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P2RX4

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P2RX4
Identifiers
AliasesP2RX4, P2X4, P2X4R, purinergic receptor P2X 4
External IDsOMIM: 600846; MGI: 1338859; HomoloGene: 1923; GeneCards: P2RX4; OMA:P2RX4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5025

18438

Ensembl

ENSG00000135124

ENSMUSG00000029470

UniProt

Q99571

Q9JJX6

RefSeq (mRNA)

NM_011026
NM_001310718
NM_001310720

RefSeq (protein)

NP_001243725
NP_001248326
NP_001248327
NP_002551

n/a

Location (UCSC)Chr 12: 121.21 – 121.23 MbChr 5: 122.85 – 122.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene. P2X purinoceptor 4 is a member of the P2X receptor family.[5][6][7] P2X receptors are trimeric protein complexes that can be homomeric or heteromeric. These receptors are ligand-gated cation channels that open in response to ATP binding.[8] Each receptor subtype, determined by the subunit composition, varies in its affinity to ATP and desensitization kinetics.

The P2X4 receptor is the homotrimer composed of three P2X4 monomers.[5] They are nonselective cation channels with high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes.[9][10][11] The P2X4 receptor is uniquely expressed on lysosomal compartments as well as the cell surface.[12]

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.[13] 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.[12][14][15][16][17][18]

Structure

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Ribbon structures of (A) the P2X4 homotrimeric receptor and (B) the subunit monomer

P2X receptors are composed of three subunits that can be homomeric or heteromeric by nature. In mammals, there are seven different subunits, each encoded in a different gene (P2RX1-P2RX7).[5] Each subunit has two transmembrane alpha helices (TM1 and TM2) linked by a large extracellular loop.[5][12][19] Analysis of x-ray crystallographic structures revealed a 'dolphin-like' tertiary structure, where the 'tail' is embedded in the phospholipid bilayer and the upper and lower ectodomains form the 'head' and 'body' respectively.[12][19][20] Adjacent interfaces of the subunits form a deep binding pocket for ATP.[12][19] ATP binding to these orthosteric sites causes a shift in conformation opening the channel pore.

The P2X4 subunits can form homomeric or heteromeric receptors.[21] In 2009, the first purinergic receptor crystallized was the closed state homomeric zebrafish P2X4 receptor.[22][19] Although truncated at its N- and C- termini, this crystal structure resolved and confirmed that these proteins were indeed trimers with an ectodomain rich with disulfide bonds.[5][12]

Gating mechanism

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Schematic of the P2X4 receptor conformational states

P2X receptors have three confirmed conformational states: ATP-unbound closed, ATP-bound open, and ATP-bound desensitized.[12][19] Imaging of the human P2X3 and rat P2X7 receptors has revealed structural similarities and differences in their cytoplasmic domains. In the ATP-bound state, both receptor types form beta sheet structures from N- and C- termini of adjacent subunits.[12][19] These newly folded secondary structures come together to form a 'cytoplasmic cap' that helps stabilize the open pore. Crystal structures of the desensitized receptor no longer exhibit the cytoplasmic cap.[12][19]

Desensitization

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Electrophysiology studies have revealed differences in the rates of receptor desensitization between different P2X subtypes.[5][12] Homotrimers P2X1 and P2X3 are the fastest, with desensitization observed milliseconds after activation, while P2X2 and P2X4 receptors are on the timescale of seconds. Notably, the P2X7 receptor uniquely does not undergo desensitization.[12] Mutational studies working with the rat P2X2 and P2X3 receptors have identified three residues in the N-terminus that majorly contribute to these differences. By changing the amino acids in the P2X3 to match the analogous P2X2, the desensitization rate slowed down. Conversely, changing residues of P2X2 to match P2X3 increased the desensitization rate.[19] In combination with the open state crystal structures, it was hypothesized that the cytoplasmic cap was stabilizing the open pore conformation.[12][19]

Additionally, structural analysis of the open P2X3 receptor revealed transient changes in TM2, the transmembrane alpha helix lining the pore. While in the open state conformation, a small mid-region of TM2 develops into a 310-helix.[12][19] This helical structure disappears with desensitization and instead TM2 reforms as a complete alpha helix repositioned closer to the extracellular side.[12]

