P2RX4: Difference between revisions

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{{Infobox_gene}}
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'''P2X purinoceptor 4''' is a [[protein]] that in humans is encoded by the ''P2RX4'' [[gene]].<ref name="pmid9016352">{{cite journal | vauthors = Garcia-Guzman M, Soto F, Gomez-Hernandez JM, Lund PE, Stühmer W | title = Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue | journal = Molecular Pharmacology | volume = 51 | issue = 1 | pages = 109–18 | date = January 1997 | pmid = 9016352 | pmc =  | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5025| accessdate = }}</ref>
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The product of this gene belongs to the family of [[Purinergic receptor|purinoceptors]] for [[Adenosine triphosphate|ATP]]. Multiple [[alternative splicing|alternatively spliced]] transcript variants have been identified for this gene although their full-length natures have not been determined.<ref name="entrez" />
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| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


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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 [[Artery|arteries]], in uterine [[endometrium]], and in [[adipocyte|fat cells]].<ref>{{cite journal | vauthors = Bo X, Kim M, Nori SL, Schoepfer R, Burnstock G, North RA | title = Tissue distribution of P2X4 receptors studied with an ectodomain antibody | journal = Cell and Tissue Research | volume = 313 | issue = 2 | pages = 159–65 | date = August 2003 | pmid = 12845522 | pmc =  | doi = 10.1007/s00441-003-0758-5 }}</ref> P2X<SUB>4</SUB> receptors have been implicated in the regulation of cardiac function, ATP-mediated [[apoptosis|cell death]], [[long-term potentiation|synaptic strengthening]], and activating of the [[inflammasome]] in response to injury.<ref>{{cite journal | vauthors = Kawano A, Tsukimoto M, Noguchi T, Hotta N, Harada H, Takenouchi T, Kitani H, Kojima S | title = Involvement of P2X4 receptor in P2X7 receptor-dependent cell death of mouse macrophages | journal = Biochemical and Biophysical Research Communications | volume = 419 | issue = 2 | pages = 374–80 | date = March 2012 | pmid = 22349510 | pmc =  | doi = 10.1016/j.bbrc.2012.01.156 }}</ref><ref>{{cite journal | vauthors = Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, Falzoni S, Lupi R, Ferrannini E, Pugliese G, Di Virgilio F | title = Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4 | journal = American Journal of Physiology. Renal Physiology | volume = 292 | issue = 5 | pages = F1537-47 | date = May 2007 | pmid = 17264311 | pmc = | doi = 10.1152/ajprenal.00440.2006 }}</ref><ref>{{cite journal | vauthors = Shen JB, Pappano AJ, Liang BT | title = Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors | journal = FASEB Journal | volume = 20 | issue = 2 | pages = 277–84 | date = February 2006 | pmid = 16449800 | pmc =  | doi = 10.1096/fj.05-4749com }}</ref><ref>{{cite journal | vauthors = Baxter AW, Choi SJ, Sim JA, North RA | title = Role of P2X4 receptors in synaptic strengthening in mouse CA1 hippocampal neurons | journal = The European Journal of Neuroscience | volume = 34 | issue = 2 | pages = 213–20 | date = July 2011 | pmid = 21749490 | pmc = 3763203| doi = 10.1111/j.1460-9568.2011.07763.x }}</ref><ref>{{cite journal | vauthors = de Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich WD, De Koninck Y, Keane RW, Lacroix S | title = P2X4 receptors influence inflammasome activation after spinal cord injury | journal = The Journal of Neuroscience | volume = 32 | issue = 9 | pages = 3058–66 | date = February 2012 | pmid = 22378878 | pmc = | doi = 10.1523/JNEUROSCI.4930-11.2012 }}</ref>
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Purinergic receptor P2X, ligand-gated ion channel, 4
| HGNCid = 8535
| Symbol = P2RX4
| AltSymbols =; P2X4; P2X4R
| OMIM = 600846
| ECnumber =
  | Homologene = 1923
| MGIid = 1338859
| GeneAtlas_image1 = PBB_GE_P2RX4_204088_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004931 |text = ATP-gated cation channel activity}} {{GNF_GO|id=GO:0005216 |text = ion channel activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}}
  | Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0007165 |text = signal transduction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5025
    | Hs_Ensembl = ENSG00000135124
    | Hs_RefseqProtein = NP_002551
    | Hs_RefseqmRNA = NM_002560
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 120132043
    | Hs_GenLoc_end = 120156290
    | Hs_Uniprot = Q99571
    | Mm_EntrezGene = 18438
    | Mm_Ensembl = ENSMUSG00000029470
    | Mm_RefseqmRNA = NM_011026
    | Mm_RefseqProtein = NP_035156
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 5
    | Mm_GenLoc_start = 122968201
    | Mm_GenLoc_end = 122989657
    | Mm_Uniprot = Q3TR36
  }}
}}
'''Purinergic receptor P2X, ligand-gated ion channel, 4''', also known as '''P2RX4''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5025| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Receptor structure and kinetics ==
{{PBB_Summary
The P2X<SUB>4</SUB> subunits can form [[homomeric]] or [[heteromeric]] receptors.<ref>{{cite journal | vauthors = Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A | title = Molecular and functional properties of P2X receptors--recent progress and persisting challenges | journal = Purinergic Signalling | volume = 8 | issue = 3 | pages = 375–417 | date = September 2012 | pmid = 22547202 | pmc = 3360091 | doi = 10.1007/s11302-012-9314-7 }}</ref> The P2X<SUB>4</SUB> receptor has a typical [[P2X purinoreceptor|P2X receptor]] structure. The [[zebrafish]] P2X<SUB>4</SUB> receptor was the first purinergic receptor to be crystallized and have its three-dimensional structure solved, forming the model for the P2X receptor family.<ref>{{cite journal | vauthors = Kawate T, Michel JC, Birdsong WT, Gouaux E | title = Crystal structure of the ATP-gated P2X(4) ion channel in the closed state | journal = Nature | volume = 460 | issue = 7255 | pages = 592–8 | date = July 2009 | pmid = 19641588 | pmc = 2720809 | doi = 10.1038/nature08198 }}</ref> 
| section_title =  
The P2X<SUB>4</SUB> receptor is a [[ligand-gated ion channel|ligand-gated cation channel]] that opens in response to ATP binding.<ref name="cite pmid| 12270951">{{cite journal | vauthors = North RA | title = Molecular physiology of P2X receptors | journal = Physiological Reviews | volume = 82 | issue = 4 | pages = 1013–67 | date = October 2002 | pmid = 12270951 | pmc =  | doi = 10.1152/physrev.00015.2002 }}</ref> The P2X<SUB>4</SUB> receptor has high [[calcium]] permeability, leading to the [[depolarization]] of the cell membrane and the activation of various Ca<sup>2+</sup>-sensitive intracellular processes.<ref name="cite pmid| 12270951"/><ref>{{cite journal | vauthors = Shigetomi E, Kato F | title = Action potential-independent release of glutamate by Ca2+ entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network | journal = The Journal of Neuroscience | volume = 24 | issue = 12 | pages = 3125–35 | date = March 2004 | pmid = 15044552 | pmc =  | doi = 10.1523/JNEUROSCI.0090-04.2004 }}</ref><ref>{{cite journal | vauthors = Koshimizu TA, Van Goor F, Tomić M, Wong AO, Tanoue A, Tsujimoto G, Stojilkovic SS | title = Characterization of calcium signaling by purinergic receptor-channels expressed in excitable cells | journal = Molecular Pharmacology | volume = 58 | issue = 5 | pages = 936–45 | date = November 2000 | pmid = 11040040 }}</ref> Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG<sup>+</sup>) in about 50% of the cells expressing the P2X<SUB>4</SUB> receptor.<ref name="cite pmid| 12270951"/>  The [[Desensitization (medicine)|desensitization]] of P2X<SUB>4</SUB> receptors is intermediate when compared to [[P2RX1|P2X1]] and [[P2RX2|P2X2]] receptors.<ref name="cite pmid| 12270951"/>
| summary_text = The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel with high calcium permeability. The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and PPADS. The product of this gene has the lowest sensitivity for these antagonists. Multiple alternatively spliced transcript variants have been identified for this gene although their full-length natures have not been determined.<ref name="entrez">{{cite web | title = Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5025| accessdate = }}</ref>
}}


