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P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7)

Written2008-01Pablo Pelegrin, Annmarie Surprenant
Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK

(Note : for Links provided by Atlas : click)

Identity

Alias_namespurinergic receptor P2X
Alias_symbol (synonym)P2X7
MGC20089
Other aliasP2Z
HGNC (Hugo) P2RX7
LocusID (NCBI) 5027
Atlas_Id 41623
Location 12q24.31  [Link to chromosome band 12q24]
Location_base_pair Starts at 121132828 and ends at 121186551 bp from pter ( according to hg19-Feb_2009)  [Mapping P2RX7.png]
Fusion genes
(updated 2016)		EVC (4p16.2) / P2RX7 (12q24.31)P2RX4 (12q24.31) / P2RX7 (12q24.31)P2RX7 (12q24.31) / COQ9 (16q21)
SPCS3 (4q34.2) / P2RX7 (12q24.31)

DNA/RNA

Description The P2RX7 gene is comprised of 13 coding exons.
Transcription The full length transcript is 3135 bp long and 10 alternative splicing isoforms have been identified.
Pseudogene Not known.

Protein

Description 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 N- to 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
    • 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 cells (mainly in antigen presenting cells, such as monocytes, macrophages and dendritic cells).
    Localisation Mainly is found in the plasma membrane, however it also can be found in intracellular membrane compartments while trafficking to the plasma membrane.
    Function 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.
    Homology 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)
  • Gain of protein function:
    489 C to T (His-155 to Tyr)
    • Somatic Not known in human.

    Implicated in

    Note
      
    Entity Extrapulmonary tuberculosis
    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.
      
      
    Entity 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.
      
      
    Entity Various cancers, including breast cancer, prostate cancer, papillary thyroid cancer and neuroblastoma.
    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.
      

    Bibliography

    Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth.
    Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F
    Molecular biology of the cell. 2005 ; 16 (7) : 3260-3272.
    PMID 15901833
     
    A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes.
    Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F
    Journal of immunology (Baltimore, Md. : 1950). 2005 ; 175 (1) : 82-89.
    PMID 15972634
     
    Identification and characterization of splice variants of the human P2X7 ATP channel.
    Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S
    Biochemical and biophysical research communications. 2005 ; 332 (1) : 17-27.
    PMID 15896293
     
    Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia.
    Dao-Ung LP, Fuller SJ, Sluyter R, SkarRatt KK, Thunberg U, Tobin G, Byth K, Ban M, Rosenquist R, Stewart GJ, Wiley JS
    British journal of haematology. 2004 ; 125 (6) : 815-817.
    PMID 15180873
     
    A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization.
    Feng YH, Li X, Wang L, Zhou L, Gorodeski GI
    The Journal of biological chemistry. 2006 ; 281 (25) : 17228-17237.
    PMID 16624800
     
    A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.
    Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB, Wiley JS, Britton WJ
    American journal of respiratory and critical care medicine. 2007 ; 175 (4) : 360-366.
    PMID 17095747
     
    The P2X7 receptor: a key player in IL-1 processing and release.
    Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F
    Journal of immunology (Baltimore, Md. : 1950). 2006 ; 176 (7) : 3877-3883.
    PMID 16547218
     
    An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor.
    Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS
    The Journal of biological chemistry. 2004 ; 279 (30) : 31287-31295.
    PMID 15123679
     
    A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.
    Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS
    The Journal of biological chemistry. 2001 ; 276 (14) : 11135-11142.
    PMID 11150303
     
    Molecular physiology of P2X receptors.
    North RA
    Physiological reviews. 2002 ; 82 (4) : 1013-1067.
    PMID 12270951
     
    Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.
    Pelegrin P, Surprenant A
    The EMBO journal. 2006 ; 25 (21) : 5071-5082.
    PMID 17036048
     
    The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism.
    Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V
    Cancer research. 2006 ; 66 (2) : 907-914.
    PMID 16424024
     