The helical recoil model uses the observed structural changes in TM2 and the transient formation of the cytoplasmic cap to describe a possible mechanism for the desensitization of P2X receptors. In this model, it is theorized that the cytoplasmic cap fixes the intracellular end of the TM2 helix while stretching its extracellular end to allow ion influx.[19] This would induce the observed 310-helix. The cap then disassembles and releases its hold on TM2 causing the helix to recoil towards the outer leaflet of the membrane.[12][19]

In support of this theory, the P2X7 uniquely has a large cytoplasmic domain with palmitoylated C-cysteine anchor sites.[5][12][19] These sites further stabilize its cytoplasmic cap by anchoring the domain into the surrounding inner leaflet. Mutations of the associated palmitoylation site residues cause observed atypical desensitization of the receptor.[12]

Receptor trafficking

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P2X4 receptors are functionally expressed on both the cell surface and in lysosomes.[20] Although preferentially localized and stored in lysosomes, P2X4 receptors are brought to the cell surface in response to extracellular signals.[23] These signals include IFN-γ, CCL21, CCL2.[24][25][26] Fibronectin is also involved in upregulation of P2X4 receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn.[27] Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.[28] Internalization of P2X4 receptors is clathrin- and dynamin-dependent endocytosis.[29]

Pharmacology

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Agonists

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P2X4 receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.[8]

Antagonists

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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[8]

