P2RX4

Purinergic receptor P2X, ligand gated ion channel, 4
Identifiers
Symbols P2RX4 ; P2X4; P2X4R
External IDs OMIM: 600846 MGI: 1338859 HomoloGene: 1923 IUPHAR: 481 ChEMBL: 2104 GeneCards: P2RX4 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 5025 18438
Ensembl ENSG00000135124 ENSMUSG00000029470
UniProt Q99571 Q9JJX6
RefSeq (mRNA) NM_001256796 NM_011026
RefSeq (protein) NP_001243725 NP_035156
Location (UCSC) Chr 12:
121.21 – 121.23 Mb		 Chr 5:
122.71 – 122.73 Mb
PubMed search

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.[1][2] The product of this gene belongs to the family of purinoceptors for ATP. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.[2]

The receptor is found in the central and peripheral nervous systems, in the epithelia of ducted glands and airways, in the smooth muscle of the bladder, gastrointestinal tract, uterus, and arteries, in uterine endometrium, and in fat cells.[3] P2X4 receptors have been implicated in the regulation of cardiac function, ATP-mediated cell death, synaptic strengthening, and activating of the inflammasome in response to injury.[4][5][6][7][8]

Receptor Structure and Kinetics

The P2X4 subunits can form homomeric or heteromeric receptors.[9] The P2X4 receptor has a typical P2X receptor structure. The zebrafish P2X4 receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.[10] The P2X4 receptor is a ligand-gated cation channel that opens in response to ATP binding.[11] The P2X4 receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes.[11][12][13] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+) in about 50% of the cells expressing the P2X4 receptor.[11] The desensitization of P2X4 receptors is intermediate when compared to P2X1 and P2X2 receptors.[11]

Pharmacology

Agonists

P2X4 receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.[11]

Antagonists

The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The product of this gene has the lowest sensitivity for these antagonists[11]

Receptor Trafficking

P2X4 receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals.[14] These signals include IFN-γ, CCL21, CCL2.[15][16][17] Fibronectin is also involved in upregulation of P2X4 receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn.[18] Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.[19] Internalization of P2X4 receptors is clathrin- and dynamin-dependent endocytosis.[20]

Neuropathic Pain

The P2X4 receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo.[21][22] P2X4 receptors are upregulated following injury.[23] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.[24] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.[25] More importantly, recent work shows that P2X4 receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.[26]