    The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA.
    Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A
    The Journal of biological chemistry. 1997 ; 272 (9) : 5482-5486.
    PMID 9038151
     
    Differentiation between cancerous and normal hyperplastic lobules in breast lesions.
    Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird A, Barden JA
    Breast cancer research and treatment. 2004 ; 83 (1) : 1-10.
    PMID 14997049
     
    Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease?
    Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG, Dardano A, Faviana P, Madec S, Di Virgilio F, Monzani F
    Endocrinology. 2008 ; 149 (1) : 389-396.
    PMID 17947359
     
    The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7).
    Surprenant A, Rassendren F, Kawashima E, North RA, Buell G
    Science (New York, N.Y.). 1996 ; 272 (5262) : 735-738.
    PMID 8614837
     
    An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor.
    Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R
    The Journal of biological chemistry. 2003 ; 278 (19) : 17108-17113.
    PMID 12586825
     

    Citation

    This paper 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.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/P2RX7ID41623ch12q24.html

    External links

    Nomenclature
    HGNC (Hugo)P2RX7   8537
    Cards
    AtlasP2RX7ID41623ch12q24
    Entrez_Gene (NCBI)P2RX7  5027  purinergic receptor P2X 7
    AliasesP2X7
    GeneCards (Weizmann)P2RX7
    Ensembl hg19 (Hinxton)ENSG00000089041 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000089041 [Gene_View]  chr12:121132828-121186551 [Contig_View]  P2RX7 [Vega]
    ICGC DataPortalENSG00000089041
    TCGA cBioPortalP2RX7
    AceView (NCBI)P2RX7
    Genatlas (Paris)P2RX7
    WikiGenes5027
    SOURCE (Princeton)P2RX7
    Genetics Home Reference (NIH)P2RX7
    Genomic and cartography
    GoldenPath hg38 (UCSC)P2RX7  -     chr12:121132828-121186551 +  12q24.31   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)P2RX7  -     12q24.31   [Description]    (hg19-Feb_2009)
    EnsemblP2RX7 - 12q24.31 [CytoView hg19]  P2RX7 - 12q24.31 [CytoView hg38]
    Mapping of homologs : NCBIP2RX7 [Mapview hg19]  P2RX7 [Mapview hg38]
    OMIM602566   
    Gene and transcription
    Genbank (Entrez)AB209709 AK090866 AK225163 AK290405 AK294126
    RefSeq transcript (Entrez)NM_002562 NM_177427
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)P2RX7
    Cluster EST : UnigeneHs.729169 [ NCBI ]
    CGAP (NCI)Hs.729169
    Alternative Splicing GalleryENSG00000089041
    Gene ExpressionP2RX7 [ NCBI-GEO ]   P2RX7 [ EBI - ARRAY_EXPRESS ]   P2RX7 [ SEEK ]   P2RX7 [ MEM ]
    Gene Expression Viewer (FireBrowse)P2RX7 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)5027
    GTEX Portal (Tissue expression)P2RX7
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ99572   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ99572  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ99572
    Splice isoforms : SwissVarQ99572
    PhosPhoSitePlusQ99572
    Domaine pattern : Prosite (Expaxy)P2X_RECEPTOR (PS01212)   
    Domains : Interpro (EBI)P2X7_purnocptor    P2X_extracellular_dom    P2X_purnocptor   
    Domain families : Pfam (Sanger)P2X_receptor (PF00864)   
    Domain families : Pfam (NCBI)pfam00864   
    Conserved Domain (NCBI)P2RX7
    DMDM Disease mutations5027
    Blocks (Seattle)P2RX7
    SuperfamilyQ99572
    Human Protein AtlasENSG00000089041
    Peptide AtlasQ99572
    HPRD03977
    IPIIPI00293328   IPI01010105   IPI01012970   IPI00396134   IPI01019121   IPI01010340   IPI01010806   IPI00654863   IPI01014845   IPI01015465   IPI01014429   IPI00377108   
    Protein Interaction databases
    DIP (DOE-UCLA)Q99572
    IntAct (EBI)Q99572
    FunCoupENSG00000089041
    BioGRIDP2RX7
    STRING (EMBL)P2RX7
    ZODIACP2RX7
    Ontologies - Pathways
    QuickGOQ99572
