P2RX4

P2RX4
Identifiers
Aliases	P2RX4, P2X4, P2X4R, purinergic receptor P2X 4
External IDs	OMIM: 600846 MGI: 1338859 HomoloGene: 1923 GeneCards: P2RX4
Gene location (Human)
Chr.	Chromosome 12 (human)[1]
End	121,234,106 bp[1]
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)[2]
End	122,729,738 bp[2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• protein homodimerization activity; • zinc ion binding; • cadherin binding; • purinergic nucleotide receptor activity; • extracellular ATP-gated cation channel activity; • ion channel activity; • GO:0001948 protein binding; • drug binding; • copper ion binding; • receptor binding; • ATP binding; • identical protein binding;
Cellular component	• integral component of membrane; • membrane; • GO:0097483, GO:0097481 postsynaptic density; • dendritic spine; • integral component of nuclear inner membrane; • synapse; • integral component of plasma membrane; • lysosomal membrane; • cell junction; • neuronal cell body; • terminal bouton; • axon; • dendrite; • perinuclear region of cytoplasm; • extracellular exosome; • cell membrane; • postsynapse;
Biological process	• response to ATP; • positive regulation of calcium-mediated signaling; • positive regulation of calcium ion transport into cytosol; • negative regulation of cardiac muscle hypertrophy; • regulation of sodium ion transport; • positive regulation of nitric oxide biosynthetic process; • membrane depolarization; • endothelial cell activation; • ion transport; • cation transmembrane transport; • response to fluid shear stress; • regulation of blood pressure; • ion transmembrane transport; • positive regulation of prostaglandin secretion; • tissue homeostasis; • apoptotic signaling pathway; • nociception; • regulation of cardiac muscle contraction; • cellular response to ATP; • protein homooligomerization; • relaxation of cardiac muscle; • signal transduction; • neuronal action potential; • purinergic nucleotide receptor signaling pathway; • positive regulation of calcium ion transport; • blood coagulation; • excitatory postsynaptic potential; • positive regulation of blood vessel endothelial cell migration; • positive regulation of endothelial cell chemotaxis; • transport;
	Sources:Amigo / QuickGO
Orthologs
	5025
	18438
	ENSG00000135124
	ENSMUSG00000029470
	Q99571
	Q9JJX6
NM_001256796; NM_001261397; NM_001261398; NM_002560; NM_175567;
	NM_175568
	NM_011026; NM_001310718; NM_001310720
	NP_001243725; NP_001248326; NP_001248327; NP_002551
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4 gene.[5][6] 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.[6]

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.[7] 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.[8][9][10][11][12]

Receptor structure and kinetics

The P2X₄ subunits can form homomeric or heteromeric receptors.[13] 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.[14] The P2X₄ receptor is a ligand-gated cation channel that opens in response to ATP binding.[15] The P2X₄ receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca²⁺-sensitive intracellular processes.[15][16][17] Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG⁺) in about 50% of the cells expressing the P2X₄ receptor.[15] The desensitization of P2X₄ receptors is intermediate when compared to P2X1 and P2X2 receptors.[15]

Pharmacology

Agonists

P2X₄ receptors respond to ATP, but not αβmeATP. These receptors are also potentiated by ivermectin, cibacron blue, and zinc.[15]

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[15]

Receptor trafficking

P2X₄ receptors are stored in lysosomes and brought to the cell surface in response to extracellular signals.[18] These signals include IFN-γ, CCL21, CCL2.[19][20][21] Fibronectin is also involved in upregulation of P2X₄ receptors through interactions with integrins that lead to the activation of SRC-family kinase member, Lyn.[22] Lyn then activates PI3K-AKT and MEK-ERK signaling pathways to stimulate receptor trafficking.[23] Internalization of P2X₄ receptors is clathrin- and dynamin-dependent endocytosis.[24]

Neuropathic pain

The P2X₄ receptor has been linked to neuropathic pain mediated by microglia in vitro and in vivo.[25][26] P2X₄ receptors are upregulated following injury.[27] This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia.[28] BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor.[29] 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.[30]

