P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene.[5][6]

P2RX7
Identifiers
AliasesP2RX7, P2X7, purinergic receptor P2X 7
External IDsOMIM: 602566; MGI: 1339957; HomoloGene: 1925; GeneCards: P2RX7; OMA:P2RX7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002562
NM_177427

NM_001038839
NM_001038845
NM_001038887
NM_001284402
NM_011027

RefSeq (protein)

NP_002553

NP_001033928
NP_001033934
NP_001033976
NP_001271331
NP_035157

Location (UCSC)Chr 12: 121.13 – 121.19 MbChr 5: 122.78 – 122.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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] Regarding inflammation, P2X7 receptor induces the NLRP3 inflammasome in myeloid cells and leads to interleukin-1beta release.[23]

Structure and kinetics

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The P2X7 subunits can form homomeric receptors only with a typical P2X receptor structure.[24] 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][25] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+).[25] P2X7 receptors do not become desensitized readily and continued signaling leads to the aforementioned increased permeability and an increase in current amplitude.[25]

Pharmacology

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Agonists

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  • P2X7 receptors respond to BzATP more readily than ATP.[25]
  • ADP and AMP are weak agonists of P2X7 receptors, but a brief exposure to ATP can increase their effectiveness.[25]
  • 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

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Receptor trafficking

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In microglia, P2X7 receptors are found mostly on the cell surface.[28] Conserved cysteine residues located in the carboxyl terminus seem to be important for receptor trafficking to the cell membrane.[29] These receptors are upregulated in response to peripheral nerve injury.[30]

In melanocytic cells P2X7 gene expression may be regulated by MITF.[31]

Recruitment of pannexin

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Activation of the P2X7 receptor by ATP leads to recruitment of pannexin pores[32] 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.[33] Moreover, this could be responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to larger molecules.

Clinical significance

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Inflammation

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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.[34] The CD38 enzyme on B lymphocytes and macrophages reduces extracellular NAD+, promoting the survival of T cells.[35]

Neuropathic pain

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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.[36][37] Moreover, P2X7 receptor signaling increases the release of proinflammatory molecules such as IL-1β, IL-6, and TNF-α.[38][39][40] In addition, P2X7 receptors have been linked to increases in proinflammatory cytokines such as CXCL2 and CCL3.[41][42] P2X7 receptors are also linked to P2X4 receptors, which are also associated with neuropathic pain mediated by microglia.[28]

Osteoporosis

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Mutations in this gene have been associated to low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women.[43]

Diabetes

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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.[44][45]

Research

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One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[46]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000089041Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029468Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A (February 1997). "The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA". The Journal of Biological Chemistry. 272 (9): 5482–6. doi:10.1074/jbc.272.9.5482. PMID 9038151.
  6. ^ 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.
  7. ^ "Entrez Gene: P2RX7 purinergic receptor P2X, ligand-gated ion channel, 7".
  8. ^ a b Faria RX, Freitas HR, Reis RA (June 2017). "P2X7 receptor large pore signaling in avian Müller glial cells". Journal of Bioenergetics and Biomembranes. 49 (3): 215–229. doi:10.1007/s10863-017-9717-9. PMID 28573491. S2CID 4122579.
  9. ^ a b Freitas HR, Reis RA (February 2017). "7R activation on Müller glia". Neurogenesis. 4 (1): e1283188. doi:10.1080/23262133.2017.1283188. PMC 5305167. PMID 28229088.
  10. ^ a b Freitas HR, Ferraz G, Ferreira GC, Ribeiro-Resende VT, Chiarini LB, do Nascimento JL, et al. (April 2016). "Glutathione-Induced Calcium Shifts in Chick Retinal Glial Cells". PLOS ONE. 11 (4): e0153677. Bibcode:2016PLoSO..1153677F. doi:10.1371/journal.pone.0153677. PMC 4831842. PMID 27078878.
  11. ^ Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, et al. (September 2001). "Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems". The Journal of Neuroscience. 21 (18): 7143–52. doi:10.1523/JNEUROSCI.21-18-07143.2001. PMC 6762981. PMID 11549725.
  12. ^ 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. S2CID 21491471.
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  21. ^ Gonzaga DT, Ferreira LB, Moreira Maramaldo Costa TE, von Ranke NL, Anastácio Furtado Pacheco P, Sposito Simões AP, et al. (October 2017). "1-Aryl-1H- and 2-aryl-2H-1,2,3-triazole derivatives blockade P2X7 receptor in vitro and inflammatory response in vivo". European Journal of Medicinal Chemistry. 139: 698–717. doi:10.1016/j.ejmech.2017.08.034. PMID 28858765.
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  26. ^ Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, et al. (August 2004). "P2X7 receptor inhibition improves recovery after spinal cord injury". Nature Medicine. 10 (8): 821–7. doi:10.1038/nm1082. PMID 15258577. S2CID 23685403.
  27. ^ Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, et al. (July 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): 12489–93. doi:10.1073/pnas.0902531106. PMC 2718350. PMID 19666625.
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Further reading

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