| Thromboxane A2 receptor |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1LBN
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| Identifiers |
| Symbols |
TBXA2R ; BDPLT13; TXA2-R |
| External IDs |
OMIM: 188070 MGI: 98496 HomoloGene: 825 IUPHAR: 346 ChEMBL: 2069 GeneCards: TBXA2R Gene |
| Gene ontology |
| Molecular function |
• thromboxane A2 receptor activity
• guanyl-nucleotide exchange factor activity
• protein binding
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| Cellular component |
• acrosomal vesicle
• plasma membrane
• integral component of plasma membrane
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| Biological process |
• inflammatory response
• G-protein coupled receptor signaling pathway
• positive regulation of cytosolic calcium ion concentration
• response to nutrient
• blood coagulation
• second-messenger-mediated signaling
• platelet activation
• response to lipopolysaccharide
• thromboxane A2 signaling pathway
• response to drug
• positive regulation of GTPase activity
• positive regulation of angiogenesis
• positive regulation of blood pressure
• positive regulation of vasoconstriction
• positive regulation of smooth muscle contraction
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
6915 |
21390 |
| Ensembl |
ENSG00000006638 |
ENSMUSG00000034881 |
| UniProt |
P21731 |
P30987 |
| RefSeq (mRNA) |
NM_001060 |
NM_001277265 |
| RefSeq (protein) |
NP_001051 |
NP_001264194 |
| Location (UCSC) |
Chr 19:
3.59 – 3.61 Mb |
Chr 10:
81.33 – 81.34 Mb |
| PubMed search |
[2] |
[3] |
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The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors[1] and was the first eicosanoid receptor cloned.[2] The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.[1]
The TP receptor is a G-protein coupled receptor coupled to the G protein Gq.[3] The initial purification and cloning of the TP receptor established this protein as a member of the G protein-coupled super family of seven-transmembrane receptors.[4] The gene responsible for the thromboxane receptor, TBXA2R is found on chromosome 19 and spans 15 kilobases.[5]
Contents
- 1 Heterogeneity
- 2 Tissue distribution
- 3 Biological roles
- 4 Antagonists
- 5 See also
- 6 References
- 7 External links
- 8 Further reading
Heterogeneity
Molecular biology findings have provided definite evidence of human TP receptor subtypes.[1] The originally cloned TP from placenta (343 amino acids in length) is known as the α isoform, and the splice variant cloned from endothelium (with 407 amino acids) is termed the β isoform.[4] The first 328 amino acids are the same for both isoforms, but the β isoform exhibits an extended C-terminal cytoplasmic domain.[4] Both isoforms functionally couple to a Gq protein leading to the phospholipase C activation, calcium release and activation of protein kinase C.[2] Nevertheless, they couple oppositely to adenylate cyclase. TPα activates adenylate cyclase while TPβ inhibits this enzyme.[2] Intrareceptor differences in C-terminal tail sequence also allow for significant differences in their ability to internalize in response to agonist exposure.[6] For example, in HEK-293 cells, TPβ but not TPα undergoes U46619-induced G protein-coupled receptor (GRK) phosphorylation and internalization, whereas the C-terminus of TPα is not capable of being phosphorylated by GRKs.[6]
The expression of α and β isoforms is not equal within or across different cell types.[4] For example, platelets express high concentrations of the α isoform (and possess residual RNA for the β isoform), while expression of the β isoform has not been documented in these cells.[4] The β isoform is expressed in human endothelium.[6]
Tissue distribution
Historically, TP receptor involvement in blood platelet function has received the greatest attention. However, it is now clear that TP receptors exhibit a wide distribution in different cell types and among different organ systems.[4] For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.[4]
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Organ/Tissue |
Cells/Cell lines |
| TP Receptor Distribution[4] |
Lung, Spleen, Uterus, Placenta, Aorta, Heart, Intestine, Liver, Eye, Thymus, Kidney, Spinal Cord, Brain |
Platelets, Glomerular mesangial cells, Oligodendrocytes, Cardiac myocytes, Epithelial cells, Hela cells, Smooth muscle cells, Endothelial cells, Trophoblasts, Schwann cells, Astrocytes, Megakaryocytes, Kupffer cells, Human erythroleukemic megakaryocyte (HEL), K562 (Human chronic myelogenous leukemia) cells, Hepatoblastoma HepG2 cells, Immature thymocytes, EL-4 (mouse T cell line) |
Biological roles
Over the years, different biological roles for TP receptor signaling have been established in both homeostatic and pathological processes. TP receptor activation is thought to be involved in thrombosis/hemostasis, modulation of the immune response, acute myocardial infarction, inflammatory lung disease, hypertension, nephrotic disease, etc.[4]
| Biological roles of TXA2/TP receptor[4] |
| Asthma
Inflammatory lung disease
Hemostasis/thrombosis
Sickle cell disease
Cardiovascular disease
Lupus nephritis
Acute myocardial infarction
Nephrotic syndrome, Hypertension
Immune complex glomerulonephritis
Pregnancy-induced hypertension (PIH)
Regulating acquired immunity
Chronic inflammation in atopic diseases
Chronic inflammatory bowel diseases
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Antagonists
TP receptor has been the easiest of the prostanoids receptors to block.[1] Several laboratories have synthesized and developed TP receptor antagonists such as Seratrodast (AA-2414), Terutroban (S18886), PTA2, 13-APA, GR-32191, Sulotroban (BM-13177), SQ-29,548, SQ-28,668, ONO-3708, Bay U3405, EP-045, BMS-180,291, S-145 etc. which belong to numerous structural classes.[1][7] TP receptor antagonists have been evaluated as potential therapeutic agents for asthma, thrombosis and hypertension.[7] Some studies have in fact revealed that TP receptor antagonists are more effective than thromboxane synthase inhibitors.[7]
See also
References
- ^ a b c d e Devillier P, Bessard G (1997). "Thromboxane A2 and related prostaglandins in airways". Fundam Clin Pharmacol 11 (1): 2–18. doi:10.1111/j.1472-8206.1997.tb00163.x. PMID 9182072.
