Alternative titles; symbols
HGNC Approved Gene Symbol: P2RX7
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:121,132,876-121,188,032 (from NCBI)
Cell surface ATP receptors can be divided into 2 classes. The metabotropic class (P2Y/P2U) are members of the 7-transmembrane superfamily of G protein-coupled receptors (see 602451). The ionotropic class (P2X) are ligand-gated channels (see 600843). P2Z receptors are ionotropic but also cause cell permeabilization. Rassendren et al. (1997) cloned the human gene for a receptor, called P2X7, that is structurally related to the P2X family and exhibits the properties of a P2Z receptor. They screened a human monocyte cDNA library with the rat P2X7 gene as a probe, and recovered a cDNA encoding a predicted 595-amino acid protein that is 80% identical to the rat P2X7 protein. On Northern blots, P2X7 was expressed as a 6-kb mRNA in many tissues.
Rassendren et al. (1997) found that treatment of P2X7-transfected cells with ATP or 2-prime, 3-prime-(4-benzoyl)-benzoyl ATP (BzATP) elicited cation-selective currents. Longer applications of agonists permeabilized the cell.
Worthington et al. (2002) studied the role of various residues in ATP binding of P2X7 receptor. This was done by transfecting into a cell line or Xenopus oocytes with either wildtype or site-directed mutants of the protein. They concluded that K193 and K311 are essential residues in ATP binding.
Atkinson et al. (2002) demonstrated that the P2RX7 ATP-binding receptor calcium channel spans the nuclear envelope. Atkinson et al. (2002) used in situ hybridization of the rat hippocampus to detect mRNA encoding P2RX7. A positive signal was seen in the cytoplasm of all neurons in the cell-body layer, 90% of which are excitatory cells. P2RX7 mRNA was also seen in inhibitory neurons of the hippocampus.
Sugiyama et al. (2004) tested whether diabetes increases the vulnerability of retinal microvessels to the potentially lethal consequences of having their P2X7 purinoceptors activated. In experiments using pericyte-containing microvessels isolated from adult rat retina, they found that soon after the onset of streptozotocin-induced diabetes, markedly lower P2X7 agonist concentrations effectively opened pores and triggered apoptosis in the retinal microvasculature. Sugiyama et al. (2004) suggested that microvascular damage in the diabetic retina may be mediated by receptors for vasoactive molecules.
Using rat alveolar macrophages expressing native P2x7 and human embryonic kidney cells expressing full-length rat P2x7 or a C-terminally truncated P2x7 mutant, Lemaire et al. (2006) showed that P2X7 was involved in the fusion process leading to multinucleated giant cells.
Alu-derived RNAs activate P2X7 and the NLRP3 (606416) inflammasome to cause cell death of the retinal epithelium in geographic atrophy, a type of age-related macular degeneration (ARMD; 603075). Fowler et al. (2014) found that nucleoside reverse transcriptase inhibitors (NRTIs) inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 (CASP1; 147678) activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Fowler et al. (2014) concluded that NRTIs might be therapeutic for both dry and wet ARMD and that these drugs work at the level of P2X7 in these systems.
Borges da Silva et al. (2018) demonstrated that P2RX7 is required for the establishment, maintenance, and functionality of long-lived central and tissue-resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP-activated protein kinase (see PRKAA1, 602739). Pharmacologic inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. Borges da Silva et al. (2018) concluded that activation of P2RX7 by extracellular ATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations.
Ryoden et al. (2020) found that P2X7 mediated phosphatidylserine exposure in mouse and human cells in response to extracellular ATP. For this function, P2X7 required EROS (618334) to be expressed at the plasma membrane. EROS localized to the endoplasmic reticulum, where it interacted with P2X7 and assisted its folding by functioning as a chaperone. P2X7 then moved to the plasma membrane, where it was present as a homotrimeric complex. EROS was also required for P2X7-mediated production of IL1-beta (IL1B; 147720) triggered by ATP in macrophages.
Buell et al. (1998) determined that the P2RX7 gene contains 13 exons.
By FISH, Buell et al. (1998) localized the P2RX7 gene to chromosome 12q24. By radiation hybrid analysis, they found that the gene lies within 130 kb of the homologous P2RX4 gene (600846).
