Baetselier, and S. Magez Tsetse Fly Saliva Accelerates the Onset of Trypanosoma brucei Infection in a Mouse Model Associated with a Reduced Host Inflammatory Response Infect. Immun., November 1, 2006; 74(11): 6324 - 6330. [Abstract] [Full Text] [PDF]
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I. Moreschi, S. Bruzzone, R. A. Nicholas, F. Fruscione, L. Sturla, F. Benvenuto, C. Usai, S. Meis, M. U. Kassack, E. Zocchi, et al. Extracellular NAD+ Is an Agonist of the Human P2Y11 Purinergic Receptor in Human Granulocytes J. Biol. Chem., October 20, 2006; 281(42): 31419 - 31429. [Abstract] [Full Text] [PDF]
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M. Tsukimoto, M. Maehata, H. Harada, A. Ikari, K. Takagi, and M. Degawa P2X7 Receptor-Dependent Cell Death Is Modulated during Murine T Cell Maturation and Mediated by Dual Signaling Pathways. J. Immunol., September 1, 2006; 177(5): 2842 - 2850. [Abstract] [Full Text] [PDF]
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S. Carta, S. Tassi, C. Semino, G. Fossati, P. Mascagni, C. A. Dinarello, and A. Rubartelli Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules Blood, September 1, 2006; 108(5): 1618 - 1626. [Abstract] [Full Text] [PDF]
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O. Levy, M. Coughlin, B. N. Cronstein, R. M. Roy, A. Desai, and M. R. Wessels The Adenosine System Selectively Inhibits TLR-Mediated TNF-{alpha} Production in the Human Newborn J. Immunol., August 1, 2006; 177(3): 1956 - 1966. [Abstract] [Full Text] [PDF]
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M. Moayeri, K. E. Wickliffe, J. F. Wiggins, and S. H. Leppla Oxidized ATP Protection against Anthrax Lethal Toxin Infect. Immun., July 1, 2006; 74(7): 3707 - 3714. [Abstract] [Full Text] [PDF]
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D. Ferrari, C. Pizzirani, E. Adinolfi, R. M. Lemoli, A. Curti, M. Idzko, E. Panther, and F. Di Virgilio The P2X7 Receptor: A Key Player in IL-1 Processing and Release J. Immunol., April 1, 2006; 176(7): 3877 - 3883. [Abstract] [Full Text] [PDF]
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A. A. Khine, L. Del Sorbo, R. Vaschetto, S. Voglis, E. Tullis, A. S. Slutsky, G. P. Downey, and H. Zhang Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway Blood, April 1, 2006; 107(7): 2936 - 2942. [Abstract] [Full Text] [PDF]
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L. Chen and C. F. Brosnan Exacerbation of Experimental Autoimmune Encephalomyelitis in P2X7R-/- Mice: Evidence for Loss of Apoptotic Activity in Lymphocytes. J. Immunol., March 1, 2006; 176(5): 3115 - 3126. [Abstract] [Full Text] [PDF]
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T. Fellin, T. Pozzan, and G. Carmignoto Purinergic Receptors Mediate Two Distinct Glutamate Release Pathways in Hippocampal Astrocytes J. Biol. Chem., February 17, 2006; 281(7): 4274 - 4284. [Abstract] [Full Text] [PDF]
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H. Kawamura, F. Aswad, M. Minagawa, S. Govindarajan, and G. Dennert P2X7 Receptors Regulate NKT Cells in Autoimmune Hepatitis J. Immunol., February 15, 2006; 176(4): 2152 - 2160. [Abstract] [Full Text] [PDF]
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A. N. Shemon, R. Sluyter, S. L. Fernando, A. L. Clarke, L.-P. Dao-Ung, K. K. Skarratt, B. M. Saunders, K. S. Tan, B. J. Gu, S. J. Fuller, et al. A Thr357 to Ser Polymorphism in Homozygous and Compound Heterozygous Subjects Causes Absent or Reduced P2X7 Function and Impairs ATP-induced Mycobacterial Killing by Macrophages J. Biol. Chem., January 27, 2006; 281(4): 2079 - 2086. [Abstract] [Full Text] [PDF]
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D. Ferrari, A. la Sala, E. Panther, J. Norgauer, F. Di Virgilio, and M. Idzko Activation of human eosinophils via P2 receptors: novel findings and future perspectives J. Leukoc. Biol., January 1, 2006; 79(1): 7 - 15. [Abstract] [Full Text] [PDF]
