Alternative titles; symbols
HGNC Approved Gene Symbol: P2RX1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:3,896,592-3,916,465 (from NCBI)
Biologic responses to ATP, ADP, and other extracellular nucleotides are mediated by P2-nucleotide receptors belonging to 2 major classes: G protein-coupled P2Y receptors (see, e.g., P2RY1, 601167) and nucleotide-gated ion channel P2X receptors. Multiple types of P2-nucleotide receptors are expressed in platelets and blood cells (Clifford et al., 1998).
The rat P2X1 gene was cloned by Valera et al. (1994). By screening a bladder library with the rat cDNA, Valera et al. (1995) isolated cDNAs encoding human P2X1, or P2RX1. The sequence of the predicted 399-amino acid human protein is 89% identical to that of the rat and mouse homologs. Northern blot analysis revealed that P2X1 was expressed predominantly as a 2.6-kb mRNA in various tissues. Additional 1.8-, 3.6- and 4.2-kb mRNAs were detected in some tissues.
Sun et al. (1998) isolated platelet cDNAs corresponding to the 1.8-kb P2RX1 transcript. Although the coding regions are identical, the platelet transcript has a longer 5-prime untranslated region and a truncated 3-prime untranslated region. Sun et al. (1998) suggested that the different transcripts arise from alternative promoters or splicing. On Western blots of extracts of mammalian cells expressing P2X1, the protein had an apparent molecular mass of 70 kD, significantly higher than the 45-kD mass predicted from the amino acid sequence. Sun et al. (1998) stated that the difference may be due to glycosylation of the extracellular domain.
By fluorescence in situ hybridization, Valera et al. (1995) mapped the P2X1 gene to 17p13.3.
Liang et al. (2001) mapped the mouse P2rx1 gene to a region of syntenic homology on chromosome 11.
By heterologous expression of human P2X1 in Xenopus oocytes, Valera et al. (1995) showed that the receptor was sensitive to the purinergic agonists ATP and alpha,beta-methylene ATP.
Sun et al. (1998) found that, when expressed in astrocytoma cells, the P2X1 receptor exhibited both ATP- and ADP-stimulated calcium influx.
Electrophysiologic and biochemical studies indicated expression of the P2X1 receptor in human and rat platelets, rat basophilic leukemia cells, and phorbol myristate acetate-differentiated myeloid cells. Although these findings suggested that P2X1 receptors are present in both blood leukocytes and blood platelets, Clifford et al. (1998) found significant expression of P2X1 receptors in human platelets, but not in mature neutrophils, monocytes, or blood lymphocytes. Studies of nucleotide-induced changes in Ca(2+) influx/mobilization demonstrated that the platelet P2X1 receptors are pharmacologically distinct from the well-characterized P2Y1 receptors. ATP was the most potent physiologic nucleotide agonist for the P2X1 receptor, with ADP a full but less potent agonist. In contrast, the P2Y1 receptor shows an absolute selectivity for ADP as physiologic agonist and is antagonized by high concentrations of extracellular ATP. These divergent selectivities indicated that platelets may use ATP and ADP for distinct types of regulation, and suggested a unique role for P2X1 receptors in hemostasis or thrombosis.
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. No change from the low basal expression of P2X1 was detected during granulocytic differentiation, but expression was upregulated 10- to 14-fold at 36 hours of monocytic differentiation.
Using human platelets, Vial et al. (2002) showed that alpha,beta-methylene ATP evoked a rapid transient P2X1 receptor-mediated increase in Ca(2+), whereas ADP evoked slower but higher and more prolonged P2Y receptor responses. Ca(2+) responses to alpha,beta-methylene ATP plus ADP were accelerated and amplified, indicating that ionotropic P2X1 plays a priming role in the subsequent activation of metabotropic P2Y receptors during platelet stimulation.
Mahaut-Smith et al. (2004) reviewed evidence that P2RX1 alone and in synergy with other receptor pathways, such as P2Y1, P2Y12 (P2RY12; 600515), and GP6 (605546), generates significant platelet and megakaryocyte responses, particularly under conditions of shear stress, such as arterial thrombosis.
