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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.

© 2001 by The American Society of Hematology.
 

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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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Cancer Res.Home page
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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J. Leukoc. Biol.Home page
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. Biol. Chem.Home page
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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J. Immunol.Home page
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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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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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J. Immunol.Home page
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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Mol. Biol. CellHome page
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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J. Immunol.Home page
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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Mol. Biol. CellHome page
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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DevelopmentHome page
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; 132(12): 2873 - 2882.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
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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Am. J. Physiol. Cell Physiol.Home page
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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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
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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J. Immunol.Home page
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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J. Immunol.Home page
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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J. Immunol.Home page
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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BloodHome page
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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Circ. Res.Home page
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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Am. J. Respir. Cell Mol. Bio.Home page
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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J. Immunol.Home page
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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Mol. Pharmacol.Home page
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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J. Leukoc. Biol.Home page
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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J. Immunol.Home page
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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J. Cell Sci.Home page
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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BloodHome page
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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J. Biol. Chem.Home page
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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Proc. Natl. Acad. Sci. USAHome page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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. Neurosci.Home page
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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Proc. Natl. Acad. Sci. USAHome page
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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Proc. Natl. Acad. Sci. USAHome page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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J. Biol. Chem.Home page
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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Innate ImmunityHome page
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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J. Immunol.Home page
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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Am. J. Physiol. Cell Physiol.Home page
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] [Full Text] [PDF]


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JCBHome page
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] [Full Text] [PDF]



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