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P2X4

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Target id: 481

Nomenclature: P2X4

Family: P2X receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 388 12q24.31 P2RX4 purinergic receptor P2X 4 5
Mouse 2 388 5 62.53 cM P2rx4 purinergic receptor P2X, ligand-gated ion channel 4 17
Rat 2 388 12q16 P2rx4 purinergic receptor P2X 4 1-2,15-17,19
Previous and Unofficial Names Click here for help
P2X purinoceptor 4 | purinergic receptor P2X, ligand-gated ion channel, 4 | purinergic receptor P2X, ligand gated ion channel, 4 | purinergic receptor P2X
Database Links Click here for help
Alphafold Q99571 (Hs), Q9JJX6 (Mm), P51577 (Rn)
CATH/Gene3D 2.60.490.10
ChEMBL Target CHEMBL2104 (Hs), CHEMBL2176849 (Mm), CHEMBL2818 (Rn)
Ensembl Gene ENSG00000135124 (Hs), ENSMUSG00000029470 (Mm), ENSRNOG00000001300 (Rn)
Entrez Gene 5025 (Hs), 18438 (Mm), 29659 (Rn)
Human Protein Atlas ENSG00000135124 (Hs)
KEGG Gene hsa:5025 (Hs), mmu:18438 (Mm), rno:29659 (Rn)
OMIM 600846 (Hs)
Pharos Q99571 (Hs)
RefSeq Nucleotide NM_002560 (Hs), NM_011026 (Mm), NM_031594 (Rn)
RefSeq Protein NP_002551 (Hs), NP_035156 (Mm), NP_113782 (Rn)
UniProtKB Q99571 (Hs), Q9JJX6 (Mm), P51577 (Rn)
Wikipedia P2RX4 (Hs)
Natural/Endogenous Ligands Click here for help
ATP

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ATP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 5.9 – 6.3 pEC50 7,9
⤷ pEC50 6.3 (EC50 5x10-7 M) [7]
pEC50 5.9 (EC50 1.259x10-6 M) [9]
ATP Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Agonist 5.6 – 6.0 pEC50 7,9
⤷ pEC50 6.0 (EC50 1x10-6 M) [7]
pEC50 5.6 (EC50 2.511x10-6 M) [9]
ATP Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Agonist 5.3 pEC50 9
⤷ pEC50 5.3 (EC50 5.011x10-6 M) [9]
αβ-meATP Small molecule or natural product Ligand has a PDB structure Mm Partial agonist 5.2 pEC50 9
⤷ pEC50 5.2 (EC50 6.309x10-6 M) [9]
αβ-meATP Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 4.7 pEC50 9
⤷ pEC50 4.7 (EC50 1.995x10-5 M) [9]
BzATP Small molecule or natural product Click here for species-specific activity table Hs Agonist - -
⤷
αβ-meATP Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - -
⤷
View species-specific agonist tables
Agonist Comments
2MeSATP and CTP are partial agonists at the human P2X4 receptor [5].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BAY-1797 Small molecule or natural product Hs Antagonist 7.0 pIC50 20
⤷ pIC50 7.0 (IC50 1x10-7 M) [20]
PSB-12054 Small molecule or natural product Hs Antagonist 6.7 pIC50 6
⤷ pIC50 6.7 (IC50 1.99x10-7 M) [6]
NP-1815-PX Small molecule or natural product Hs Antagonist 6.6 pIC50 11
⤷ pIC50 6.6 (IC50 2.51x10-7 M) [11]
paroxetine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.0 – 6.0 pIC50 8,12
⤷ pIC50 5.0 – 6.0 [8,12]
5-BDBD Small molecule or natural product Hs Antagonist 5.0 – 6.0 pIC50 8,12
⤷ pIC50 5.0 – 6.0 [8,12]
PSB-12062 Small molecule or natural product Hs Antagonist 5.0 – 6.0 pIC50 8,12
⤷ pIC50 5.0 – 6.0 [8,12]
BX-430 Small molecule or natural product Hs Antagonist 5.0 – 6.0 pIC50 8,12
⤷ pIC50 5.0 – 6.0 [8,12]
PPADS Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.0 pIC50 9
⤷ pIC50 5.0 (IC50 1x10-5 M) [9]
PPADS Small molecule or natural product Mm Antagonist 5.0 pIC50 9
⤷ pIC50 5.0 (IC50 1x10-5 M) [9]
View species-specific antagonist tables
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
ivermectin Small molecule or natural product Approved drug Rn Positive ~6.6 pEC50 - no 10
⤷ pEC50 ~6.6 (EC50 ~2.5x10-7 M) [10]
Not voltage dependent
nimodipine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Positive - - - no 14
⤷ [14]
Not voltage dependent
amlodipine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Negative - - - no 14
⤷ [14]
Not voltage dependent
View species-specific allosteric modulator tables
Immunopharmacology Comments
P2X ligand-gated ion channels elicit pro-inflammatory immune responses upon activation by extracellular ATP that acts as a DAMP when released from damaged or infected cells [3-4].
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Comment:  Human B cells express all P2 receptor subtypes.
References:  13
Immuno Cell Type:  T cells
Comment:  T cells express P2X receptors 1, 4 and 5. ATP-induced activation of these receptors in T cells is associated with proliferation, cytokine production and thymocyte apoptosis.
References:  4,18
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:1904141 positive regulation of microglial cell migration ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:1904141 positive regulation of microglial cell migration ISS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:1904141 positive regulation of microglial cell migration ISS