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J. Li, D. Liu, H. Z. Ke, R. L. Duncan, and C. H. Turner The P2X7 Nucleotide Receptor Mediates Skeletal Mechanotransduction J. Biol. Chem., December 30, 2005; 280(52): 42952 - 42959. [Abstract] [Full Text] [PDF]
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P. A. Verhoef, S. B. Kertesy, K. Lundberg, J. M. Kahlenberg, and G. R. Dubyak Inhibitory Effects of Chloride on the Activation of Caspase-1, IL-1{beta} Secretion, and Cytolysis by the P2X7 Receptor J. Immunol., December 1, 2005; 175(11): 7623 - 7634. [Abstract] [Full Text] [PDF]
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C. Geary, H. Akinbi, T. Korfhagen, J.-E. Fabre, R. Boucher, and W. Rice Increased susceptibility of purinergic receptor-deficient mice to lung infection with Pseudomonas aeruginosa Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L890 - L895. [Abstract] [Full Text] [PDF]
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F. Aswad, H. Kawamura, and G. Dennert High Sensitivity of CD4+CD25+ Regulatory T Cells to Extracellular Metabolites Nicotinamide Adenine Dinucleotide and ATP: A Role for P2X7 Receptors J. Immunol., September 1, 2005; 175(5): 3075 - 3083. [Abstract] [Full Text] [PDF]
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P. Pellegatti, S. Falzoni, P. Pinton, R. Rizzuto, and F. Di Virgilio A Novel Recombinant Plasma Membrane-targeted Luciferase Reveals a New Pathway for ATP Secretion Mol. Biol. Cell, August 1, 2005; 16(8): 3659 - 3665. [Abstract] [Full Text] [PDF]
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G. Cabrini, S. Falzoni, S. L. Forchap, P. Pellegatti, A. Balboni, P. Agostini, A. Cuneo, G. Castoldi, O. R. Baricordi, and F. Di Virgilio A His-155 to Tyr Polymorphism Confers Gain-of-Function to the Human P2X7 Receptor of Human Leukemic Lymphocytes J. Immunol., July 1, 2005; 175(1): 82 - 89. [Abstract] [Full Text] [PDF]
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E. Adinolfi, M. G. Callegari, D. Ferrari, C. Bolognesi, M. Minelli, M. R. Wieckowski, P. Pinton, R. Rizzuto, and F. Di Virgilio Basal Activation of the P2X7 ATP Receptor Elevates Mitochondrial Calcium and Potential, Increases Cellular ATP Levels, and Promotes Serum-independent Growth Mol. Biol. Cell, July 1, 2005; 16(7): 3260 - 3272. [Abstract] [Full Text] [PDF]
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R. D. Granstein, W. Ding, J. Huang, A. Holzer, R. L. Gallo, A. Di Nardo, and J. A. Wagner Augmentation of Cutaneous Immune Responses by ATP{gamma}S: Purinergic Agonists Define a Novel Class of Immunologic Adjuvants J. Immunol., June 15, 2005; 174(12): 7725 - 7731. [Abstract] [Full Text] [PDF]
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Y.-H. Feng, L. Wang, Q. Wang, X. Li, R. Zeng, and G. I. Gorodeski ATP stimulates GRK-3 phosphorylation and {beta}-arrestin-2-dependent internalization of P2X7 receptor Am J Physiol Cell Physiol, June 1, 2005; 288(6): C1342 - C1356. [Abstract] [Full Text] [PDF]
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R. Coutinho-Silva, L. Stahl, K.-K. Cheung, N. E. de Campos, C. de Oliveira Souza, D. M. Ojcius, and G. Burnstock P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G1024 - G1035. [Abstract] [Full Text] [PDF]
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E. Bulanova, V. Budagian, Z. Orinska, M. Hein, F. Petersen, L. Thon, D. Adam, and S. Bulfone-Paus Extracellular ATP Induces Cytokine Expression and Apoptosis through P2X7 Receptor in Murine Mast Cells J. Immunol., April 1, 2005; 174(7): 3880 - 3890. [Abstract] [Full Text] [PDF]
