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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) Pablo Pelegrin, Annmarie Surprenant Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK Published in Atlas Database: January 2008 Online updated version: http://AtlasGeneticsOncology.org/Genes/P2RX7ID41623ch12q24.html DOI: 10.4267/2042/38574 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity cells (mainly in antigen presenting cells, such as monocytes, macrophages and dendritic cells). Hugo: P2RX7 Other names: MGC20089; P2X7; P2Z Location: 12q24.31 Localisation Mainly is found in the plasma membrane, however it also can be found in intracellular membrane compartments while trafficking to the plasma membrane. DNA/RNA Description Function The P2RX7 gene is comprised of 13 coding exons. Acts as a ligand gated ion channel, sensing high concentration of extracellular ATP. Responsible for ATP-dependent activation and release of proinflammatory cytokines of the interleukin-1 family, mainly interleukin-1beta, interleukin-18 and interleukin-1alpha, playing a pivotal role in inflammatory responses. Prolonged stimulation of the P2X7 receptor can lead to plasma membrane bleb formation, opening of pannexin-1 dependent membrane pores and eventual cell death. Transcription The full length transcript is 3135 bp long and 10 alternative splicing isoforms have been identified. Pseudogene Not known. Protein Description Homology The protein has 595 residues amino acids and compromises a 69 kDa calculated molecular weight. However, N-glycosylation in the extracellular loop increases the size of the P2X7 receptor to about 75-85 kDa; the protein is composed successively (from the Nto the C-terminus) by: - 25 amino acid intracellular N-terminus - 21 amino acid first transmembrane domain - 288 amino acid extracellular loop - 21 amino acid second transmembrane domain - 240 amino acid intracellular C-terminal region With other P2X receptors, with the higher homology with P2RX4. Excluding the unique C-terminal domain, homology is 39-49% with other P2X receptors. Mutations Germinal The human P2X7 receptor gene is highly polymorphic and more then 260 SNP have been described, only four loss-of-function and one gain-of-function SNP have been described to date: - Loss of protein function: 946 G to A (Arg-307 to Gln) 1068 G to A (Ala-348 to Thr) 1513 A to C (Glu-496 to Ala) 1729 T to A (Ile-568 to Asp) Expression In a wide variety of tissues including heart, liver, pancreas, thymus, skeletal muscle and brain, although in brain the expression is mainly restricted to microglia. It also has relevant expression and function in immune Atlas Genet Cytogenet Oncol Haematol. 2008;12(5) 377 P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) Pelegrin P, Surprenant A Dao-Ung LP, Fuller SJ, Sluyter R, SkarRatt KK, Thunberg U, Tobin G, Byth K, Ban M, Rosenquist R, Stewart GJ, Wiley JS. Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia. Br J Haematol 2004;125:815-817. - Gain of protein function: 489 C to T (His-155 to Tyr) Somatic Not known in human. Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS. An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor. J Biol Chem 2004;279:31287-31295. Implicated in Extrapulmonary tuberculosis Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird A, Barden JA. Differentiation between cancerous and normal hyperplastic lobules in breast lesions. Breast Cancer Res Treat 2004;83:1-10. Note: The P2RX7 1513C allele has been strongly associated with extrapulmonary tuberculosis. The allele was associated with a reduced killing of Mycobacterium tuberculosis by macrophages. Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA. Early prostate cancer detected using expression of nonfunctional cytolytic P2X7 receptors. Histopathology 2004;44:206-215. Chronic lymphoid leukemia (CLL) Note: The 1513C allele of P2RX7 has been associated with the clinical course of patients affected by chronic lymphocytic leukemia (CLL). There is a possible role for the P2X7 receptor in the susceptibility to familial CLL or, alternately, the 1513C allele may be in linkage disequilibrium with a nearby susceptibility gene. Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 2005;16:3260-3272. Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F. A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J Immunol 2005;175:82-89. Various cancers, including breast cancer, prostate cancer, papillary thyroid cancer and neuroblastoma Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S. Identification and characterization of splice variants of the human P2X7 ATP channel. Biochem Biophys Res Commun 2005;332:17-27. Note: P2X7 receptor is overexpressed in a variety of cancers (see above). A detailed understanding of the mechanistic contribution mediated by P2RX7 has yet to be established. However, there is substantial evidence that the P2X7 receptor may mediate cell survival and growth by increasing the efficiency of oxidative phosphorylation and total intracellular ATP stores. Finally it has been proposed that the P2X7 receptor may be a candidate marker of papillary thyroid cancer. Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem 2006;281:1722817237. Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F. The P2X7 receptor: a key player in IL1 processing and release. J Immunol 2006;176:3877-3883. (Review). References Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 2006;25:5071-5082. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 1996;272:735-738. Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V. The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res 2006;66:907-914. Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A. The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. J Biol Chem 1997;272:5482-5486. Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB, Wiley JS, Britton WJ. A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am J Respir Crit Care Med 2007;175:360-366. Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS. A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem 2001;276:11135-11142. Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG, Dardano A, Faviana P, Madec S, Di Virgilio F, Monzani F. Increased P2X7 Receptor Expression and Function in Thyroid Papillary Cancer: A New Potential Marker of the Disease?. Endocrinology 2008;149:389-396. Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR. P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 2002;99:706-708. North RA. Molecular physiology of P2X receptors. Physiol Rev 2002;82:1013-1067. (Review). This article should be referenced as such: Pelegrin P, Surprenant A. P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7). Atlas Genet Cytogenet Oncol Haematol.2008;12(5):377-378. Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R. An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem 2003;278:17108-17113. Atlas Genet Cytogenet Oncol Haematol. 2008;12(5) 378