References

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1. Bo X, Zhang Y, Nassar M, Burnstock G, Schoepfer R. (1995) A P2X purinoceptor cDNA conferring a novel pharmacological profile. FEBS Lett, 375 (1-2): 129-33. [PMID:7498461]

2. Buell G, Lewis C, Collo G, North RA, Surprenant A. (1996) An antagonist-insensitive P2X receptor expressed in epithelia and brain. EMBO J, 15 (1): 55-62. [PMID:8598206]

3. Burnstock G, Boeynaems JM. (2014) Purinergic signalling and immune cells. Purinergic Signal, 10 (4): 529-64. [PMID:25352330]

4. Cekic C, Linden J. (2016) Purinergic regulation of the immune system. Nat Rev Immunol, 16 (3): 177-92. [PMID:26922909]

5. Garcia-Guzman M, Soto F, Gomez-Hernandez JM, Lund PE, Stühmer W. (1997) Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue. Mol Pharmacol, 51 (1): 109-18. [PMID:9016352]

6. Hernandez-Olmos V, Abdelrahman A, El-Tayeb A, Freudendahl D, Weinhausen S, Müller CE. (2012) N-substituted phenoxazine and acridone derivatives: structure-activity relationships of potent P2X4 receptor antagonists. J Med Chem, 55 (22): 9576-88. [PMID:23075067]

7. Jacobson KA, Jarvis MF, Williams M. (2002) Purine and pyrimidine (P2) receptors as drug targets. J Med Chem, 45 (19): 4057-93. [PMID:12213051]

8. Jacobson KA, Müller CE. (2016) Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology, 104: 31-49. [PMID:26686393]

9. Jones CA, Chessell IP, Simon J, Barnard EA, Miller KJ, Michel AD, Humphrey PP. (2000) Functional characterization of the P2X(4) receptor orthologues. Br J Pharmacol, 129 (2): 388-94. [PMID:10694247]

10. Khakh BS, Proctor WR, Dunwiddie TV, Labarca C, Lester HA. (1999) Allosteric control of gating and kinetics at P2X(4) receptor channels. J Neurosci, 19 (17): 7289-99. [PMID:10460235]

11. Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, Tozaki-Saitoh H, Imai T, Kuraishi Y, Tsuda M et al.. (2016) A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci Rep, 6: 32461. [PMID:27576299]

12. North RA, Jarvis MF. (2013) P2X receptors as drug targets. Mol Pharmacol, 83 (4): 759-69. [PMID:23253448]

13. Przybyła T, Sakowicz-Burkiewicz M, Pawełczyk T. (2018) Purinergic signaling in B cells. Acta Biochim Pol, 65 (1): 1-7. [PMID:29360885]

14. Schiller IC, Jacobson KA, Wen Z, Malisetty A, Schmalzing G, Markwardt F. (2022) Dihydropyridines Potentiate ATP-Induced Currents Mediated by the Full-Length Human P2X5 Receptor. Molecules, 27 (6). [PMID:35335209]

15. Soto F, Garcia-Guzman M, Gomez-Hernandez JM, Hollmann M, Karschin C, Stühmer W. (1996) P2X4: an ATP-activated ionotropic receptor cloned from rat brain. Proc Natl Acad Sci USA, 93 (8): 3684-8. [PMID:8622997]

16. Séguéla P, Haghighi A, Soghomonian JJ, Cooper E. (1996) A novel neuronal P2x ATP receptor ion channel with widespread distribution in the brain. J Neurosci, 16 (2): 448-55. [PMID:8551329]

17. Townsend-Nicholson A, King BF, Wildman SS, Burnstock G. (1999) Molecular cloning, functional characterization and possible cooperativity between the murine P2X4 and P2X4a receptors. Brain Res Mol Brain Res, 64 (2): 246-54. [PMID:9931497]

18. Vaeth M, Feske S. (2018) Ion channelopathies of the immune system. Curr Opin Immunol, 52: 39-50. [PMID:29635109]

19. Wang CZ, Namba N, Gonoi T, Inagaki N, Seino S. (1996) Cloning and pharmacological characterization of a fourth P2X receptor subtype widely expressed in brain and peripheral tissues including various endocrine tissues. Biochem Biophys Res Commun, 220 (1): 196-202. [PMID:8602843]

20. Werner S, Mesch S, Hillig RC, Ter Laak A, Klint J, Neagoe I, Laux-Biehlmann A, Dahllöf H, Bräuer N, Puetter V et al.. (2019) Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure-Guided Amelioration of Its CYP3A4 Induction Profile. J Med Chem, 62 (24): 11194-11217. [PMID:31746599]

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