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L. C. Denlinger, G. Angelini, K. Schell, D. N. Green, A. G. Guadarrama, U. Prabhu, D. B. Coursin, P. J. Bertics, and K. Hogan Detection of Human P2X7 Nucleotide Receptor Polymorphisms by a Novel Monocyte Pore Assay Predictive of Alterations in Lipopolysaccharide-Induced Cytokine Production J. Immunol., April 1, 2005; 174(7): 4424 - 4431. [Abstract] [Full Text] [PDF]
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C. Krebs, S. Adriouch, F. Braasch, W. Koestner, E. H. Leiter, M. Seman, F. E. Lund, N. Oppenheimer, F. Haag, and F. Koch-Nolte CD38 Controls ADP-Ribosyltransferase-2-Catalyzed ADP-Ribosylation of T Cell Surface Proteins J. Immunol., March 15, 2005; 174(6): 3298 - 3305. [Abstract] [Full Text] [PDF]
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M. Schnurr, T. Toy, A. Shin, M. Wagner, J. Cebon, and E. Maraskovsky Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway Blood, February 15, 2005; 105(4): 1582 - 1589. [Abstract] [Full Text] [PDF]
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 L. Wang, G. Olivecrona, M. Gotberg, M. L. Olsson, M. S. Winzell, and D. Erlinge ADP Acting on P2Y13 Receptors Is a Negative Feedback Pathway for ATP Release From Human Red Blood Cells Circ. Res., February 4, 2005; 96(2): 189 - 196. [Abstract] [Full Text] [PDF]
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C. D. Douillet, W. P. Robinson III, B. L. Zarzaur, E. R. Lazarowski, R. C. Boucher, and P. B. Rich Mechanical Ventilation Alters Airway Nucleotides and Purinoceptors in Lung and Extrapulmonary Organs Am. J. Respir. Cell Mol. Biol., January 1, 2005; 32(1): 52 - 58. [Abstract] [Full Text] [PDF]
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C. Feng, A. G. Mery, E. M. Beller, C. Favot, and J. A. Boyce Adenine Nucleotides Inhibit Cytokine Generation by Human Mast Cells through a Gs-Coupled Receptor J. Immunol., December 15, 2004; 173(12): 7539 - 7547. [Abstract] [Full Text] [PDF]
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 P. A. Verhoef, S. B. Kertesy, M. Estacion, W. P. Schilling, and G. R. Dubyak Maitotoxin Induces Biphasic Interleukin-1{beta} Secretion and Membrane Blebbing in Murine Macrophages Mol. Pharmacol., October 1, 2004; 66(4): 909 - 920. [Abstract] [Full Text] [PDF]
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F. Marteau, D. Communi, J.-M. Boeynaems, and N. Suarez Gonzalez Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells J. Leukoc. Biol., October 1, 2004; 76(4): 796 - 803. [Abstract] [Full Text] [PDF]
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D. Ferrari, C. Pizzirani, E. Adinolfi, S. Forchap, B. Sitta, L. Turchet, S. Falzoni, M. Minelli, R. Baricordi, and F. Di Virgilio The Antibiotic Polymyxin B Modulates P2X7 Receptor Function J. Immunol., October 1, 2004; 173(7): 4652 - 4660. [Abstract] [Full Text] [PDF]
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F. S. A. Fortes, I. L. Pecora, P. M. Persechini, S. Hurtado, V. Costa, R. Coutinho-Silva, M. B. M. Braga, F. C. Silva-Filho, R. C. Bisaggio, F. P. de Farias, et al. Modulation of intercellular communication in macrophages: possible interactions between GAP junctions and P2 receptors J. Cell Sci., September 15, 2004; 117(20): 4717 - 4726. [Abstract] [Full Text] [PDF]
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R. M. Lemoli, D. Ferrari, M. Fogli, L. Rossi, C. Pizzirani, S. Forchap, P. Chiozzi, D. Vaselli, F. Bertolini, T. Foutz, et al. Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo Blood, September 15, 2004; 104(6): 1662 - 1670. [Abstract] [Full Text] [PDF]
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G. J. Zwartz, A. Chigaev, D. C. Dwyer, T. D. Foutz, B. S. Edwards, and L. A. Sklar Real-time Analysis of Very Late Antigen-4 Affinity Modulation by Shear J. Biol. Chem., September 10, 2004; 279(37): 38277 - 38286. [Abstract] [Full Text] [PDF]