    Ontology : AmiGOactivation of MAPK activity  cell morphogenesis  lipopolysaccharide binding  purinergic nucleotide receptor activity  phagolysosome assembly  positive regulation of T cell mediated cytotoxicity  regulation of sodium ion transport  extracellular ATP-gated cation channel activity  extracellular ATP-gated cation channel activity  receptor binding  protein binding  ATP binding  integral component of nuclear inner membrane  cytoplasm  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  cell-cell junction  protein phosphorylation  membrane protein ectodomain proteolysis  phospholipid transfer to membrane  membrane budding  inflammatory response  mitochondrion organization  cell surface receptor signaling pathway  blood coagulation  response to mechanical stimulus  external side of plasma membrane  response to zinc ion  positive regulation of calcium ion transport into cytosol  positive regulation of gene expression  positive regulation of glutamate secretion  positive regulation of gamma-aminobutyric acid secretion  membrane  synaptic vesicle exocytosis  protein processing  phospholipid scrambling  sensory perception of pain  cytolysis  positive regulation of bone mineralization  neuromuscular junction  cellular response to extracellular stimulus  bleb  bleb assembly  bleb assembly  positive regulation of prostaglandin secretion  response to lipopolysaccharide  positive regulation of interleukin-6 production  collagen metabolic process  response to ATP  response to fluid shear stress  positive regulation of ion transmembrane transport  purinergic nucleotide receptor signaling pathway  T cell proliferation  response to drug  protein homodimerization activity  neuronal cell body  T cell homeostasis  NAD transport  negative regulation of MAPK cascade  multicellular organismal protein catabolic process  phospholipid translocation  negative regulation of bone resorption  negative regulation of cell volume  positive regulation of glycolytic process  positive regulation of cytolysis  ceramide biosynthetic process  pore complex assembly  pore complex assembly  skeletal system morphogenesis  homeostasis of number of cells within a tissue  positive regulation of interleukin-1 alpha secretion  positive regulation of interleukin-1 beta secretion  defense response to Gram-positive bacterium  release of sequestered calcium ion into cytosol  protein oligomerization  positive regulation of cytoskeleton organization  response to calcium ion  response to electrical stimulus  regulation of killing of cells of other organism  membrane depolarization  positive regulation of mitochondrial depolarization  excitatory postsynaptic potential  positive regulation of lymphocyte apoptotic process  cellular response to dsRNA  reactive oxygen species metabolic process  apoptotic signaling pathway  extrinsic apoptotic signaling pathway  presynapse  postsynapse  positive regulation of bleb assembly  
    Ontology : EGO-EBIactivation of MAPK activity  cell morphogenesis  lipopolysaccharide binding  purinergic nucleotide receptor activity  phagolysosome assembly  positive regulation of T cell mediated cytotoxicity  regulation of sodium ion transport  extracellular ATP-gated cation channel activity  extracellular ATP-gated cation channel activity  receptor binding  protein binding  ATP binding  integral component of nuclear inner membrane  cytoplasm  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  cell-cell junction  protein phosphorylation  membrane protein ectodomain proteolysis  phospholipid transfer to membrane  membrane budding  inflammatory response  mitochondrion organization  cell surface receptor signaling pathway  blood coagulation  response to mechanical stimulus  external side of plasma membrane  response to zinc ion  positive regulation of calcium ion transport into cytosol  positive regulation of gene expression  positive regulation of glutamate secretion  positive regulation of gamma-aminobutyric acid secretion  membrane  synaptic vesicle exocytosis  protein processing  phospholipid scrambling  sensory perception of pain  cytolysis  positive regulation of bone mineralization  neuromuscular junction  cellular response to