Neuropathic pain

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The P2X4 receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo.[30][31] P2X4 receptors are upregulated following injury.[32] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.[33] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.[34] 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.[35]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135124 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029470 – 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.
  5. ^ a b c d e f g Suurväli J, Boudinot P, Kanellopoulos J, Rüütel Boudinot S (October 2017). "P2X4: A fast and sensitive purinergic receptor". Biomedical Journal. 40 (5): 245–256. doi:10.1016/j.bj.2017.06.010. PMC 6138603. PMID 29179879.
  6. ^ Garcia-Guzman M, Soto F, Gomez-Hernandez JM, Lund PE, Stühmer W (January 1997). "Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue". Molecular Pharmacology. 51 (1): 109–118. doi:10.1124/mol.51.1.109. PMID 9016352.
  7. ^ "Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".
  8. ^ a b c North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–1067. doi:10.1152/physrev.00015.2002. PMID 12270951.
  9. ^ North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–1067. doi:10.1152/physrev.00015.2002. PMID 12270951.
  10. ^ Shigetomi E, Kato F (March 2004). "Action potential-independent release of glutamate by Ca2+ entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network". The Journal of Neuroscience. 24 (12): 3125–3135. doi:10.1523/JNEUROSCI.0090-04.2004. PMC 6729830. PMID 15044552.
  11. ^ Koshimizu TA, Van Goor F, Tomić M, Wong AO, Tanoue A, Tsujimoto G, Stojilkovic SS (November 2000). "Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells". Molecular Pharmacology. 58 (5): 936–945. doi:10.1124/mol.58.5.936. PMID 11040040.
  12. ^ a b c d e f g h i j k l m n o p q Kanellopoulos JM, Almeida-da-Silva CL, Rüütel Boudinot S, Ojcius DM (2021-03-25). "Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective". Frontiers in Immunology. 12: 645834. doi:10.3389/fimmu.2021.645834. PMC 8059410. PMID 33897694.
  13. ^ Bo X, Kim M, Nori SL, Schoepfer R, Burnstock G, North RA (August 2003). "Tissue distribution of P2X4 receptors studied with an ectodomain antibody". Cell and Tissue Research. 313 (2): 159–165. doi:10.1007/s00441-003-0758-5. PMID 12845522. S2CID 18060944.
  14. ^ Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, et al. (March 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.
  15. ^ Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, et al. (May 2007). "Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4". American Journal of Physiology. Renal Physiology. 292 (5): F1537–F1547. doi:10.1152/ajprenal.00440.2006. hdl:11573/412000. PMID 17264311. S2CID 18668753.
  16. ^ Shen JB, Pappano AJ, Liang BT (February 2006). "Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors". FASEB Journal. 20 (2): 277–284. doi:10.1096/fj.05-4749com. PMID 16449800. S2CID 7174797.
  17. ^ Baxter AW, Choi SJ, Sim JA, North RA (July 2011). "Role of P2X4 receptors in synaptic strengthening in mouse CA1 hippocampal neurons". The European Journal of Neuroscience. 34 (2): 213–220. doi:10.1111/j.1460-9568.2011.07763.x. PMC 3763203. PMID 21749490.
  18. ^ de Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich WD, De Koninck Y, et al. (February 2012). "P2X4 receptors influence inflammasome activation after spinal cord injury". The Journal of Neuroscience. 32 (9): 3058–3066. doi:10.1523/JNEUROSCI.4930-11.2012. PMC 6622016. PMID 22378878.
  19. ^ a b c d e f g h i j k l m Mansoor SE (2022). "How Structural Biology Has Directly Impacted Our Understanding of P2X Receptor Function and Gating". In Nicke A (ed.). The P2X7 Receptor. Methods in Molecular Biology. Vol. 2510. New York, NY: Springer US. pp. 1–29. doi:10.1007/978-1-0716-2384-8_1. ISBN 978-1-0716-2384-8. PMID 35776317.
  20. ^ a b Sophocleous RA, Ooi L, Sluyter R (May 2022). "The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target". International Journal of Molecular Sciences. 23 (10): 5739. doi:10.3390/ijms23105739. PMC 9147237. PMID 35628550.
  21. ^ Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (September 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.
  22. ^ Kawate T, Michel JC, Birdsong WT, Gouaux E (July 2009). "Crystal structure of the ATP-gated P2X(4) ion channel in the closed state". Nature. 460 (7255): 592–598. Bibcode:2009Natur.460..592K. doi:10.1038/nature08198. PMC 2720809. PMID 19641588.
  23. ^ Qureshi OS, Paramasivam A, Yu JC, Murrell-Lagnado RD (November 2007). "Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis". Journal of Cell Science. 120 (Pt 21): 3838–3849. doi:10.1242/jcs.010348. PMID 17940064.
  24. ^ Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (May 2009). "IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain". Proceedings of the National Academy of Sciences of the United States of America. 106 (19): 8032–8037. Bibcode:2009PNAS..106.8032T. doi:10.1073/pnas.0810420106. PMC 2683100. PMID 19380717.
  25. ^ Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, et al. (May 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.
  26. ^ Toyomitsu E, Tsuda M, Yamashita T, Tozaki-Saitoh H, Tanaka Y, Inoue K (June 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.
  27. ^ Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T, Inoue K (January 2008). "Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury". Glia. 56 (1): 50–58. doi:10.1002/glia.20591. PMID 17918263. S2CID 8834339.
  28. ^ Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K (September 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. PMC 4516482. PMID 19298529.
  29. ^ Royle SJ, Bobanović LK, Murrell-Lagnado RD (September 2002). "Identification of a non-canonical tyrosine-based endocytic motif in an ionotropic receptor". The Journal of Biological Chemistry. 277 (38): 35378–35385. doi:10.1074/jbc.M204844200. PMID 12105201.
  30. ^ Ulmann L, Hirbec H, Rassendren F (July 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.
  31. ^ Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K (June 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.
  32. ^ Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, et al. (October 2008). "Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain". The Journal of Neuroscience. 28 (44): 11263–11268. doi:10.1523/JNEUROSCI.2308-08.2008. PMC 6671487. PMID 18971468.
  33. ^ Trang T, Beggs S, Wan X, Salter MW (March 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". The Journal of Neuroscience. 29 (11): 3518–3528. doi:10.1523/JNEUROSCI.5714-08.2009. PMC 3589565. PMID 19295157.
  34. ^ Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. (December 2005). "BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain". Nature. 438 (7070): 1017–1021. Bibcode:2005Natur.438.1017C. doi:10.1038/nature04223. PMID 16355225. S2CID 4403946.
  35. ^ Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (August 2003). "P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury". Nature. 424 (6950): 778–783. Bibcode:2003Natur.424..778T. doi:10.1038/nature01786. PMID 12917686. S2CID 4358793.

Further reading

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

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