P2RX7
P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.[5][6]
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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.[7]
The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, in uterine endometrium, and in the retina.[8][9][10][11][12][13][14] The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death,[15][16][17] regulation of receptor trafficking,[18] mast cell degranulation,[19][20] and inflammation.[21][19][20][22]
Structure and kinetics
The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure.[23] 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.[8][24] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+).[24] P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.[24]
Pharmacology
Agonists
P2X7 receptors respond to BzATP more readily than ATP.[24] ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness.[24] Glutathione has been proposed to act as a P2X7 receptor agonist when present at milimolar levels, inducing calcium transients and GABA release from retinal cells.[10][9]
Antagonists
The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper.[24] 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. Oxidized ATP (OxATP) and Brilliant Blue G has also been used for blocking P2X7 in inflammation.[25][26] Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).[24]
Receptor trafficking
In microglia, P2X7 receptors are found mostly on the cell surface.[27] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.[28] These receptors are upregulated in response to peripheral nerve injury.[29]
In melanocytic cells P2X7 gene expression may be regulated by MITF.[30]
Recruitment of pannexin
Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores[31] 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.[32] Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.
Clinical significance
Inflammation
On T cells activation of P2X7 receptors can activate the T cells or cause T cell differentiation, can affect T cell migration or (at high extracellular levels of ATP and/or NAD+) can induce cell death.[33] The CD38 enzyme on B lymphocytes and macrophages reduces extracellular NAD+, promoting the survival of T cells.[34]
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.[35][36] Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.[37][38][39] In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.[40][41] P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia.[27]
Osteoporosis
Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.[42]
Research
Possible link to hepatic fibrosis
One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[45]
See also
References
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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". Critical Reviews in Eukaryotic Gene Expression. 13 (2–4): 237–42. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.150. PMID 14696970.
- Gartland A, Buckley KA, Bowler WB, Gallagher JA (October 2003). "Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro". Calcified Tissue International. 73 (4): 361–9. doi:10.1007/s00223-002-2098-y. PMID 12874700. S2CID 23793221.
- Bowler WB, Buckley KA, Gartland A, Hipskind RA, Bilbe G, Gallagher JA (May 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 (May 2001). "Expression of a P2X7 receptor by a subpopulation of human osteoblasts". Journal of Bone and Mineral Research. 16 (5): 846–56. doi:10.1359/jbmr.2001.16.5.846. PMID 11341329. S2CID 37561770.
- Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, et al. (2003). "Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice". Critical Reviews in Eukaryotic Gene Expression. 13 (2–4): 243–53. doi:10.1615/CritRevEukaryotGeneExpr.v13.i24.160. PMID 14696971.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 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, Sluyter R, Dao-Ung P, Petrou S, et al. (April 2001). "A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor". The Journal of Biological Chemistry. 276 (14): 11135–42. doi:10.1074/jbc.M010353200. PMID 11150303.
- Kim M, Jiang LH, Wilson HL, North RA, Surprenant A (November 2001). "Proteomic and functional evidence for a P2X7 receptor signalling complex". The EMBO Journal. 20 (22): 6347–58. doi:10.1093/emboj/20.22.6347. PMC 125721. PMID 11707406.
- Worthington RA, Smart ML, Gu BJ, Williams DA, Petrou S, Wiley JS, Barden JA (February 2002). "Point mutations confer loss of ATP-induced human P2X(7) receptor function". FEBS Letters. 512 (1–3): 43–6. doi:10.1016/S0014-5793(01)03311-7. PMID 11852049. S2CID 35680551.
- Wiley JS, Dao-Ung LP, Gu BJ, Sluyter R, Shemon AN, Li C, et al. (March 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. S2CID 6019286.
- Wilson HL, Wilson SA, Surprenant A, North RA (September 2002). "Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus". The Journal of Biological Chemistry. 277 (37): 34017–23. doi:10.1074/jbc.M205120200. PMID 12107182.
- Atkinson L, Milligan CJ, Buckley NJ, Deuchars J (November 2002). "An ATP-gated ion channel at the cell nucleus". Nature. 420 (6911): 42. doi:10.1038/420042a. PMID 12422208. S2CID 4313025.
- Sluyter R, Wiley JS (December 2002). "Extracellular adenosine 5'-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors". International Immunology. 14 (12): 1415–21. doi:10.1093/intimm/dxf111. PMID 12456589.
- Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, et al. (May 2003). "An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor". The Journal of Biological Chemistry. 278 (19): 17108–13. doi:10.1074/jbc.M212759200. PMID 12586825.
- Barden JA, Sluyter R, Gu BJ, Wiley JS (March 2003). "Specific detection of non-functional human P2X(7) receptors in HEK293 cells and B-lymphocytes". FEBS Letters. 538 (1–3): 159–62. doi:10.1016/S0014-5793(03)00172-8. PMID 12633871. S2CID 9252812.
- Verhoef PA, Estacion M, Schilling W, Dubyak GR (June 2003). "P2X7 receptor-dependent blebbing and the activation of Rho-effector kinases, caspases, and IL-1 beta release". Journal of Immunology. 170 (11): 5728–38. doi:10.4049/jimmunol.170.11.5728. PMID 12759456.
- Greig AV, Linge C, Terenghi G, McGrouther DA, Burnstock G (June 2003). "Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes". The Journal of Investigative Dermatology. 120 (6): 1007–15. doi:10.1046/j.1523-1747.2003.12261.x. PMID 12787128.
- Denlinger LC, Sommer JA, Parker K, Gudipaty L, Fisette PL, Watters JW, et al. (August 2003). "Mutation of a dibasic amino acid motif within the C terminus of the P2X7 nucleotide receptor results in trafficking defects and impaired function". Journal of Immunology. 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.