Alternative titles; symbols
HGNC Approved Gene Symbol: P2RX4
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:121,210,129-121,234,106 (from NCBI)
The binding of ATP to P2-purinergic receptors exerts widespread biologic responses in different tissues. The ionotropic (P2X) class of cell surface ATP receptors are ligand-gated channels. Activation of P2X receptors leads to the opening of nonselective cation channels that are permeable to Na+, K+, and, in some cases, Ca(2+). See P2X3 (600843). The rat P2X4 gene was cloned by Buell et al. (1995, 1996). Garcia-Guzman et al. (1997) isolated brain cDNAs encoding human P2X4. The predicted 388-amino acid protein shares 87% identity with that of rat P2X4. By RT-PCR of various human tissues, these authors determined that P2X4 has a broad expression pattern. Heterologous expression of P2X4 in Xenopus oocytes and human embryonic kidney cells generated an ATP-activated channel with high Ca(2+) permeability.
Adrian et al. (2000) analyzed the expression of several purinergic receptors during differentiation in a promyelocytic leukemia cell line. Granulocytic differentiation was induced by dimethylsulfoxide, and a monocytic/macrophage phenotype was induced by phorbol esters. P2X4 expression was nearly undetectable in promyelocytes and after granulocyte differentiation. During monocytic differentiation, P2X4 was highly expressed, showing a biphasic peak in early and later stages of differentiation.
Pain after nerve damage is an expression of pathologic operation of the nervous system, one hallmark of which is tactile allodynia. Tsuda et al. (2003) reported that pharmacologic blockade of P2X4 receptors reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviors in naive animals. After nerve injury, P2X4 receptor expression increased strikingly in the ipsilateral spinal cord, and P2X4 receptors were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4R and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4 receptors had been induced and stimulated produced tactile allodynia in naive rats. Tsuda et al. (2003) concluded that taken together, their results demonstrated that activation of P2X4 receptors in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals.
By fluorescence in situ hybridization, Garcia-Guzman et al. (1997) mapped the human P2RX4 gene to 12q24.32.
Crystal Structure
Kawate et al. (2009) presented the crystal structures of the zebrafish P2X4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8-angstrom slab of protein. Kawate et al. (2009) defined the location of 3 noncanonical, intersubunit ATP-binding sites, and suggested that ATP binding promotes subunit rearrangement and ion channel opening.
In a study of 1,094 female dizygotic twin pairs, Wilson et al. (2006) found suggestive linkage for central fat mass (see 601665) to 12q24 (lod score, 2.2); SNP analysis of 1,102 individuals selected from the twin cohort provided evidence for an association between central fat mass and SNPs in 2 genes located on chromosome 12q24, PLA2G1B (172410) and P2RX4, with p values of 0.0067 and 0.017, respectively.
The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow. Yamamoto et al. (2006) showed that the ATP-gated P2X4 ion channel, expressed on endothelial cells and encoded by P2rx4 in mice, has a key role in the response of endothelial cells to changes in blood flow. P2rx4 -/- mice do not have normal endothelial cell responses to flow, such as influx of Ca(2+) and subsequent production of the potent vasodilator nitric oxide (NO). Additionally, vessel dilation induced by acute increases in blood flow is markedly suppressed in P2rx4 -/- mice. Furthermore, P2rx4 -/- mice have higher blood pressure and excrete smaller amounts of NO products in their urine than do wildtype mice. Moreover, no adaptive vascular remodeling, i.e., a decrease in vessel size in response to a chronic decrease in blood flow, was observed in P2rx4 -/- mice. Thus, endothelial P2X4 channels are crucial to flow-sensitive mechanisms that regulate blood pressure and vascular remodeling.
Adrian, K., Bernhard, M. K., Breitinger, H.-G., Ogilvie, A. Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochim. Biophys. Acta 1492: 127-138, 2000. [PubMed: 11004484] [Full Text: https://doi.org/10.1016/s0167-4781(00)00094-4]
Buell, G., Lewis, C., Collo, G., North, R. A., Surprenant, A. Cloning and expression of a family of ATP-gated ion channels. (Abstract) Soc. Neurosci. 21: 1262, 1995.
Buell, G., Lewis, C., Collo, G., North, R. A., Surprenant, A. An antagonist-insensitive P2X receptor expressed in epithelia and brain. EMBO J. 15: 55-62, 1996. [PubMed: 8598206]
Garcia-Guzman, M., Soto, F., Gomez-Hernandez, J. M., Lund, P. E., Stuhmer, W. Characterization of the recombinant human P2X4 receptor reveals pharmacological differences to the rat homologue. Molec. Pharm. 51: 109-118, 1997. [PubMed: 9016352] [Full Text: https://doi.org/10.1124/mol.51.1.109]
Kawate, T., Michel, J. C., Birdsong, W. T., Gouaux, E. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature 460: 592-598, 2009. [PubMed: 19641588] [Full Text: https://doi.org/10.1038/nature08198]
Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M. W., Inoue, K. P2X(4) receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424: 778-783, 2003. [PubMed: 12917686] [Full Text: https://doi.org/10.1038/nature01786]
Wilson, S. G., Adam, G., Langdown, M., Reneland, R., Braun, A., Andrew, T., Surdulescu, G. L., Norberg, M., Dudbridge, F., Reed, P. W., Sambrook, P. N., Kleyn, P. W., Spector, T. D. Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort. Europ. J. Hum. Genet. 14: 340-348, 2006. [PubMed: 16391564] [Full Text: https://doi.org/10.1038/sj.ejhg.5201551]
Yamamoto, K., Sokabe, T., Matsumoto, T., Yoshimura, K., Shibata, M., Ohura, N., Fukuda, T., Sato, T., Sekine, K., Kato, S., Isshiki, M., Fujita, T., Kobayashi, M., Kawamura, K., Masuda, H., Kamiya, A., Ando, J. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nature Med. 12: 133-137, 2006. [PubMed: 16327800] [Full Text: https://doi.org/10.1038/nm1338]