extracellular stimulus  bleb  bleb assembly  bleb assembly  positive regulation of prostaglandin secretion  response to lipopolysaccharide  positive regulation of interleukin-6 production  collagen metabolic process  response to ATP  response to fluid shear stress  positive regulation of ion transmembrane transport  purinergic nucleotide receptor signaling pathway  T cell proliferation  response to drug  protein homodimerization activity  neuronal cell body  T cell homeostasis  NAD transport  negative regulation of MAPK cascade  multicellular organismal protein catabolic process  phospholipid translocation  negative regulation of bone resorption  negative regulation of cell volume  positive regulation of glycolytic process  positive regulation of cytolysis  ceramide biosynthetic process  pore complex assembly  pore complex assembly  skeletal system morphogenesis  homeostasis of number of cells within a tissue  positive regulation of interleukin-1 alpha secretion  positive regulation of interleukin-1 beta secretion  defense response to Gram-positive bacterium  release of sequestered calcium ion into cytosol  protein oligomerization  positive regulation of cytoskeleton organization  response to calcium ion  response to electrical stimulus  regulation of killing of cells of other organism  membrane depolarization  positive regulation of mitochondrial depolarization  excitatory postsynaptic potential  positive regulation of lymphocyte apoptotic process  cellular response to dsRNA  reactive oxygen species metabolic process  apoptotic signaling pathway  extrinsic apoptotic signaling pathway  presynapse  postsynapse  positive regulation of bleb assembly  
    Pathways : KEGGCalcium signaling pathway    Neuroactive ligand-receptor interaction   
    REACTOMEQ99572 [protein]
    REACTOME PathwaysR-HSA-844456 [pathway]   
    NDEx NetworkP2RX7
    Atlas of Cancer Signalling NetworkP2RX7
    Wikipedia pathwaysP2RX7
    Orthology - Evolution
    OrthoDB5027
    GeneTree (enSembl)ENSG00000089041
    Phylogenetic Trees/Animal Genes : TreeFamP2RX7
    HOVERGENQ99572
    HOGENOMQ99572
    Homologs : HomoloGeneP2RX7
    Homology/Alignments : Family Browser (UCSC)P2RX7
    Gene fusions - Rearrangements
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerP2RX7 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)P2RX7
    dbVarP2RX7
    ClinVarP2RX7
    1000_GenomesP2RX7 
    Exome Variant ServerP2RX7
    ExAC (Exome Aggregation Consortium)P2RX7 (select the gene name)
    Genetic variants : HAPMAP5027
    Genomic Variants (DGV)P2RX7 [DGVbeta]
    DECIPHERP2RX7 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisP2RX7 
    Mutations
    ICGC Data PortalP2RX7 
    TCGA Data PortalP2RX7 
    Broad Tumor PortalP2RX7
    OASIS PortalP2RX7 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICP2RX7  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDP2RX7
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    LOVD (Leiden Open Variation Database)TBsLVD Tuberculosis susceptibility Locus Variation Database
    BioMutasearch P2RX7
    DgiDB (Drug Gene Interaction Database)P2RX7
    DoCM (Curated mutations)P2RX7 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)P2RX7 (select a term)
    intoGenP2RX7
    NCG5 (London)P2RX7
    Cancer3DP2RX7(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM602566   
    Orphanet
    MedgenP2RX7
    Genetic Testing Registry P2RX7
    NextProtQ99572 [Medical]
    TSGene5027
    GENETestsP2RX7
    Target ValidationP2RX7
    Huge Navigator P2RX7 [HugePedia]
    snp3D : Map Gene to Disease5027
    BioCentury BCIQP2RX7
    ClinGenP2RX7
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD5027
    Chemical/Pharm GKB GenePA32866
    Clinical trialP2RX7
    Miscellaneous
    canSAR (ICR)P2RX7 (select the gene name)
    Probes
    Litterature
    PubMed336 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineP2RX7
    EVEXP2RX7
    GoPubMedP2RX7
    iHOPP2RX7
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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