Associations Pending Confirmation
For discussion of a possible association between somatic mutation in the P2X1 gene and a bleeding disorder, see 600845.0001.
P2X1 receptors for ATP are ligand-gated cation channels, present on many excitable cells including vas deferens smooth muscle cells. A substantial component of the contractile response of the vas deferens to sympathetic nerve stimulation, which propels sperm into the ejaculate, is mediated through P2X receptors. Mulryan et al. (2000) demonstrated that male fertility is reduced by approximately 90% in mice with a targeted deletion of the P2X1 receptor gene. P2X1 -/- male mice copulated normally. Reduced fertility resulted from a reduction of sperm in the ejaculate and not from sperm dysfunction. Female and heterozygous mice were unaffected. In P2X1-receptor-deficient mice, contraction of the vas deferens to sympathetic nerve stimulation was reduced by up to 60%, and responses to P2X receptor agonists were abolished. Mulryan et al. (2000) stated that P2X1 receptors are essential for normal male reproductive function and suggested that the development of selective P2X1 receptor antagonists may provide an effective nonhormonal male contraceptive pill. In addition, agents that potentiate the actions of ATP at P2X1 receptors may be useful in the treatment of male infertility. P2X1 receptors are present on a variety of smooth muscle preparations in addition to the vas deferens, including the urinary bladder, arteries, and parts of the nervous system. There was no obvious effect on the behavior of P2X1-receptor -/- mice, and heart rate and bladder function appeared normal. There was, however, a small increase in systolic blood pressure at rest in P2X1 -/- mice when compared to their wildtype littermates.
Vial et al. (2002) found that megakaryocytes were devoid of alpha,beta-methylene ATP- and ATP-evoked ionotropic inward currents in mice lacking P2x1. Megakaryocyte numbers and sizes were normal, as were P2y1 and P2y12 responses, in mice lacking P2x1. However, the inward cation current associated with Ca(2+) release was reduced 50% in mice lacking P2x1, suggesting interaction of P2x1 and P2y receptors.
Using P2x1 -/- and wildtype mouse platelets, Hechler et al. (2003) examined P2x1 function in response to thrombogenic stimuli. Collagen-induced aggregation and secretion of P2x1 -/- platelets were reduced, as were adhesion and thrombus growth on collagen surfaces, particularly when the wall shear rate was elevated. In a mouse model of systemic thromboembolism, mortality was reduced in P2x1 -/- mice, as was the size of thrombi on vessel walls after laser-induced injury. The time for complete clot removal was also shortened in P2x1 -/- mice. Hechler et al. (2003) concluded that P2RX1 contributes to the formation of platelet thrombi, particularly in arteries in which shear forces are high.
This variant, formerly titled BLEEDING DISORDER DUE TO P2RX1 DEFECT, SOMATIC, has been reclassified based on the report of Cattaneo (2005).
In platelet cDNA isolated from a 6-year-old girl with a severe bleeding disorder, Oury et al. (2000) identified a somatic heterozygous 3-bp deletion in the P2RX1 gene (1051delCTG), resulting in the deletion of residue leu351 within a stretch of 4 leucine residues in the second transmembrane-2 domain of the P2X1 receptor, which is believed to be part of the ion-conducting region. The mutation was not identified in cDNAs from the patient's reticulocytes or in the P2X1 gene from patient neutrophil and mononuclear cells, suggesting a clonal origin. Functional expression studies showed that the mutant P2X1 receptor had exhibited proper membrane localization, but formed a nonfunctional channel. Coexpressed with wildtype P2RX1 showed that the mutant protein exhibited a dose-dependent dominant-negative effect on the normal ATP- or ADP-induced P2X1 channel activity. Clinically, the patient presented at age 19 months with pronounced bleeding and was hospitalized for severe exsanguination from a nosebleed. She continued to have recurrent spontaneous generalized petechiae and ecchymoses. Laboratory studies showed normal platelet count and size, but a selective impairment of ADP-induced platelet aggregation. However, Cattaneo (2005) noted that the defect of ADP-induced platelet aggregation in the patient reported by Oury et al. (2000) could not be explained by the P2X1 receptor defect, since that receptor has no role in ADP-induced platelet aggregation. Thus, the relationship between genotype and phenotype in this patient is unclear.