See also

References

  1. ↑ Garcia-Guzman M, Soto F, Gomez-Hernandez JM, Lund PE, Stuhmer W (Feb 1997). "Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue". Mol Pharmacol 51 (1): 109–18. PMID 9016352.
  2. 1 2 "Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".
  3. ↑ Bo, X.; Kim, M.; Nori, S. L.; Schoepfer, R.; Burnstock, G.; North, R. A. (2003). "Tissue distribution of P2X 4 receptors studied with an ectodomain antibody". Cell and Tissue Research 313 (2): 159–165. doi:10.1007/s00441-003-0758-5. PMID 12845522.
  4. ↑ Kawano, A.; Tsukimoto, M.; Noguchi, T.; Hotta, N.; Harada, H.; Takenouchi, T.; Kitani, H.; Kojima, S. (2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages". Biochemical and Biophysical Research Communications 419 (2): 374–380. doi:10.1016/j.bbrc.2012.01.156. PMID 22349510.
  5. ↑ Solini, A.; Santini, E.; Chimenti, D.; Chiozzi, P.; Pratesi, F.; Cuccato, S.; Falzoni, S.; Lupi, R.; Ferrannini, E.; Pugliese, G.; Virgilio, F. D. (2007). "Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: Evidence for a role of P2X4". AJP: Renal Physiology 292 (5): F1537–F1547. doi:10.1152/ajprenal.00440.2006. PMID 17264311.
  6. ↑ Shen, J. -B.; Pappano, A. J.; Liang, B. T. (2006). "Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: Implications for a cardiac physiologic role of P2X4 receptors". The FASEB Journal 20 (2): 277–284. doi:10.1096/fj.05-4749com. PMID 16449800.
  7. ↑ Baxter, A. W.; Choi, S. J.; Sim, J. A.; North, R. A. (2011). "Role of P2X4 receptors in synaptic strengthening in mouse CA1 hippocampal neurons". European Journal of Neuroscience 34 (2): 213–220. doi:10.1111/j.1460-9568.2011.07763.x. PMID 21749490.
  8. ↑ De Rivero Vaccari, J. P.; Bastien, D.; Yurcisin, G.; Pineau, I.; Dietrich, W. D.; De Koninck, Y.; Keane, R. W.; Lacroix, S. (2012). "P2X4 Receptors Influence Inflammasome Activation after Spinal Cord Injury". Journal of Neuroscience 32 (9): 3058–3066. doi:10.1523/JNEUROSCI.4930-11.2012. PMID 22378878.
  9. ↑ Kaczmarek-Hájek, K.; Lörinczi, É.; Hausmann, R.; Nicke, A. (2012). "Molecular and functional properties of P2X receptors—recent progress and persisting challenges". Purinergic Signalling 8 (3): 375–417. doi:10.1007/s11302-012-9314-7. PMC 3360091. PMID 22547202.
  10. ↑ Kawate, T.; Michel, J. C.; Birdsong, W. T.; Gouaux, E. (2009). "Crystal structure of the ATP-gated P2X4 ion channel in the closed state". Nature 460 (7255): 592–598. doi:10.1038/nature08198. PMC 2720809. PMID 19641588.
  11. 1 2 3 4 5 6 North, R. A. (2002). "Molecular physiology of P2X receptors". Physiological reviews 82 (4): 1013–1067. doi:10.1152/physrev.00015.2002. PMID 12270951.
  12. ↑ Shigetomi, E.; Kato, F. (2004). "Action Potential-Independent Release of Glutamate by Ca2+ Entry through Presynaptic P2X Receptors Elicits Postsynaptic Firing in the Brainstem Autonomic Network". Journal of Neuroscience 24 (12): 3125–3135. doi:10.1523/JNEUROSCI.0090-04.2004. PMID 15044552.
  13. ↑ Koshimizu, T. A.; Van Goor, F.; Tomić, M.; Wong, A. O.; Tanoue, A.; Tsujimoto, G.; Stojilkovic, S. S. (2000). "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells". Molecular Pharmacology 58 (5): 936–945. PMID 11040040.
  14. ↑ Qureshi, O. S.; Paramasivam, A.; Yu, J. C. H.; Murrell-Lagnado, R. D. (2007). "Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis". Journal of Cell Science 120 (21): 3838–3849. doi:10.1242/jcs.010348. PMID 17940064.
  15. ↑ Tsuda, M.; Masuda, T.; Kitano, J.; Shimoyama, H.; Tozaki-Saitoh, H.; Inoue, K. (2009). "IFN- receptor signaling mediates spinal microglia activation driving neuropathic pain". Proceedings of the National Academy of Sciences 106 (19): 8032–8037. doi:10.1073/pnas.0810420106. PMC 2683100. PMID 19380717.
  16. ↑ Biber, K.; Tsuda, M.; Tozaki-Saitoh, H.; Tsukamoto, K.; Toyomitsu, E.; Masuda, T.; Boddeke, H.; Inoue, K. (2011). "Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development". The EMBO Journal 30 (9): 1864–1873. doi:10.1038/emboj.2011.89. PMC 3101996. PMID 21441897.
  17. ↑ Toyomitsu, E.; Tsuda, M.; Yamashita, T.; Tozaki-Saitoh, H.; Tanaka, Y.; Inoue, K. (2012). "CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia". Purinergic Signalling 8 (2): 301–310. doi:10.1007/s11302-011-9288-x. PMC 3350584. PMID 22222817.
  18. ↑ Tsuda, M.; Tozaki-Saitoh, H.; Masuda, T.; Toyomitsu, E.; Tezuka, T.; Yamamoto, T.; Inoue, K. (2008). "Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury". Glia 56 (1): 50–58. doi:10.1002/glia.20591. PMID 17918263.
  19. ↑ Tsuda, M.; Toyomitsu, E.; Kometani, M.; Tozaki-Saitoh, H.; Inoue, K. (2009). "Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: Distinct roles of PI3K-Akt and MEK-ERK signalling pathways". Journal of Cellular and Molecular Medicine 13 (9b): 3251–3259. doi:10.1111/j.1582-4934.2009.00719.x. PMID 19298529.
  20. ↑ Royle, S. J.; Bobanović, L. K.; Murrell-Lagnado, R. D. (2002). "Identification of a Non-canonical Tyrosine-based Endocytic Motif in an Ionotropic Receptor". Journal of Biological Chemistry 277 (38): 35378–35385. doi:10.1074/jbc.M204844200. PMID 12105201.
  21. ↑ Ulmann, L.; Hirbec, H. L. N.; Rassendren, F. O. (2010). "P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain". The EMBO Journal 29 (14): 2290–2300. doi:10.1038/emboj.2010.126. PMC 2910276. PMID 20562826.
  22. ↑ Tsuda, M.; Kuboyama, K.; Inoue, T.; Nagata, K.; Tozaki-Saitoh, H.; Inoue, K. (2009). "Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays". Molecular Pain 5: 28. doi:10.1186/1744-8069-5-28. PMC 2704200. PMID 19515262.
  23. ↑ Ulmann, L.; Hatcher, J. P.; Hughes, J. P.; Chaumont, S.; Green, P. J.; Conquet, F.; Buell, G. N.; Reeve, A. J.; Chessell, I. P.; Rassendren, F. (2008). "Up-Regulation of P2X4 Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain". Journal of Neuroscience 28 (44): 11263–11268. doi:10.1523/JNEUROSCI.2308-08.2008. PMID 18971468.
  24. ↑ Trang, T.; Beggs, S.; Wan, X.; Salter, M. W. (2009). "P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation". Journal of Neuroscience 29 (11): 3518–3528. doi:10.1523/JNEUROSCI.5714-08.2009. PMC 3589565. PMID 19295157.
  25. ↑ Coull, J. A. M.; Beggs, S.; Boudreau, D.; Boivin, D.; Tsuda, M.; Inoue, K.; Gravel, C.; Salter, M. W.; De Koninck, Y. (2005). "BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain". Nature 438 (7070): 1017–1021. doi:10.1038/nature04223. PMID 16355225.
  26. ↑ Tsuda, M.; Shigemoto-Mogami, Y.; Koizumi, S.; Mizokoshi, A.; Kohsaka, S.; Salter, M. W.; Inoue, K. (2003). "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury". Nature 424 (6950): 778–783. doi:10.1038/nature01786. PMID 12917686.