==See also==
== Pharmacology ==
 
=== Agonists ===
P2X<SUB>4</SUB> receptors respond to ATP, but not αβmeATP.  These receptors are also potentiated by [[ivermectin]], cibacron blue, and [[zinc]].<ref name="cite pmid| 12270951"/>
 
=== Antagonists ===
The main pharmacological distinction between the members of the [[Purinergic receptor|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<ref name="cite pmid| 12270951"/>
 
== Receptor trafficking ==
P2X<SUB>4</SUB> receptors are stored in [[lysosome]]s and brought to the cell surface in response to extracellular signals.<ref>{{cite journal | vauthors = Qureshi OS, Paramasivam A, Yu JC, Murrell-Lagnado RD | title = Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis | journal = Journal of Cell Science | volume = 120 | issue = Pt 21 | pages = 3838–49 | date = November 2007 | pmid = 17940064 | pmc =  | doi = 10.1242/jcs.010348 }}</ref>  These signals include [[Interferon-gamma|IFN-γ]], [[CCL21]], [[CCL2]].<ref>{{cite journal | vauthors = Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K | title = IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 19 | pages = 8032–7 | date = May 2009 | pmid = 19380717 | pmc = 2683100 | doi = 10.1073/pnas.0810420106 }}</ref><ref>{{cite journal | vauthors = Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K | title = Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development | journal = The EMBO Journal | volume = 30 | issue = 9 | pages = 1864–73 | date = May 2011 | pmid = 21441897 | pmc = 3101996 | doi = 10.1038/emboj.2011.89 }}</ref><ref>{{cite journal | vauthors = Toyomitsu E, Tsuda M, Yamashita T, Tozaki-Saitoh H, Tanaka Y, Inoue K | title = CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia | journal = Purinergic Signalling | volume = 8 | issue = 2 | pages = 301–10 | date = June 2012 | pmid = 22222817 | pmc = 3350584 | doi = 10.1007/s11302-011-9288-x }}</ref> [[Fibronectin]] is also involved in upregulation of P2X<SUB>4</SUB> receptors through interactions with [[integrin]]s that lead to the activation of [[src gene|SRC-family kinase]] member, [[Lyn src family kinase|Lyn]].<ref>{{cite journal | vauthors = Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T, Inoue K | title = Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury | journal = Glia | volume = 56 | issue = 1 | pages = 50–8 | date = January 2008 | pmid = 17918263 | pmc =  | doi = 10.1002/glia.20591 }}</ref> Lyn then activates [[PI3K/AKT/mTOR|PI3K-AKT]] and [[MAPK/ERK|MEK-ERK]] signaling pathways to stimulate receptor trafficking.<ref>{{cite journal | vauthors = Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K | title = Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: distinct roles of PI3K-Akt and MEK-ERK signalling pathways | journal = Journal of Cellular and Molecular Medicine | volume = 13 | issue = 9B | pages = 3251–9 | date = September 2009 | pmid = 19298529 | pmc =  4516482| doi = 10.1111/j.1582-4934.2009.00719.x }}</ref> Internalization of P2X<SUB>4</SUB> receptors is [[clathrin]]- and [[dynamin]]-dependent [[endocytosis]].<ref>{{cite journal | vauthors = Royle SJ, Bobanović LK, Murrell-Lagnado RD | title = Identification of a non-canonical tyrosine-based endocytic motif in an ionotropic receptor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 38 | pages = 35378–85 | date = September 2002 | pmid = 12105201 | pmc =  | doi = 10.1074/jbc.M204844200 }}</ref>
 
