P2X purinoceptor 4 is a protein that in humans is encoded by the P2RX4gene. 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.
The P2X4 subunits can form homomeric or heteromeric receptors. 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. The P2X4 receptor is a ligand-gated cation channel that opens in response to ATP binding. The P2X4 receptor has high calcium permeability, leading to the depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. Continued binding leads to increased permeability to N-methyl-D-glucamine (NMDG+) in about 50% of the cells expressing the P2X4 receptor. The desensitization of P2X4 receptors is intermediate when compared to P2X1 and P2X2 receptors.
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
The P2X4 receptor has been linked to neuropathic pain mediated by microgliain vitro and in vivo. P2X4 receptors are upregulated following injury. This upregulation allows for increased activation of p38 mitogen-activated protein kinases, thereby increasing the release of brain-derived neurotrophic factor (BDNF) from microglia. BDNF released from microglia induces neuronal hyperexcitability through interaction with the TrkB receptor. 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.
^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. PMID9016352.
^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. PMID12845522.
^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. PMID22349510.
^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. PMID17264311.
^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. PMID16449800.
^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. PMID22378878.
^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. PMID15044552.
^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. PMID11040040.
^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. PMID17940064.
^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. PMID12105201.
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. PMID8125298.
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. PMID9221902.
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. PMID9373149.
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. PMID11299224.
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. PMID12088286.
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. PMID12714321.
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. PMID15006691.
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. PMID15130891.
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. PMID15262999.
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. PMID16533808.
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. PMID16949036.
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. PMID17264311.