Further reading

  • North RA (2002). "Molecular physiology of P2X receptors". Physiol. Rev. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951. 
  • Maruyama K, Sugano S (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. 
  • Garcia-Guzman M, Stühmer W, Soto F (1997). "Molecular characterization and pharmacological properties of the human P2X3 purinoceptor". Brain Res. Mol. Brain Res. 47 (1–2): 59–66. doi:10.1016/S0169-328X(97)00036-3. PMID 9221902. 
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (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. 
  • Korenaga R, Yamamoto K, Ohura N, et al. (2001). "Sp1-mediated downregulation of P2X4 receptor gene transcription in endothelial cells exposed to shear stress". Am. J. Physiol. Heart Circ. Physiol. 280 (5): H2214–21. PMID 11299224. 
  • Glass R, Loesch A, Bodin P, Burnstock G (2002). "P2X4 and P2X6 receptors associate with VE-cadherin in human endothelial cells". Cell. Mol. Life Sci. 59 (5): 870–81. doi:10.1007/s00018-002-8474-y. PMID 12088286. 
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
  • Yamamoto K, Sokabe T, Ohura N, et al. (2003). "Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells". Am. J. Physiol. Heart Circ. Physiol. 285 (2): H793–803. doi:10.1152/ajpheart.01155.2002. PMID 12714321. 
  • Yeung D, Kharidia R, Brown SC, Górecki DC (2004). "Enhanced expression of the P2X4 receptor in Duchenne muscular dystrophy correlates with macrophage invasion". Neurobiol. Dis. 15 (2): 212–20. doi:10.1016/j.nbd.2003.10.014. PMID 15006691. 
  • Yang A, Sonin D, Jones L, et al. (2004). "A beneficial role of cardiac P2X4 receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy". Am. J. Physiol. Heart Circ. Physiol. 287 (3): H1096–103. doi:10.1152/ajpheart.00079.2004. PMID 15130891. 
  • Brown DA, Bruce JI, Straub SV, Yule DI (2004). "cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells". J. Biol. Chem. 279 (38): 39485–94. doi:10.1074/jbc.M406201200. PMID 15262999. 
  • Fountain SJ, North RA (2006). "A C-terminal lysine that controls human P2X4 receptor desensitization". J. Biol. Chem. 281 (22): 15044–9. doi:10.1074/jbc.M600442200. PMID 16533808. 
  • Jelínková I, Yan Z, Liang Z, et al. (2006). "Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation". Biochem. Biophys. Res. Commun. 349 (2): 619–25. doi:10.1016/j.bbrc.2006.08.084. PMID 16949036. 
  • Solini A, Santini E, Chimenti D, et al. (2007). "Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4". Am. J. Physiol. Renal Physiol. 292 (5): F1537–47. doi:10.1152/ajprenal.00440.2006. PMID 17264311. 

External links

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