Several investigators had shown that P2X7 is nonfunctional both in lymphocytes and monocytes from some subjects. To study a possible genetic basis, Gu et al. (2001) sequenced DNA coding for the carboxyl-terminal tail of P2X7. They found a 1513A-C substitution, which resulted in a glu496-to-ala (E496A) mutation. Nine of 45 normal subjects were heterozygous, whereas 1 subject was homozygous. Surface expression of P2X7 on lymphocytes was not affected by this E496A polymorphism, demonstrated both by confocal microscopy and immunofluorescent staining. Monocytes and lymphocytes from the E496A homozygote subject expressed nonfunctional receptor, whereas heterozygotes showed P2X7 function that was half that of germline P2X7. Transfection experiments showed that the mutant P2X7 receptor was nonfunctional when expressed at low receptor density but regained function at a high receptor density. This density dependence of mutant P2X7 function was also seen on differentiation of fresh monocytes to macrophages with interferon-gamma, which upregulated mutant P2X7 and partially restored its function. P2X7-mediated apoptosis of lymphocytes was impaired in homozygous mutant P2X7 compared with germline (8.6 vs 35.2%). The data suggested that the glutamic acid at position 496 is required for optimal assembly of the P2X7 receptor.
Treatment of mycobacteria-infected macrophages with ATP induces P2X7-mediated apoptosis that leads to death of the host cell and intracellular bacilli. Saunders et al. (2003) found that neither apoptosis nor killing of mycobacteria occurred in macrophages from individuals homozygous for E496A after brief ATP exposure.
Cabrini et al. (2005) noted that in addition to the E496A variant, several other polymorphisms cause loss of function of P2X7R in CLL patients. By monitoring ATP-induced Ca(2+) influx in peripheral blood lymphocytes from CLL patients and in embryonic kidney cells transfected with P2X7R variants, they confirmed loss of function with E496A, but found that other cytoplasmic tail variants resulted in only minor functional decreases. Cabrini et al. (2005) identified the 489C-T polymorphism, which causes a his155-to-tyr (H155Y) change in the extracellular portion of the receptor, as a gain-of-function polymorphism. Significant Ca(2+) flux increase was observed in CLL patient lymphocytes bearing 489C/T and 489T/T genotypes. None of the polymorphisms studied occurred at a significantly different frequency in CLL patients compared with controls.
Wiley et al. (2002) investigated whether a glu496-to-ala (E496A; 1513A-C) single-nucleotide polymorphism that results in loss of function of P2X7 in healthy individuals was present in leukemic B lymphocytes of patients with chronic lymphatic leukemia (CLL; 151400). They studied genomic DNA from the peripheral blood leukocytes of 36 unrelated individuals with CLL, 4 individuals with familial CLL, and 46 age-matched controls. The prevalence of the polymorphic mutation and the frequency of the mutant allele were 3-fold greater in individuals with CLL than in white, elderly controls. Individuals homozygous for the polymorphic allele had no P2X7 receptor function and heterozygotes had half the normal function of that seen in individuals homozygous for the wildtype allele; amounts of ATP-induced apoptosis varied accordingly. In 2 families in which Wiley et al. (2002) studied a father-son pair and a sister-sister pair with CLL, loss of P2X7 function arose because of inheritance of 1 or 2 1513A-C alleles for P2X7. They concluded that activation of the P2X7 receptor leads to apoptosis of lymphocytes in individuals with CLL, and reduced function of this receptor has an antiapoptotic effect, resulting in an increase in B-cell numbers. Thus, inheritance of a loss-of-function polymorphic mutation at position 1513 in the P2X7 gene would contribute to the pathogenesis of CLL.
To explore further the involvement of P2X7 as a susceptibility gene in CLL, Dao-Ung et al. (2004) expanded the study of Wiley et al. (2002) to include 42 cases of familial and 74 cases of sporadic CLL. Three intergenerational pairs, 6 sib pairs, and 8 single familial cases (affected relatives unavailable for study) were recruited. The 1513C allele frequency was significantly increased in familial CLL patients (0.286) compared with normal subjects (0.157) (OR = 2.1, p = 0.008). In contrast, the 1513C allele frequency in patients with sporadic CLL was very similar to that observed in normal subjects, with an OR close to 1.
Thunberg et al. (2002) found that the 1513A-C polymorphism affected clinical outcome in CLL, especially in patients with mutated immunoglobulin heavy chain variable genes (V(H); see 147070). Survival was significantly longer for patients with CLL heterozygous for the 1513C allele than those with the 1513A/A genotype: median survival was 104 months and 72 months, respectively (P = 0.009). Of the 165 patients with CLL in whom they assessed V(H) gene mutation status, the genes were mutated in 71 (43%) patients and unmutated in 94; 18 (25%) of the 71 patients with mutated genes had the 1513C allele, compared with 17 (18%) of the 94 who had unmutated genes. In patients with mutated immunoglobulin heavy chain variable genes, those with CLL who were 1513C-positive had 53 months' longer median survival than those with the 1513A/A genotype (151 vs 98 months, P = 0.011). Di Virgilio and Wiley (2002) commented on these findings.