== Neuropathic pain ==
The P2X<SUB>4</SUB> receptor has been linked to [[neuropathic pain]] mediated by [[microglia]] ''[[in vitro]]'' and ''[[in vivo]]''.<ref>{{cite journal | vauthors = Ulmann L, Hirbec H, Rassendren F | title = P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain | journal = The EMBO Journal | volume = 29 | issue = 14 | pages = 2290–300 | date = July 2010 | pmid = 20562826 | pmc = 2910276 | doi = 10.1038/emboj.2010.126 }}</ref><ref>{{cite journal | vauthors = Tsuda M, Kuboyama K, Inoue T, Nagata K, Tozaki-Saitoh H, Inoue K | title = Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays | journal = Molecular Pain | volume = 5 | pages = 28 | date = June 2009 | pmid = 19515262 | pmc = 2704200 | doi = 10.1186/1744-8069-5-28 }}</ref>  P2X<SUB>4</SUB> receptors are upregulated following injury.<ref>{{cite journal | vauthors = Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F | title = Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain | journal = The Journal of Neuroscience | volume = 28 | issue = 44 | pages = 11263–8 | date = October 2008 | pmid = 18971468 | pmc =  | doi = 10.1523/JNEUROSCI.2308-08.2008 }}</ref>  This upregulation allows for increased activation of [[p38 mitogen-activated protein kinases]], thereby increasing the release of brain-derived neurotrophic factor ([[Brain-derived neurotrophic factor|BDNF]]) from microglia.<ref>{{cite journal | vauthors = Trang T, Beggs S, Wan X, Salter MW | title = 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 = The Journal of Neuroscience | volume = 29 | issue = 11 | pages = 3518–28 | date = March 2009 | pmid = 19295157 | pmc = 3589565 | doi = 10.1523/JNEUROSCI.5714-08.2009 }}</ref>  BDNF released from microglia induces neuronal hyperexcitability through interaction with the [[TrkB receptor]].<ref>{{cite journal | vauthors = Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y | title = BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain | journal = Nature | volume = 438 | issue = 7070 | pages = 1017–21 | date = December 2005 | pmid = 16355225 | pmc =  | doi = 10.1038/nature04223 }}</ref> More importantly, recent work shows that P2X<SUB>4</SUB> receptor activation is not only necessary for neuropathic pain, but it is also sufficient to cause neuropathic pain.<ref>{{cite journal | vauthors = Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K | title = P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury | journal = Nature | volume = 424 | issue = 6950 | pages = 778–83 | date = August 2003 | pmid = 12917686 | pmc =  | doi = 10.1038/nature01786 }}</ref>
 