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]
Cattaneo, M. The P2 receptors and congenital platelet function defects. Semin. Thromb. Hemost. 31: 168-173, 2005. Note: Erratum: Semin. Thromb. Hemost. 32: 77 only, 2006. [PubMed: 15852220] [Full Text: https://doi.org/10.1055/s-2005-869522]
Clifford, E. E., Parker, K., Humphreys, B. D., Kertesy, S. B., Dubyak, G. R. The P2X(1) receptor, an adenosine triphosphate-gated cation channel, is expressed in human platelets but not in human blood leukocytes. Blood 91: 3172-3181, 1998. [PubMed: 9558372]
Hechler, B., Lenain, N., Marchese, P., Vial, C., Heim, V., Freund, M., Cazenave, J.-P., Cattaneo, M., Ruggeri, Z. M., Evans, R., Gachet, C. :A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo. J. Exp. Med. 198: 661-667, 2003. [PubMed: 12913094] [Full Text: https://doi.org/10.1084/jem.20030144]
Liang, S. X., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Phillips, W. D. Structure and chromosome location of the mouse P2X(1) purinoceptor gene (P2rx1). Cytogenet. Cell Genet. 92: 333-336, 2001. [PubMed: 11435708] [Full Text: https://doi.org/10.1159/000056923]
Mahaut-Smith, M. P., Tolhurst, G., Evans, R. J. Emerging roles for P2X1 receptors in platelet activation. Platelets 15: 131-144, 2004. [PubMed: 15203715] [Full Text: https://doi.org/10.1080/09537100410001682788]
Mulryan, K., Gitterman, D. P., Lewis, C. J., Vial, C., Leckle, B. J., Cobb, A. L., Brown, J. E., Conley, E. C., Buell, G., Pritchard, C. A., Evans, R. J. Reduced vas deferens contraction and male fertility in mice lacking P2X1 receptors. Nature 403: 86-89, 2000. [PubMed: 10638758] [Full Text: https://doi.org/10.1038/47495]
Oury, C., Toth-Zsamboki, E., Van Geet, C., Thys, C., Wei, L., Nilius, B., Vermylen, J., Hoylaerts, M. F. A natural dominant negative P2X1 receptor due to deletion of a single amino acid residue. J. Biol. Chem. 275: 22611-22614, 2000. [PubMed: 10816552] [Full Text: https://doi.org/10.1074/jbc.C000305200]
Sun, B., Li, J., Okahara, K., Kambayashi, J. P2X1 purinoceptor in human platelets: molecular cloning and functional characterization after heterologous expression. J. Biol. Chem. 273: 11544-11547, 1998. [PubMed: 9565569] [Full Text: https://doi.org/10.1074/jbc.273.19.11544]
Valera, S., Hussy, N., Evans, R. J., Adami, N., North, R. A., Surprenant, A., Buell, G. A new class of ligand-gated ion channel defined by P-2X receptor for extracellular ATP. Nature 371: 516-519, 1994. [PubMed: 7523951] [Full Text: https://doi.org/10.1038/371516a0]
Valera, S., Talabot, F., Evans, R. J., Gos, A., Antonarakis, S. E., Morris, M. A., Buell, G. N. Characterization and chromosomal localization of a human P2X receptor from the urinary bladder. Receptors Channels 3: 283-289, 1995. [PubMed: 8834001]
Vial, C., Rolf, M. G., Mahaut-Smith, M. P., Evans, R. J. A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors. Brit. J. Pharm. 135: 363-372, 2002. [PubMed: 11815371] [Full Text: https://doi.org/10.1038/sj.bjp.0704486]