Solle et al. (2001) generated P2rx7-deficient mice by homologous recombination. Macrophages from the mutant mice were unable to respond to extracellular ATP as measured by fluorescent dye accumulation. In addition, ATP or lipopolysaccharide (LPS) stimulation of macrophages resulted in the accumulation of 35-kD pro-Il1b in amounts comparable to wildtype, but only wildtype macrophages secreted the 17-kD Il1b. Both wildtype and mutant macrophages produced and released the 17-kD form in response to the potassium ionophore nigericin. Likewise, in vivo, mutant mice primed with LPS and challenged with ATP failed to generate significant levels of Il1b. Il6 (147620), on the other hand, was produced by the mutant mice in response to LPS but without additional production after ATP challenge, suggesting that ATP affects IL6 production via both P2RX7-dependent and -independent mechanisms.
The capacity of P2X7R to form large pores and mediate apoptosis depends on its large cytoplasmic tail, which harbors a putative TNFR-related death domain. Adriouch et al. (2002) stated that transfected mouse P2x7r forms pores less efficiently than its human and rat counterparts. Using flow cytometric analysis, they demonstrated that splenic T cells from C57BL/6 mice were less sensitive to extracellular ATP-induced calcium uptake and apoptosis than were those from BALB/c mice. Adriouch et al. (2002) identified a coding mutation in the C57BL/6 allele, a T-to-C transition at nucleotide 1352, that led to a pro451-to-leu (P451L) substitution in the TNFR-related death domain. In contrast, the BALB/c sequence was in accord with those of human and rat P2X7R. The mutant form of P2x7r was present in 2 C57BL and 2 DBA strains, but not in 10 other strains examined, including 4 derived from wild mice. Adriouch et al. (2002) suggested that the P451L mutation has effects analogous to those seen with the human E496A mutation.
Weber et al. (2010) found that P2x7 -/- mice were resistant to contact hypersensitivity (CHS). Injection of Il1b restored the capacity to develop CHS in P2x7 -/- mice. P2x7 -/- dendritic cells failed to make Il1b in response to LPS and ATP, but they did make Il1b, in an Nlrp3 (606416)- and Asc (PYCARD; 606838)-dependent manner, if primed with LPS and alum. Weber et al. (2010) concluded that P2X7 is a crucial receptor for extracellular ATP released in skin in response to contact allergens and for the release of IL1B, which is also essential in the sensitization process.
Adriouch, S., Dox, C., Welge, V., Seman, M., Koch-Nolte, F., Haag, F. Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J. Immun. 169: 4108-4112, 2002. [PubMed: 12370338] [Full Text: https://doi.org/10.4049/jimmunol.169.8.4108]
Atkinson, L., Milligan, C. J., Buckley, N. J., Deuchars, J. An ATP-gated ion channel at the cell nucleus. Nature 420: 42 only, 2002. [PubMed: 12422208] [Full Text: https://doi.org/10.1038/420042a]
Borges da Silva, H., Beura, L. K., Wang, H., Hanse, E. A., Gore, R., Scott, M. C., Walsh, D. A., Block, K. E., Fonseca, R., Yan, Y., Hippen, K. L., Blazar, B. R., Masopust, D., Kelekar, A., Vulchanova, L., Hogquist, K. A., Jameson, S. C. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559: 264-268, 2018. [PubMed: 29973721] [Full Text: https://doi.org/10.1038/s41586-018-0282-0]
Buell, G. N., Talabot, F., Gos, A., Lorenz, J., Lai, E., Morris, M. A., Antonarakis, S. E. Gene structure and chromosomal localization of the human P2X7 receptor. Receptors Channels 5: 347-354, 1998. [PubMed: 9826911]
Cabrini, G., Falzoni, S., Forchap, S. L., Pellegatti, P., Balboni, A., Agostini, P., Cuneo, A., Castoldi, G., Baricordi, O. R., Di Virgilio, F. A his-155 to tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J. Immun. 175: 82-89, 2005. [PubMed: 15972634] [Full Text: https://doi.org/10.4049/jimmunol.175.1.82]