References

GRCh38: Ensembl release 89: ENSG00000135124 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000029470 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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): 109–18. doi:10.1124/mol.51.1.109. PMID 9016352.
"Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".
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): 159–65. doi:10.1007/s00441-003-0758-5. PMID 12845522. S2CID 18060944.
Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, Kitani H, Kojima S (March 2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages". Biochemical and Biophysical Research Communications. 419 (2): 374–80. doi:10.1016/j.bbrc.2012.01.156. PMID 22349510.
Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, Falzoni S, Lupi R, Ferrannini E, Pugliese G, Di Virgilio F (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): F1537-47. doi:10.1152/ajprenal.00440.2006. PMID 17264311.
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): 277–84. doi:10.1096/fj.05-4749com. PMID 16449800. S2CID 7174797.
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): 213–20. doi:10.1111/j.1460-9568.2011.07763.x. PMC 3763203. PMID 21749490.
de Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich WD, De Koninck Y, Keane RW, Lacroix S (February 2012). "P2X4 receptors influence inflammasome activation after spinal cord injury". The Journal of Neuroscience. 32 (9): 3058–66. doi:10.1523/JNEUROSCI.4930-11.2012. PMC 6622016. PMID 22378878.
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.
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): 592–8. doi:10.1038/nature08198. PMC 2720809. PMID 19641588.
North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.
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): 3125–35. doi:10.1523/JNEUROSCI.0090-04.2004. PMC 6729830. PMID 15044552.
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): 936–45. doi:10.1124/mol.58.5.936. PMID 11040040.
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): 3838–49. doi:10.1242/jcs.010348. PMID 17940064.
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): 8032–7. doi:10.1073/pnas.0810420106. PMC 2683100. PMID 19380717.
Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K (May 2011). "Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development". The EMBO Journal. 30 (9): 1864–73. doi:10.1038/emboj.2011.89. PMC 3101996. PMID 21441897.
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): 301–10. doi:10.1007/s11302-011-9288-x. PMC 3350584. PMID 22222817.
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): 50–8. doi:10.1002/glia.20591. PMID 17918263. S2CID 8834339.
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): 3251–9. doi:10.1111/j.1582-4934.2009.00719.x. PMC 4516482. PMID 19298529.
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): 35378–85. doi:10.1074/jbc.M204844200. PMID 12105201.
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): 2290–300. doi:10.1038/emboj.2010.126. PMC 2910276. PMID 20562826.
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: 1744-8069–5-28. doi:10.1186/1744-8069-5-28. PMC 2704200. PMID 19515262.
Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (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): 11263–8. doi:10.1523/JNEUROSCI.2308-08.2008. PMC 6671487. PMID 18971468.
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): 3518–28. doi:10.1523/JNEUROSCI.5714-08.2009. PMC 3589565. PMID 19295157.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (December 2005). "BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain". Nature. 438 (7070): 1017–21. doi:10.1038/nature04223. PMID 16355225. S2CID 4403946.
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): 778–83. doi:10.1038/nature01786. PMID 12917686. S2CID 4358793.

External links

P2RX4+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

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

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000135124 - Ensembl, May 2017

[refGRCm38Ensembl-2] 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.

[pmid9016352-5] 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): 109–18. doi:10.1124/mol.51.1.109. PMID 9016352.

[entrez-6] "Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".

[7] 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): 159–65. doi:10.1007/s00441-003-0758-5. PMID 12845522. S2CID 18060944.

[8] Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, Kitani H, Kojima S (March 2012). "Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages". Biochemical and Biophysical Research Communications. 419 (2): 374–80. doi:10.1016/j.bbrc.2012.01.156. PMID 22349510.

[9] Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, Falzoni S, Lupi R, Ferrannini E, Pugliese G, Di Virgilio F (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): F1537-47. doi:10.1152/ajprenal.00440.2006. PMID 17264311.

[10] 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): 277–84. doi:10.1096/fj.05-4749com. PMID 16449800. S2CID 7174797.

[11] 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): 213–20. doi:10.1111/j.1460-9568.2011.07763.x. PMC 3763203. PMID 21749490.

[12] Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich WD, De Koninck Y, Keane RW, Lacroix S (February 2012). "P2X4 receptors influence inflammasome activation after spinal cord injury". The Journal of Neuroscience. 32 (9): 3058–66. doi:10.1523/JNEUROSCI.4930-11.2012. PMC 6622016. PMID 22378878.

[13] 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.

[14] 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): 592–8. doi:10.1038/nature08198. PMC 2720809. PMID 19641588.

[cite_pmid|_12270951-15] North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.

[16] 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): 3125–35. doi:10.1523/JNEUROSCI.0090-04.2004. PMC 6729830. PMID 15044552.

[17] 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): 936–45. doi:10.1124/mol.58.5.936. PMID 11040040.

[18] 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): 3838–49. doi:10.1242/jcs.010348. PMID 17940064.

[19] 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): 8032–7. doi:10.1073/pnas.0810420106. PMC 2683100. PMID 19380717.

[20] Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K (May 2011). "Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development". The EMBO Journal. 30 (9): 1864–73. doi:10.1038/emboj.2011.89. PMC 3101996. PMID 21441897.

[21] 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): 301–10. doi:10.1007/s11302-011-9288-x. PMC 3350584. PMID 22222817.

[22] 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): 50–8. doi:10.1002/glia.20591. PMID 17918263. S2CID 8834339.

[23] 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): 3251–9. doi:10.1111/j.1582-4934.2009.00719.x. PMC 4516482. PMID 19298529.

[24] 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): 35378–85. doi:10.1074/jbc.M204844200. PMID 12105201.

[25] 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): 2290–300. doi:10.1038/emboj.2010.126. PMC 2910276. PMID 20562826.

[26] 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: 1744-8069–5-28. doi:10.1186/1744-8069-5-28. PMC 2704200. PMID 19515262.

[27] Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (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): 11263–8. doi:10.1523/JNEUROSCI.2308-08.2008. PMC 6671487. PMID 18971468.

[28] 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): 3518–28. doi:10.1523/JNEUROSCI.5714-08.2009. PMC 3589565. PMID 19295157.

[29] Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (December 2005). "BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain". Nature. 438 (7070): 1017–21. doi:10.1038/nature04223. PMID 16355225. S2CID 4403946.

[30] 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): 778–83. doi:10.1038/nature01786. PMID 12917686. S2CID 4358793.