P2RX7

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Purinergic signalling
File:Purinergic signalling.jpg
Simplified illustration of extracellular purinergic signalling
Concepts

Purinergic signalling

Membrane transporters

Nucleoside transporters

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] The P2X7 receptor also serves as a pattern recognition receptor for extracellular ATP-mediated apoptotic cell death,[8] regulation of receptor trafficking,[9] mast cell degranulation,[10][11] and inflammation.[10][11][12]

Structure and kinetics

The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure.[13] 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.[14] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+).[14] P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.[14]

Pharmacology

Agonists

P2X7 receptors respond to BzATP more readily than ATP.[14] ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness.[14] 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.[15][16]

Antagonists

The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper.[14] 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.[17][18] Other blockers include the large organic cations calmidazolium (a calmodulin antagonist) and KN-62 (a CaM kinase II antagonist).[14]

Receptor trafficking

In microglia, P2X7 receptors are found mostly on the cell surface.[19] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.[20] These receptors are upregulated in response to peripheral nerve injury.[21]

In melanocytic cells P2X7 gene expression may be regulated by MITF.[22]

Recruitment of pannexin

Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores[23] 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.[24] 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.[25][26] Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.[27][28][29] In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.[30][31] P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia.[19]

Osteoporosis

Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.[32]

Diabetes

The ATP/P2X7R pathway may trigger T-cell attacks on the pancreas, rendering it unable to produce insulin. This autoimmune response may be an early mechanism by which the onset of diabetes is caused.[33][34]

Researches

Possible link to hepatic fibrosis

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[35]

See also

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". Journal of Biological Chemistry. 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". Journal of Neuroscience. 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". Histochemical Journal. 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". Journal of Comparative Neurology. 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". Biochemical and Biophysical Research Communications. 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 Signalling. 5 (2): 163–73. doi:10.1007/s11302-009-9132-8. PMC 2686822. PMID 19189228.
  10. ↑ 10.0 10.1 Kurashima Y, Kiyono H (2014). "New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development". Experimental & Molecular Medicine. 46 (3): e83. doi:10.1038/emm.2014.7. PMC 3972796. PMID 24626169.
  11. ↑ 11.0 11.1 Wareham KJ, Seward EP (June 2016). "P2X7 receptors induce degranulation in human mast cells". Purinergic Signalling. 12 (2): 235–246. doi:10.1007/s11302-016-9497-4. PMC 4854833. PMID 26910735.
  12. ↑ Russo MV, McGavern DB (October 2015). "Immune Surveillance of the CNS following Infection and Injury". Trends in Immunology. 36 (10): 637–650. doi:10.1016/j.it.2015.08.002. PMC 4592776. PMID 26431941.
  13. ↑ Torres GE, Egan TM, Voigt MM (March 1999). "Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners". Journal of Biological Chemistry. 274 (10): 6653–9. doi:10.1074/jbc.274.10.6653. PMID 10037762.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.
  15. ↑ Freitas HR, Ferraz G, Ferreira GC, Ribeiro-Resende VT, Chiarini LB, do Nascimento JL, Matos Oliveira KR, Pereira Tde L, Ferreira LG, Kubrusly RC, Faria RX, Herculano AM, Reis RA (April 2016). "Glutathione-Induced Calcium Shifts in Chick Retinal Glial Cells". PLoS One. 11 (4): e0153677. doi:10.1371/journal.pone.0153677. PMC 4831842. PMID 27078878.
  16. ↑ Freitas HR, Reis RA (February 2017). "Glutathione induces GABA release through P2X7R activation on Müller glia". Neurogenesis. 4 (1): e1283188. doi:10.1080/23262133.2017.1283188. PMC 5305167. PMID 28229088.
  17. ↑ Wang, Xiaohai; Arcuino, Gregory; Takano, Takahiro; Lin, Jane; Peng, Wei Guo; Wan, Pinglan; Li, Pingjia; Xu, Qiwu; Liu, Qing Song; Goldman, Steven A; Nedergaard, Maiken (18 July 2004). "P2X7 receptor inhibition improves recovery after spinal cord injury". Nature Medicine. 10 (8): 821–827. doi:10.1038/nm1082. PMID 15258577.
  18. ↑ Peng, W.; Cotrina, M. L.; Han, X.; Yu, H.; Bekar, L.; Blum, L.; Takano, T.; Tian, G. F.; et al. (2009). "Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury". Proceedings of the National Academy of Sciences of the United States of America. 106 (30): 12489–12493. doi:10.1073/pnas.0902531106. PMC 2718350. PMID 19666625.
  19. ↑ 19.0 19.1 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". Journal of Biological Chemistry. 284 (20): 13446–54. doi:10.1074/jbc.M901255200. PMC 2679444. PMID 19304656.
  20. ↑ Jindrichova M, Kuzyk P, Li S, Stojilkovic SS, Zemkova H (June 2012). "Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking". Purinergic Signalling. 8 (2): 317–25. doi:10.1007/s11302-012-9291-x. PMC 3350585. PMID 22286664.
  21. ↑ 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". Neuroscience Letters. 504 (1): 57–61. doi:10.1016/j.neulet.2011.08.058. PMID 21924325.
  22. ↑ 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 Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  23. ↑ Iglesias R, Locovei S, Roque A, Alberto AP, Dahl G, Spray DC, Scemes E (September 2008). "P2X7 receptor-Pannexin1 complex: pharmacology and signaling". American Journal of Physiology. Cell Physiology. 295 (3): C752–60. doi:10.1152/ajpcell.00228.2008. PMC 2544446. PMID 18596211.
  24. ↑ Boison D, Chen JF, Fredholm BB (July 2010). "Adenosine signaling and function in glial cells". Cell Death & Differentiation. 17 (7): 1071–82. doi:10.1038/cdd.2009.131. PMC 2885470. PMID 19763139.
  25. ↑ 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". Journal of Pharmacology and Experimental Therapeutics. 319 (3): 1376–85. doi:10.1124/jpet.106.111559. PMID 16982702.
  26. ↑ 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.
  27. ↑ 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". Journal of Neuroscience. 30 (2): 573–82. doi:10.1523/JNEUROSCI.3295-09.2010. PMC 2880485. PMID 20071520.
  28. ↑ 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.
  29. ↑ 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". Journal of Neurochemistry. 75 (3): 965–72. doi:10.1046/j.1471-4159.2000.0750965.x. PMID 10936177.
  30. ↑ 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". Journal of Neurochemistry. 114 (3): 810–9. doi:10.1111/j.1471-4159.2010.06809.x. PMID 20477948.
  31. ↑ 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". Journal of Neurochemistry. 108 (1): 115–25. doi:10.1111/j.1471-4159.2008.05744.x. PMID 19014371.
  32. ↑ 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". European Journal of Human Genetics. 20 (5): 559–64. doi:10.1038/ejhg.2011.245. PMC 3330223. PMID 22234152.
  33. ↑ "Silencing immune attacks in type 1 diabetes". June 10, 2013. Retrieved June 15, 2013.
  34. ↑ "Boston Children's Hospital Finds Root Cause of Diabetes". June 13, 2013. Retrieved June 15, 2013.
  35. ↑ Huang C1 (Jan 2014). "P2X7 blockade attenuates mouse liver fibrosis". Journal of Molecular Medicine Reports. 9 (1): 57–62. doi:10.3892/mmr.2013.1807. PMID 24247209.

Further reading

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