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Blood, 1 February 2001, Vol. 97, No. 3, pp. 587-600
REVIEW ARTICLE
Nucleotide receptors: an emerging family of regulatory molecules
in blood cells
Francesco Di Virgilio,
Paola Chiozzi,
Davide Ferrari,
Simonetta Falzoni,
Juana M. Sanz,
Anna Morelli,
Maurizia Torboli,
Giorgio Bolognesi, and
O. Roberto Baricordi
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.

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[Full Text]
[PDF]
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G. Burnstock
Pathophysiology and therapeutic potential of purinergic signaling.
Pharmacol. Rev.,
March 1, 2006;
58(1):
58 - 86.
[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]
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[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]
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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]
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L. Raffaghello, P. Chiozzi, S. Falzoni, F. Di Virgilio, and V. Pistoia
The P2X7 Receptor Sustains the Growth of Human Neuroblastoma Cells through a Substance P-Dependent Mechanism
Cancer Res.,
January 15, 2006;
66(2):
907 - 914.
[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]
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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]
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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]
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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]
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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.
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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]
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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.
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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]
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V. Resta, E. Novelli, F. Di Virgilio, and L. Galli-Resta
Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control
Development,
June 15, 2005;
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2873 - 2882.
[Abstract]
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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.
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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;
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C1342 - C1356.
[Abstract]
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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):
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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.
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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.
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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.
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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]
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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;
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[Abstract]
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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]
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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]
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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.
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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.
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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;
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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]
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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]
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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.
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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]
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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.
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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]
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K. Kawa
Discrete but simultaneous release of adenine nucleotides and serotonin from mouse megakaryocytes as detected with patch- and carbon-fiber electrodes
Am J Physiol Cell Physiol,
January 1, 2004;
286(1):
C119 - C128.
[Abstract]
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S. Bruzzone, S. Kunerth, E. Zocchi, A. De Flora, and A. H. Guse
Spatio-temporal propagation of Ca2+ signals by cyclic ADP-ribose in 3T3 cells stimulated via purinergic P2Y receptors
J. Cell Biol.,
November 24, 2003;
163(4):
837 - 845.
[Abstract]
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