== See also ==
* [[P2X receptor]]
* [[P2X receptor]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = North RA | title = Molecular physiology of P2X receptors | journal = Physiological Reviews | volume = 82 | issue = 4 | pages = 1013–67 | date = October 2002 | pmid = 12270951 | doi = 10.1152/physrev.00015.2002 }}
| citations =
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | author=North RA |title=Molecular physiology of P2X receptors. |journal=Physiol. Rev. |volume=82 |issue= 4 |pages= 1013-67 |year= 2002 |pmid= 12270951 |doi= 10.1152/physrev.00015.2002 }}
* {{cite journal | vauthors = Garcia-Guzman M, Stühmer W, Soto F | title = Molecular characterization and pharmacological properties of the human P2X3 purinoceptor | journal = Brain Research. Molecular Brain Research | volume = 47 | issue = 1–2 | pages = 59–66 | date = July 1997 | pmid = 9221902 | doi = 10.1016/S0169-328X(97)00036-3 }}
*{{cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal  | author=Garcia-Guzman M, Soto F, Gomez-Hernandez JM, ''et al.'' |title=Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue. |journal=Mol. Pharmacol. |volume=51 |issue= 1 |pages= 109-18 |year= 1997 |pmid= 9016352 |doi=  }}
* {{cite journal | vauthors = Korenaga R, Yamamoto K, Ohura N, Sokabe T, Kamiya A, Ando J | title = Sp1-mediated downregulation of P2X4 receptor gene transcription in endothelial cells exposed to shear stress | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 280 | issue = 5 | pages = H2214-21 | date = May 2001 | pmid = 11299224 | doi =  }}
*{{cite journal | author=Garcia-Guzman M, Stühmer W, Soto F |title=Molecular characterization and pharmacological properties of the human P2X3 purinoceptor. |journal=Brain Res. Mol. Brain Res. |volume=47 |issue= 1-2 |pages= 59-66 |year= 1997 |pmid= 9221902 |doi= }}
* {{cite journal | vauthors = Glass R, Loesch A, Bodin P, Burnstock G | title = P2X4 and P2X6 receptors associate with VE-cadherin in human endothelial cells | journal = Cellular and Molecular Life Sciences | volume = 59 | issue = 5 | pages = 870–81 | date = May 2002 | pmid = 12088286 | doi = 10.1007/s00018-002-8474-y }}
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
* {{cite journal | vauthors = Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J | title = Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 285 | issue = 2 | pages = H793-803 | date = August 2003 | pmid = 12714321 | doi = 10.1152/ajpheart.01155.2002 }}
*{{cite journal | author=Korenaga R, Yamamoto K, Ohura N, ''et al.'' |title=Sp1-mediated downregulation of P2X4 receptor gene transcription in endothelial cells exposed to shear stress. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=280 |issue= 5 |pages= H2214-21 |year= 2001 |pmid= 11299224 |doi=  }}
* {{cite journal | vauthors = Yeung D, Kharidia R, Brown SC, Górecki DC | title = Enhanced expression of the P2X4 receptor in Duchenne muscular dystrophy correlates with macrophage invasion | journal = Neurobiology of Disease | volume = 15 | issue = 2 | pages = 212–20 | date = March 2004 | pmid = 15006691 | doi = 10.1016/j.nbd.2003.10.014 }}
*{{cite journal | author=Glass R, Loesch A, Bodin P, Burnstock G |title=P2X4 and P2X6 receptors associate with VE-cadherin in human endothelial cells. |journal=Cell. Mol. Life Sci. |volume=59 |issue= 5 |pages= 870-81 |year= 2002 |pmid= 12088286 |doi= }}
* {{cite journal | vauthors = Yang A, Sonin D, Jones L, Barry WH, Liang BT | title = A beneficial role of cardiac P2X4 receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 287 | issue = 3 | pages = H1096-103 | date = September 2004 | pmid = 15130891 | doi = 10.1152/ajpheart.00079.2004 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Brown DA, Bruce JI, Straub SV, Yule DI | title = cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 39485–94 | date = September 2004 | pmid = 15262999 | doi = 10.1074/jbc.M406201200 }}
*{{cite journal | author=Yamamoto K, Sokabe T, Ohura N, ''et al.'' |title=Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=285 |issue= 2 |pages= H793-803 |year= 2003 |pmid= 12714321 |doi= 10.1152/ajpheart.01155.2002 }}
* {{cite journal | vauthors = Fountain SJ, North RA | title = A C-terminal lysine that controls human P2X4 receptor desensitization | journal = The Journal of Biological Chemistry | volume = 281 | issue = 22 | pages = 15044–9 | date = June 2006 | pmid = 16533808 | doi = 10.1074/jbc.M600442200 }}
*{{cite journal | author=Yeung D, Kharidia R, Brown SC, Górecki DC |title=Enhanced expression of the P2X4 receptor in Duchenne muscular dystrophy correlates with macrophage invasion. |journal=Neurobiol. Dis. |volume=15 |issue= 2 |pages= 212-20 |year= 2004 |pmid= 15006691 |doi= 10.1016/j.nbd.2003.10.014 }}
* {{cite journal | vauthors = Jelínková I, Yan Z, Liang Z, Moonat S, Teisinger J, Stojilkovic SS, Zemková H | title = Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation | journal = Biochemical and Biophysical Research Communications | volume = 349 | issue = 2 | pages = 619–25 | date = October 2006 | pmid = 16949036 | doi = 10.1016/j.bbrc.2006.08.084 }}
*{{cite journal | author=Yang A, Sonin D, Jones L, ''et al.'' |title=A beneficial role of cardiac P2X4 receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=287 |issue= 3 |pages= H1096-103 |year= 2004 |pmid= 15130891 |doi= 10.1152/ajpheart.00079.2004 }}
* {{cite journal | vauthors = Solini A, Santini E, Chimenti D, Chiozzi P, Pratesi F, Cuccato S, Falzoni S, Lupi R, Ferrannini E, Pugliese G, Di Virgilio F | title = Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4 | journal = American Journal of Physiology. Renal Physiology | volume = 292 | issue = 5 | pages = F1537-47 | date = May 2007 | pmid = 17264311 | doi = 10.1152/ajprenal.00440.2006 }}
*{{cite journal | author=Brown DA, Bruce JI, Straub SV, Yule DI |title=cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells. |journal=J. Biol. Chem. |volume=279 |issue= 38 |pages= 39485-94 |year= 2004 |pmid= 15262999 |doi= 10.1074/jbc.M406201200 }}
*{{cite journal | author=Fountain SJ, North RA |title=A C-terminal lysine that controls human P2X4 receptor desensitization. |journal=J. Biol. Chem. |volume=281 |issue= 22 |pages= 15044-9 |year= 2006 |pmid= 16533808 |doi= 10.1074/jbc.M600442200 }}
*{{cite journal | author=Jelínková I, Yan Z, Liang Z, ''et al.'' |title=Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation. |journal=Biochem. Biophys. Res. Commun. |volume=349 |issue= 2 |pages= 619-25 |year= 2006 |pmid= 16949036 |doi= 10.1016/j.bbrc.2006.08.084 }}
*{{cite journal | author=Solini A, Santini E, Chimenti D, ''et al.'' |title=Multiple P2X receptors are involved in the modulation of apoptosis in human mesangial cells: evidence for a role of P2X4. |journal=Am. J. Physiol. Renal Physiol. |volume=292 |issue= 5 |pages= F1537-47 |year= 2007 |pmid= 17264311 |doi= 10.1152/ajprenal.00440.2006 }}
}}
{{refend}}
{{refend}}