Dao-Ung, L.-P., Fuller, S. J., Sluyter, R., SkarRatt, K. K., Thunberg, U., Tobin, G., Byth, K., Ban, M., Rosenquist, R., Stewart, G. J., Wiley, J. S. Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia. (Letter) Brit. J. Haemat. 125: 815-817, 2004. [PubMed: 15180873] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.04976.x]
Di Virgilio, F., Wiley, J. S. The P2X7 receptor of CLL lymphocytes--a molecule with a split personality. (Commentary) Lancet 360: 1898-1899, 2002. [PubMed: 12493250] [Full Text: https://doi.org/10.1016/S0140-6736(02)11933-7]
Fowler, B. J., Gelfand, B. D., Kim, Y., Kerur, N., Tarallo, V., Hirano, Y., Amarnath, S., Fowler, D. H., Radwan, M., Young, M. T., Pittman, K., Kubes, P., and 10 others. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346: 1000-1003, 2014. [PubMed: 25414314] [Full Text: https://doi.org/10.1126/science.1261754]
Gu, B. J., Zhang, W., Worthington, R. A., Sluyter, R., Dao-Ung, P., Petrou, S., Barden, J. A., Wiley, J. S. A glu-496 to ala polymorphism leads to loss of function of the human P2X(7) receptor. J. Biol. Chem. 276: 11135-11142, 2001. [PubMed: 11150303] [Full Text: https://doi.org/10.1074/jbc.M010353200]
Lemaire, I., Falzoni, S., Leduc, N., Zhang, B., Pellegatti, P., Adinolfi, E., Chiozzi, P., Di Virgilio, F. Involvement of the purinergic P2X7 receptor in the formation of multinucleated giant cells. J. Immun. 177: 7257-7265, 2006. [PubMed: 17082644] [Full Text: https://doi.org/10.4049/jimmunol.177.10.7257]
Rassendren, F., Buell, G. N., Virginio, C., Collo, G., North, R. A., Surprenant, A. The permeabilizing ATP receptor, P2X(7). J. Biol. Chem. 272: 5482-5486, 1997. [PubMed: 9038151] [Full Text: https://doi.org/10.1074/jbc.272.9.5482]
Ryoden, Y., Fujii, T., Segawa, K., Nagata, S. Functional expression of the P2X7 ATP receptor requires Eros. J. Immun. 204: 559-568, 2020. [PubMed: 31862710] [Full Text: https://doi.org/10.4049/jimmunol.1900448]
Saunders, B. M., Fernando, S. L., Sluyter, R., Britton, W. J., Wiley, J. S. A loss-of-function polymorphism in the human P2X(7) receptor abolishes ATP-mediated killing of mycobacteria. J. Immun. 171: 5442-5446, 2003. [PubMed: 14607949] [Full Text: https://doi.org/10.4049/jimmunol.171.10.5442]
Solle, M., Labasi, J., Perregaux, D. G., Stam, E., Petrushova, N., Koller, B. H., Griffiths, R. J., Gabel, C. A. Altered cytokine production in mice lacking P2X7 receptors. J. Biol. Chem. 276: 125-132, 2001. [PubMed: 11016935] [Full Text: https://doi.org/10.1074/jbc.M006781200]
Sugiyama, T., Kobayashi, M., Kawamura, H., Li, Q., Puro, D. G. Enhancement of P2X7-induced pore formation and apoptosis: an early effect of diabetes on the retinal microvasculature. Invest. Ophthal. Vis. Sci. 45: 1026-1032, 2004. Note: Erratum: Invest. Ophthal. Vis. Sci. 45: 1296 only, 2004. [PubMed: 14985326] [Full Text: https://doi.org/10.1167/iovs.03-1062]
Thunberg, U., Tobin, G., Johnson, A., Soderberg, O., Padyukov, L., Hultdin, M., Klareskog, L., Enblad, G., Sundstrom, C., Roos, G., Rosenquist, R. Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia. Lancet 360: 1935-1939, 2002. [PubMed: 12493261] [Full Text: https://doi.org/10.1016/S0140-6736(02)11917-9]
Weber, F. C., Esser, P. R., Muller, T., Ganesan, J., Pellegatti, P., Simon, M. M., Zeiser, R., Idzko, M., Jakob, T., Martin, S. F. Lack of the purinergic receptor P2X(7) results in resistance to contact hypersensitivity. J. Exp. Med. 207: 2609-2619, 2010. [PubMed: 21059855] [Full Text: https://doi.org/10.1084/jem.20092489]
Wiley, J. S., Dao-Ung, L. P., Gu, B. J., Sluyter, R., Shemon, A. N., Li, C., Taper, J., Gallo, J., Manoharan, A. A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocyte leukaemia: a molecular study. Lancet 359: 1114-1119, 2002. [PubMed: 11943260] [Full Text: https://doi.org/10.1016/S0140-6736(02)08156-4]
Worthington, R. A., Smart, M. L., Gu, B. J., Williams, D. A., Petrou, S., Wiley, J. S., Barden, J. A. Point mutations confer loss of ATP-induced human P2X(7) receptor function. FEBS Lett. 512: 43-46, 2002. [PubMed: 11852049] [Full Text: https://doi.org/10.1016/s0014-5793(01)03311-7]