P2RX7

Purinergic receptor P2X, ligand gated ion channel, 7
Identifiers
Symbols	P2RX7 ; P2X7
External IDs	OMIM: 602566 MGI: 1339957 HomoloGene: 1925 IUPHAR: 484 GeneCards: P2RX7 Gene
Gene ontology Molecular function • lipopolysaccharide binding • purinergic nucleotide receptor activity • extracellular ATP-gated cation channel activity • receptor binding • protein binding • ATP binding • protein homodimerization activity Cellular component • integral component of nuclear inner membrane • cytoplasm • plasma membrane • integral component of plasma membrane • cell-cell junction • external side of plasma membrane • membrane • neuromuscular junction • bleb • neuronal cell body Biological process • activation of MAPK activity • cell morphogenesis • phagolysosome assembly • positive regulation of T cell mediated cytotoxicity • regulation of sodium ion transport • protein phosphorylation • membrane protein ectodomain proteolysis • phospholipid transfer to membrane • cation transport • membrane budding • inflammatory response • mitochondrion organization • cell surface receptor signaling pathway • response to mechanical stimulus • 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 • synaptic vesicle exocytosis • protein processing • phospholipid scrambling • sensory perception of pain • cytolysis • positive regulation of bone mineralization • cellular response to extracellular stimulus • bleb assembly • positive regulation of prostaglandin secretion • response to lipopolysaccharide • positive regulation of interleukin-6 production • collagen metabolic process • response to ATP • ion transmembrane transport • response to fluid shear stress • positive regulation of ion transmembrane transport • purinergic nucleotide receptor signaling pathway • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • T cell proliferation • response to drug • T cell homeostasis • NAD transport • negative regulation of MAPK cascade • multicellular organismal protein catabolic process • innate immune response • 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 • 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 • positive regulation of lymphocyte apoptotic process • cellular response to organic cyclic compound • reactive oxygen species metabolic process • apoptotic signaling pathway • extrinsic apoptotic signaling pathway • cation transmembrane transport • positive regulation of bleb assembly Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5027	18439
Ensembl	ENSG00000089041	ENSMUSG00000029468
UniProt	Q99572	Q9Z1M0
RefSeq (mRNA)	NM_002562	NM_001038839
RefSeq (protein)	NP_002553	NP_001033928
Location (UCSC)	Chr 12: 121.13 – 121.19 Mb	Chr 5: 122.64 – 122.69 Mb
PubMed search

P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.^[1][2]

The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced variants which would encode different isoforms have been identified although some fit nonsense-mediated decay criteria.^[3]

The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina.^[4][5][6][7] P2X₇ receptors have been implicated in ATP-mediated cell death, regulation of receptor trafficking, and inflammation.^[8][9][10]

Structure and kinetics

The P2X₇ subunits can form homomeric receptors only with a typical P2X receptor structure.^[11] The P2X₇ receptor is a ligand-gated cation channel that opens in response to ATP binding and leads to cell depolarization. The P2X₇ receptor requires higher levels of ATP than other P2X receptors; however, the response can be potentiated by reducing the concentration of divalent cations such as calcium or magnesium.^[12] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG⁺).^[12] P2X₇ receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.^[12]

Pharmacology

Agonists

P2X₇ receptors respond to BzATP more readily than ATP.^[12] ADP and AMP are weak agonists of P2X₇ receptors, but a brief exposure to ATP can increase their effectiveness.^[12]

Antagonists

The P2X₇ receptor current can be blocked by zinc, calcium, magnesium, and copper.^[12] P2X₇ receptors are sensitive to pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and relatively insensitive to suramin, but the suramin analog, NF279, is much more effective. Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).^[12]

Receptor trafficking

In microglia, P2X₇ receptors are found mostly on the cell surface.^[13] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.^[14] These receptors are upregulated in response to peripheral nerve injury.^[15]

In melanocytic cells P2X₇ gene expression may be regulated by MITF.^[16]

Recruitment of pannexin

Activation of the P2X₇ receptor by ATP leads to recruitment of pannexin pores^[17] which allow small molecules such as ATP to leak out of cells. This allows further activation of purinergic receptors and physiological responses such a spreading cytoplasmic waves of calcium.^[18] Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.