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* {{MeshName|P2RX4+protein,+human}}


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{{Ligand-gated ion channels}}
{{Purinergics}}
[[Category:Ion channels]]
[[Category:Ion channels]]
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Revision as of 02:26, 27 October 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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RefSeq (mRNA)

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RefSeq (protein)

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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, Stühmer W (January 1997). "Characterization of recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue". Molecular Pharmacology. 51 (1): 109–18. PMID 9016352.
  2. ↑ 2.0 2.1 "Entrez Gene: P2RX4 purinergic receptor P2X, ligand-gated ion channel, 4".
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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. PMID 22378878.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.
  12. ↑ 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. PMID 15044552.
  13. ↑ 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. PMID 11040040.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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. PMID 18971468.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.

Further reading

  • North RA (October 2002). "Molecular physiology of P2X receptors". Physiological Reviews. 82 (4): 1013–67. doi:10.1152/physrev.00015.2002. PMID 12270951.
  • Maruyama K, Sugano S (January 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 (July 1997). "Molecular characterization and pharmacological properties of the human P2X3 purinoceptor". Brain Research. Molecular Brain Research. 47 (1–2): 59–66. doi:10.1016/S0169-328X(97)00036-3. PMID 9221902.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 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, Sokabe T, Kamiya A, Ando J (May 2001). "Sp1-mediated downregulation of P2X4 receptor gene transcription in endothelial cells exposed to shear stress". American Journal of Physiology. Heart and Circulatory Physiology. 280 (5): H2214–21. PMID 11299224.
  • Glass R, Loesch A, Bodin P, Burnstock G (May 2002). "P2X4 and P2X6 receptors associate with VE-cadherin in human endothelial cells". Cellular and Molecular Life Sciences. 59 (5): 870–81. doi:10.1007/s00018-002-8474-y. PMID 12088286.
  • Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J (August 2003). "Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells". American Journal of Physiology. Heart and Circulatory Physiology. 285 (2): H793–803. doi:10.1152/ajpheart.01155.2002. PMID 12714321.
  • Yeung D, Kharidia R, Brown SC, Górecki DC (March 2004). "Enhanced expression of the P2X4 receptor in Duchenne muscular dystrophy correlates with macrophage invasion". Neurobiology of Disease. 15 (2): 212–20. doi:10.1016/j.nbd.2003.10.014. PMID 15006691.
  • Yang A, Sonin D, Jones L, Barry WH, Liang BT (September 2004). "A beneficial role of cardiac P2X4 receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy". American Journal of Physiology. Heart and Circulatory Physiology. 287 (3): H1096–103. doi:10.1152/ajpheart.00079.2004. PMID 15130891.
  • Brown DA, Bruce JI, Straub SV, Yule DI (September 2004). "cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells". The Journal of Biological Chemistry. 279 (38): 39485–94. doi:10.1074/jbc.M406201200. PMID 15262999.
  • Fountain SJ, North RA (June 2006). "A C-terminal lysine that controls human P2X4 receptor desensitization". The Journal of Biological Chemistry. 281 (22): 15044–9. doi:10.1074/jbc.M600442200. PMID 16533808.
  • Jelínková I, Yan Z, Liang Z, Moonat S, Teisinger J, Stojilkovic SS, Zemková H (October 2006). "Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation". Biochemical and Biophysical Research Communications. 349 (2): 619–25. doi:10.1016/j.bbrc.2006.08.084. PMID 16949036.
  • 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.

External links

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