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

2008-01-01   Pablo Pelegrin , Annmarie Surprenant 

Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK

Identity

HGNC
LOCATION
12q24.31
LOCUSID
ALIAS
P2X7
FUSION GENES

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.

Proteins

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

    Entity name
    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 name
    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 name
    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

    Pubmed IDLast YearTitleAuthors
    159018332005Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth.Adinolfi E et al
    159726342005A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes.Cabrini G et al
    158962932005Identification and characterization of splice variants of the human P2X7 ATP channel.Cheewatrakoolpong B et al
    151808732004Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia.Dao-Ung LP et al
    166248002006A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization.Feng YH et al
    170957472007A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis.Fernando SL et al
    165472182006The P2X7 receptor: a key player in IL-1 processing and release.Ferrari D et al
    151236792004An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor.Gu BJ et al
    111503032001A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor.Gu BJ et al
    122709512002Molecular physiology of P2X receptors.North RA et al
    170360482006Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.Pelegrin P et al
    164240242006The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism.Raffaghello L et al
    90381511997The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA.Rassendren F et al
    149970492004Differentiation between cancerous and normal hyperplastic lobules in breast lesions.Slater M et al
    179473592008Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease?Solini A et al
    86148371996The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7).Surprenant A et al
    125868252003An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor.Wiley JS et al

    Other Information

    Locus ID:

    NCBI: 5027
    MIM: 602566
    HGNC: 8537
    Ensembl: ENSG00000089041

    Variants:

    dbSNP: 5027
    ClinVar: 5027
    TCGA: ENSG00000089041
    COSMIC: P2RX7

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000089041ENST00000261826J3KN30
    ENSG00000089041ENST00000328963Q99572
    ENSG00000089041ENST00000535250Q99572
    ENSG00000089041ENST00000535600Q99572
    ENSG00000089041ENST00000535928F5H237
    ENSG00000089041ENST00000537312F5H237
    ENSG00000089041ENST00000538011F5H2X6
    ENSG00000089041ENST00000539606F5H2X6
    ENSG00000089041ENST00000541022Q99572
    ENSG00000089041ENST00000541564F5H8E7
    ENSG00000089041ENST00000541716Q99572
    ENSG00000089041ENST00000545434F5H237

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30

    Pathways

    PathwaySourceExternal ID
    Calcium signaling pathwayKEGGko04020
    Neuroactive ligand-receptor interactionKEGGko04080
    Calcium signaling pathwayKEGGhsa04020
    Neuroactive ligand-receptor interactionKEGGhsa04080
    NOD-like receptor signaling pathwayKEGGko04621
    NOD-like receptor signaling pathwayKEGGhsa04621
    Immune SystemREACTOMER-HSA-168256
    Innate Immune SystemREACTOMER-HSA-168249
    Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
    InflammasomesREACTOMER-HSA-622312
    The NLRP3 inflammasomeREACTOMER-HSA-844456
    HemostasisREACTOMER-HSA-109582
    Platelet homeostasisREACTOMER-HSA-418346
    Platelet calcium homeostasisREACTOMER-HSA-418360
    Elevation of cytosolic Ca2+ levelsREACTOMER-HSA-139853

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    PharmGKB

    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA445210Pain, PostoperativeDiseaseClinicalAnnotationassociatedPD
    PA449599fentanylChemicalClinicalAnnotationassociatedPD

    References

    Pubmed IDYearTitleCitations
    170360482006Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.495
    157778642005Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain.236
    185962112008P2X7 receptor-Pannexin1 complex: pharmacology and signaling.144
    287235472017The P2X7 Receptor in Infection and Inflammation.129
    192119242009Autocrine regulation of T-cell activation by ATP release and P2X7 receptors.107
    215082632011Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway.104
    224470752012Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity.101
    225056532012Expression of P2X7 receptor increases in vivo tumor growth.95
    203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92
    265720622015Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock.90

    Citation

    Pablo Pelegrin ; Annmarie Surprenant

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

    Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

    Online version: http://atlasgeneticsoncology.org/gene/41623/p2rx7