Clinical significance

Neuropathic pain

Microglial P2X₇ receptors are thought to be involved in neuropathic pain because blockade or deletion of P2X₇ receptors results in decreased responses to pain, as demonstrated in vivo.^[19][20] Moreover, P2X₇ receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.^[21][22][23] In addition, P2X₇ receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.^[24][25] Interestingly, P2X₇ receptors are also linked to P2X₄ receptors, which are also associated with neuropathic pain mediated by microglia.^[13]

Osteoporosis

Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.^[26]

Possible link to diabetes

Paolo Fiorina, MD, PhD, of the Nephrology Division at Boston Children’s Hospital and his team studied hundreds of pathways in animals with diabetes. They eventually isolated one, known as ATP/P2X7R, which triggers the T-cell attacks on the pancreas, rendering it unable to produce insulin.

“By identifying the ATP/P2X7R pathway as the early mechanism in the body that fires up an autoimmune response, we found the root cause of diabetes” says Fiorina.^[27][28]

Researches

Possible link to hepatic fibrosis

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis. ^[29]

See also

• Purinergic receptor
• P2X receptor

References

1. Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A (Apr 1997). "The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA". J Biol Chem 272 (9): 5482–6. doi:10.1074/jbc.272.9.5482. PMID 9038151.
2. Buell GN, Talabot F, Gos A, Lorenz J, Lai E, Morris MA, Antonarakis SE (Feb 1999). "Gene structure and chromosomal localization of the human P2X7 receptor". Receptors Channels 5 (6): 347–54. PMID 9826911.
3. "Entrez Gene: P2RX7 purinergic receptor P2X, ligand-gated ion channel, 7".
4. Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, Buckley NJ, Parson SH, Deuchars J (September 2001). "Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems". J. Neurosci. 21 (18): 7143–52. PMID 11549725.
5. Collo G, Neidhart S, Kawashima E, Kosco-Vilbois M, North RA, Buell G (September 1997). "Tissue distribution of the P2X7 receptor". Neuropharmacology 36 (9): 1277–83. doi:10.1016/S0028-3908(97)00140-8. PMID 9364482.
6. Slater NM, Barden JA, Murphy CR (June 2000). "Distributional changes of purinergic receptor subtypes (P2X 1-7) in uterine epithelial cells during early pregnancy". Histochem. J. 32 (6): 365–72. doi:10.1023/A:1004017714702. PMID 10943851.
7. Ishii K, Kaneda M, Li H, Rockland KS, Hashikawa T (May 2003). "Neuron-specific distribution of P2X7 purinergic receptors in the monkey retina". J. Comp. Neurol. 459 (3): 267–77. doi:10.1002/cne.10608. PMID 12655509.
8. Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, Kitani H, Kojima S (March 2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages". Biochem. Biophys. Res. Commun. 419 (2): 374–80. doi:10.1016/j.bbrc.2012.01.156. PMID 22349510.
9. Qu Y, Dubyak GR (June 2009). "P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways". Purinergic Signal. 5 (2): 163–73. doi:10.1007/s11302-009-9132-8. PMC 2686822. PMID 19189228.
10. Lee BH, Hwang DM, Palaniyar N, Grinstein S, Philpott DJ, Hu J (2012). "Activation of P2X(7) receptor by ATP plays an important role in regulating inflammatory responses during acute viral infection". PLoS ONE 7 (4): e35812. doi:10.1371/journal.pone.0035812. PMC 3338466. PMID 22558229.
11. Torres GE, Egan TM, Voigt MM (March 1999). "Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners". J. Biol. Chem. 274 (10): 6653–9. doi:10.1074/jbc.274.10.6653. PMID 10037762.