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J. F. Hoffman, A. Dodson, A. Wickrema, and S. D. Dib-Hajj Tetrodotoxin-sensitive Na+ channels and muscarinic and purinergic receptors identified in human erythroid progenitor cells and red blood cell ghosts PNAS, August 17, 2004; 101(33): 12370 - 12374. [Abstract] [Full Text] [PDF]
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A. Chigaev, G. J. Zwartz, T. Buranda, B. S. Edwards, E. R. Prossnitz, and L. A. Sklar Conformational Regulation of {alpha}4{beta}1-Integrin Affinity by Reducing Agents: "INSIDE-OUT" SIGNALING IS INDEPENDENT OF AND ADDITIVE TO REDUCTION-REGULATED INTEGRIN ACTIVATION J. Biol. Chem., July 30, 2004; 279(31): 32435 - 32443. [Abstract] [Full Text] [PDF]
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B. J. Gu, R. Sluyter, K. K. Skarratt, A. N. Shemon, L.-P. Dao-Ung, S. J. Fuller, J. A. Barden, A. L. Clarke, S. Petrou, and J. S. Wiley An Arg307 to Gln Polymorphism within the ATP-binding Site Causes Loss of Function of the Human P2X7 Receptor J. Biol. Chem., July 23, 2004; 279(30): 31287 - 31295. [Abstract] [Full Text] [PDF]
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J. A. Sim, M. T. Young, H.-Y. Sung, R. A. North, and A. Surprenant Reanalysis of P2X7 Receptor Expression in Rodent Brain J. Neurosci., July 14, 2004; 24(28): 6307 - 6314. [Abstract] [Full Text] [PDF]
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C. Andrei, P. Margiocco, A. Poggi, L. V. Lotti, M. R. Torrisi, and A. Rubartelli From The Cover: Phospholipases C and A2 control lysosome-mediated IL-1{beta} secretion: Implications for inflammatory processes PNAS, June 29, 2004; 101(26): 9745 - 9750. [Abstract] [Full Text] [PDF]
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P. J. Hanley, B. Musset, V. Renigunta, S. H. Limberg, A. H. Dalpke, R. Sus, K. M. Heeg, R. Preisig-Muller, and J. Daut Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages PNAS, June 22, 2004; 101(25): 9479 - 9484. [Abstract] [Full Text] [PDF]
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M.-P. Courageot, S. Lepine, M. Hours, F. Giraud, and J.-C. Sulpice Involvement of Sodium in Early Phosphatidylserine Exposure and Phospholipid Scrambling Induced by P2X7 Purinoceptor Activation in Thymocytes J. Biol. Chem., May 21, 2004; 279(21): 21815 - 21823. [Abstract] [Full Text] [PDF]
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H. Inbe, S. Watanabe, M. Miyawaki, E. Tanabe, and J. A. Encinas Identification and Characterization of a Cell-Surface Receptor, P2Y15, for AMP and Adenosine J. Biol. Chem., May 7, 2004; 279(19): 19790 - 19799. [Abstract] [Full Text] [PDF]
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H. Le Stunff, R. Auger, J. Kanellopoulos, and M.-N. Raymond The Pro-451 to Leu Polymorphism within the C-terminal Tail of P2X7 Receptor Impairs Cell Death but Not Phospholipase D Activation in Murine Thymocytes J. Biol. Chem., April 23, 2004; 279(17): 16918 - 16926. [Abstract] [Full Text] [PDF]
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 L. C. Denlinger, K. Schell, G. Angelini, D. Green, A. Guadarrama, U. Prabhu, D. B. Coursin, K. Hogan, and P. J. Bertics A novel assay to detect nucleotide receptor P2X7 genetic polymorphisms influencing numerous innate immune functions Innate Immunity, April 1, 2004; 10(2): 137 - 142. [Abstract] [PDF]
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R. Sluyter, A. N. Shemon, and J. S. Wiley Glu496 to Ala Polymorphism in the P2X7 Receptor Impairs ATP-Induced IL-1{beta} Release from Human Monocytes J. Immunol., March 15, 2004; 172(6): 3399 - 3405. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
and inhibition of adenylate
cyclase via Gq/11 and Gi proteins,
respectively.
originally cloned and
characterized in excitable cells
) or tetra-anionic (ATP4
, 
and tumor
necrosis factor (TNF)-
B and
mitogen-associated protein kinase (MAPK) activation are profoundly
inhibited by oATP or by PPADS.