P2RX7

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
Orthologs
SpeciesHumanMouse
Entrez

5027

18439

Ensembl

ENSG00000089041

ENSMUSG00000029468

UniProt

Q99572

Q9Z1M0

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
Part of a series on
Purinergic signalling
Simplified illustration of extracellular purinergic signalling
Concepts

Purinergic signalling
Membrane transporters

Nucleoside transporters

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]

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.[43][44]

Research

One study in mice showed that blockade of P2X7 receptors attenuates onset of liver fibrosis.[45]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000089041 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029468 - Ensembl, 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.
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  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".
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  9. 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.
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Further reading

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