12. North RA (October 2002). "Molecular physiology of P2X receptors". Physiol. Rev. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.
13. Boumechache M, Masin M, Edwardson JM, Górecki DC, Murrell-Lagnado R (May 2009). "Analysis of assembly and trafficking of native P2X4 and P2X7 receptor complexes in rodent immune cells". J. Biol. Chem. 284 (20): 13446–54. doi:10.1074/jbc.M901255200. PMC 2679444. PMID 19304656.
14. Jindrichova M, Kuzyk P, Li S, Stojilkovic SS, Zemkova H (June 2012). "Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking". Purinergic Signal. 8 (2): 317–25. doi:10.1007/s11302-012-9291-x. PMC 3350585. PMID 22286664.
15. Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K (October 2011). "Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model". Neurosci. Lett. 504 (1): 57–61. doi:10.1016/j.neulet.2011.08.058. PMID 21924325.
16. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
17. Iglesias R, Locovei S, Roque A, Alberto AP, Dahl G, Spray DC, Scemes E (September 2008). "P2X7 receptor-Pannexin1 complex: pharmacology and signaling". Am. J. Physiol., Cell Physiol. 295 (3): C752–60. doi:10.1152/ajpcell.00228.2008. PMC 2544446. PMID 18596211.
18. Boison D, Chen JF, Fredholm BB (July 2010). "Adenosine signaling and function in glial cells". Cell Death Differ. 17 (7): 1071–82. doi:10.1038/cdd.2009.131. PMC 2885470. PMID 19763139.
19. Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, Harris R, Medrano AP, Carroll W, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF (December 2006). "A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat". J. Pharmacol. Exp. Ther. 319 (3): 1376–85. doi:10.1124/jpet.106.111559. PMID 16982702.
20. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (April 2005). "Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain". Pain 114 (3): 386–96. doi:10.1016/j.pain.2005.01.002. PMID 15777864.
21. Clark AK, Staniland AA, Marchand F, Kaan TK, McMahon SB, Malcangio M (January 2010). "P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide". J. Neurosci. 30 (2): 573–82. doi:10.1523/JNEUROSCI.3295-09.2010. PMC 2880485. PMID 20071520.
22. Shigemoto-Mogami Y, Koizumi S, Tsuda M, Ohsawa K, Kohsaka S, Inoue K (September 2001). "Mechanisms underlying extracellular ATP-evoked interleukin-6 release in mouse microglial cell line, MG-5". J. Neurochem. 78 (6): 1339–49. doi:10.1046/j.1471-4159.2001.00514.x. PMID 11579142.
23. Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, Nakata Y (September 2000). "Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia". J. Neurochem. 75 (3): 965–72. doi:10.1046/j.1471-4159.2000.0750965.x. PMID 10936177.
24. Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K (August 2010). "P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways". J. Neurochem. 114 (3): 810–9. doi:10.1111/j.1471-4159.2010.06809.x. PMID 20477948.
25. Kataoka A, Tozaki-Saitoh H, Koga Y, Tsuda M, Inoue K (January 2009). "Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT". J. Neurochem. 108 (1): 115–25. doi:10.1111/j.1471-4159.2008.05744.x. PMID 19014371.
26. Gartland A, Skarratt KK, Hocking LJ, Parsons C, Stokes L, Jørgensen NR, Fraser WD, Reid DM, Gallagher JA, Wiley JS (May 2012). "Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women". Eur. J. Hum. Genet. 20 (5): 559–64. doi:10.1038/ejhg.2011.245. PMC 3330223. PMID 22234152.
27. "Silencing immune attacks in type 1 diabetes". June 10, 2013. Retrieved June 15, 2013.
28. "Boston Children’s Hospital Finds Root Cause of Diabetes". June 13, 2013. Retrieved June 15, 2013.
29. Huang C1 (Jan 2014). "P2X7 blockade attenuates mouse liver fibrosis.". J Mol Med Rep 9 (1): 57–62. doi:10.3892/mmr.2013.1807. PMID 24247209.

