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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
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

P2X purinoceptor 4is aproteinthat in humans is encoded by theP2RX4gene.P2X purinoceptor 4 is a member of theP2X receptorfamily.[5][6][7]P2X receptors aretrimericprotein complexes that can behomomericorheteromeric.These receptors areligand-gated cation channelsthat open in response to ATP binding.[8]Each receptor subtype, determined by the subunit composition, varies in its affinity to ATP anddesensitization kinetics.

TheP2X4receptoris thehomotrimercomposed of three P2X4monomers.[5]They are nonselective cation channels with highcalciumpermeability, leading to thedepolarizationof the cell membrane and the activation of various Ca2+-sensitive intracellular processes.[9][10][11]The P2X4receptor is uniquely expressed onlysosomal compartmentsas well as thecell 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 thebladder,gastrointestinal tract,uterus,andarteries,in uterineendometrium,and infat cells.[13]P2X4receptors have been implicated in the regulation of cardiac function, ATP-mediatedcell death,synaptic strengthening,and activating of theinflammasomein 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 twotransmembraneAlpha helices(TM1 and TM2) linked by a large extracellular loop.[5][12][19]Analysis ofx-ray crystallographicstructures revealed a 'dolphin-like'tertiary structure,where the 'tail' is embedded in thephospholipid bilayerand the upper and lowerectodomainsform 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 theseorthostericsites causes a shift inconformationopening the channel pore.

The P2X4subunits can form homomeric or heteromeric receptors.[21]In 2009, the first purinergic receptor crystallized was the closed state homomericzebrafishP2X4receptor.[22][19]Although truncated at itsN-andC- termini,thiscrystal structureresolved and confirmed that these proteins were indeedtrimerswith an ectodomain rich withdisulfide 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 P2X3and rat P2X7receptors has revealed structural similarities and differences in their cytoplasmic domains. In the ATP-bound state, both receptor types formbeta sheetstructures from N- and C- termini of adjacent subunits.[12][19]These newly foldedsecondary structurescome 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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Electrophysiologystudies have revealed differences in the rates of receptor desensitization between different P2X subtypes.[5][12]HomotrimersP2X1and P2X3are the fastest, with desensitization observed milliseconds after activation, while P2X2and P2X4receptors are on the timescale of seconds. Notably, the P2X7receptor uniquely does not undergo desensitization.[12]Mutational studies working with the rat P2X2and P2X3receptors have identified threeresiduesin the N-terminus that majorly contribute to these differences. By changing theamino acidsin the P2X3to match the analogous P2X2,the desensitization rate slowed down. Conversely, changing residues of P2X2to match P2X3increased 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 P2X3receptor 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 a310-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 P2X7uniquely has a large cytoplasmic domain withpalmitoylatedC-cysteine anchorsites.[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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P2X4receptors are functionally expressed on both the cell surface and in lysosomes.[20]Although preferentially localized and stored inlysosomes,P2X4receptors are brought to the cell surface in response to extracellular signals.[23]These signals includeIFN-γ,CCL21,CCL2.[24][25][26]Fibronectinis also involved in upregulation of P2X4receptors through interactions withintegrinsthat lead to the activation ofSRC-family kinasemember,Lyn.[27]Lyn then activatesPI3K-AKTandMEK-ERKsignaling pathways to stimulate receptor trafficking.[28]Internalization of P2X4receptors isclathrin- anddynamin-dependentendocytosis.[29]

Pharmacology

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Agonists

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P2X4receptors respond to ATP, but not αβmeATP. These receptors are also potentiated byivermectin,cibacron blue, andzinc.[8]

Antagonists

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The main pharmacological distinction between the members of thepurinoceptorfamily is the relative sensitivity to the antagonistssuraminand 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 P2X4receptor has been linked toneuropathic painmediated bymicrogliain vitroandin vivo.[30][31]P2X4receptors are upregulated following injury.[32]This upregulation allows for increased activation ofp38 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 theTrkB receptor.[34]More importantly, recent work shows that P2X4receptor 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. ^abcGRCh38: Ensembl release 89: ENSG00000135124–Ensembl,May 2017
  2. ^abcGRCm38: 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. ^abcdefgSuurväli 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.PMC6138603.PMID29179879.
  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.PMID9016352.
  7. ^"Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".
  8. ^abcNorth RA (October 2002). "Molecular physiology of P2X receptors".Physiological Reviews.82(4): 1013–1067.doi:10.1152/physrev.00015.2002.PMID12270951.
  9. ^North RA (October 2002). "Molecular physiology of P2X receptors".Physiological Reviews.82(4): 1013–1067.doi:10.1152/physrev.00015.2002.PMID12270951.
  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.PMC6729830.PMID15044552.
  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.PMID11040040.
  12. ^abcdefghijklmnopqKanellopoulos 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.PMC8059410.PMID33897694.
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  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.PMID17264311.S2CID18668753.
  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.PMID16449800.S2CID7174797.
  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.PMC3763203.PMID21749490.
  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.PMC6622016.PMID22378878.
  19. ^abcdefghijklmMansoor 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.ISBN978-1-0716-2384-8.PMID35776317.
  20. ^abSophocleous 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.PMC9147237.PMID35628550.
  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.PMC3360091.PMID22547202.
  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.PMC2720809.PMID19641588.
  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.PMID17940064.
  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.PMC2683100.PMID19380717.
  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.PMC3101996.PMID21441897.
  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.PMC3350584.PMID22222817.
  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.PMID17918263.S2CID8834339.
  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.PMC4516482.PMID19298529.
  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.PMID12105201.
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  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.PMC2704200.PMID19515262.
  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.PMC6671487.PMID18971468.
  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.PMC3589565.PMID19295157.
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Further reading

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This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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