Further reading

• Gartland A, Buckley KA, Hipskind RA, Bowler WB, Gallagher JA. (2003). "P2 receptors in bone--modulation of osteoclast formation and activity via P2X7 activation". Crit Rev Eukaryot Gene Expr. 13 (2–4): 237–42. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.150. PMID 14696970.
• Gartland A, Buckley KA, Bowler WB, Gallagher JA. (2003). "Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro". Calcif Tissue Int. 72 (4): 361–9. doi:10.1007/s00223-002-2098-y. PMID 12874700.
• Bowler WB, Buckley KA, Gartland A, Hipskind RA, Bilbe G, Gallagher JA. (2001). "Extracellular nucleotide signaling: a mechanism for integrating local and systemic responses in the activation of bone remodeling". Bone 28 (5): 507–12. doi:10.1016/S8756-3282(01)00430-6. PMID 11344050.
• Gartland A, Hipskind RA, Gallagher JA, Bowler WB. (2001). "Expression of a P2X7 receptor by a subpopulation of human osteoblasts". J Bone Miner Res . 16 (5): 846–56. doi:10.1359/jbmr.2001.16.5.846. PMID 11341329.
• Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, Chessell I, Bowler WB, Gallagher JA. (2003). "Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice". Crit Rev Eukaryot Gene Expr. 13 (2–4): 243–53. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.160. PMID 14696971.

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• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Gu BJ, Zhang W, Worthington RA, et al. (2001). "A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor". J. Biol. Chem. 276 (14): 11135–42. doi:10.1074/jbc.M010353200. PMID 11150303.
• Kim M, Jiang LH, Wilson HL, et al. (2002). "Proteomic and functional evidence for a P2X7 receptor signalling complex". EMBO J. 20 (22): 6347–58. doi:10.1093/emboj/20.22.6347. PMC 125721. PMID 11707406.
• Worthington RA, Smart ML, Gu BJ, et al. (2002). "Point mutations confer loss of ATP-induced human P2X(7) receptor function". FEBS Lett. 512 (1–3): 43–6. doi:10.1016/S0014-5793(01)03311-7. PMID 11852049.
• Wiley JS, Dao-Ung LP, Gu BJ, et al. (2002). "A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocytic leukaemia: a molecular study". Lancet 359 (9312): 1114–9. doi:10.1016/S0140-6736(02)08156-4. PMID 11943260.
• Wilson HL, Wilson SA, Surprenant A, North RA (2002). "Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus". J. Biol. Chem. 277 (37): 34017–23. doi:10.1074/jbc.M205120200. PMID 12107182.
• Atkinson L, Milligan CJ, Buckley NJ, Deuchars J (2002). "An ATP-gated ion channel at the cell nucleus". Nature 420 (6911): 42. doi:10.1038/420042a. PMID 12422208.
• Sluyter R, Wiley JS (2003). "Extracellular adenosine 5'-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors". Int. Immunol. 14 (12): 1415–21. doi:10.1093/intimm/dxf111. PMID 12456589.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Wiley JS, Dao-Ung LP, Li C, et al. (2003). "An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor". J. Biol. Chem. 278 (19): 17108–13. doi:10.1074/jbc.M212759200. PMID 12586825.
• Barden JA, Sluyter R, Gu BJ, Wiley JS (2003). "Specific detection of non-functional human P2X(7) receptors in HEK293 cells and B-lymphocytes". FEBS Lett. 538 (1–3): 159–62. doi:10.1016/S0014-5793(03)00172-8. PMID 12633871.
• Verhoef PA, Estacion M, Schilling W, Dubyak GR (2003). "P2X7 receptor-dependent blebbing and the activation of Rho-effector kinases, caspases, and IL-1 beta release". J. Immunol. 170 (11): 5728–38. doi:10.4049/jimmunol.170.11.5728. PMID 12759456.
• Greig AV, Linge C, Terenghi G, et al. (2003). "Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes". J. Invest. Dermatol. 120 (6): 1007–15. doi:10.1046/j.1523-1747.2003.12261.x. PMID 12787128.
• Denlinger LC, Sommer JA, Parker K, et al. (2003). "Mutation of a dibasic amino acid motif within the C terminus of the P2X7 nucleotide receptor results in trafficking defects and impaired function". J. Immunol. 171 (3): 1304–11. doi:10.4049/jimmunol.171.3.1304. PMID 12874219.

External links

• P2RX7 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.