- ^ a b c Rolin S, Masereel B, Dogné JM (March 2006). "Prostanoids as pharmacological targets in COPD and asthma". Eur J Pharmacol 533 (1-3): 89–100. doi:10.1016/j.ejphar.2005.12.058. PMID 16458293.
- ^ Abe T, Takeuchi K, Takahashi N, Tsutsumi E, Taniyama Y, Abe K (1995). "Rat kidney thromboxane receptor: molecular cloning, signal transduction, and intrarenal expression localization". J. Clin. Invest. 96 (2): 657–64. doi:10.1172/JCI118108. PMC 185246. PMID 7635958.
- ^ a b c d e f g h i j Huang JS, Ramamurthy SK, Lin X, Le Breton GC (May 2004). "Cell signalling through thromboxane A2 receptors". Cell Signal 16 (5): 521–33. doi:10.1016/j.cellsig.2003.10.008. PMID 14751539.
- ^ TBXA2R thromboxane A2 receptor (Homo sapiens) [1]
- ^ a b c Farooque SP, Arm JP, Lee TH (2008). "Lipid Mediators: Leukotrienes, Prostanoids, Lipoxins, and Platelet-Activating Factor". In Holt PG, Kaplan AP, Bousquet J. Allergy and Allergic Diseases 1 (2 ed.). Oxford, UK: Wiley-Blackwell. ISBN 1-4051-5720-8.
- ^ a b c Shen RF, Tai HH (1998). "Thromboxanes: synthase and receptors". J Biomed Sci 5 (3): 153–72. doi:10.1007/BF02253465. PMID 9678486.
External links
- "Prostanoid Receptors: TP". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Further reading
- Namba T, Narumiya S (1993). "[Thromboxane A2 receptor; structure, function and tissue distribution]". Nippon Rinsho 51 (1): 233–40. PMID 8433523.
- Murugappan S, Shankar H, Kunapuli SP (2005). "Platelet receptors for adenine nucleotides and thromboxane A2". Semin. Thromb. Hemost. 30 (4): 411–8. doi:10.1055/s-2004-833476. PMID 15354262.
- Hirata M, Hayashi Y, Ushikubi F et al. (1991). "Cloning and expression of cDNA for a human thromboxane A2 receptor". Nature 349 (6310): 617–20. doi:10.1038/349617a0. PMID 1825698.
- Raychowdhury MK, Yukawa M, Collins LJ et al. (1995). "Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor". J. Biol. Chem. 270 (12): 7011. doi:10.1074/jbc.270.12.7011. PMID 7896853.
- Hirata T, Kakizuka A, Ushikubi F et al. (1994). "Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder". J. Clin. Invest. 94 (4): 1662–7. doi:10.1172/JCI117510. PMC 295328. PMID 7929844.
- D'Angelo DD, Davis MG, Ali S, Dorn GW (1994). "Cloning and pharmacologic characterization of a thromboxane A2 receptor from K562 (human chronic myelogenous leukemia) cells". J. Pharmacol. Exp. Ther. 271 (2): 1034–41. PMID 7965765.
- Raychowdhury MK, Yukawa M, Collins LJ et al. (1994). "Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor". J. Biol. Chem. 269 (30): 19256–61. PMID 8034687.
- Borg C, Lim CT, Yeomans DC et al. (1994). "Purification of rat brain, rabbit aorta, and human platelet thromboxane A2/prostaglandin H2 receptors by immunoaffinity chromatography employing anti-peptide and anti-receptor antibodies". J. Biol. Chem. 269 (8): 6109–16. PMID 8119956.
- Nüsing RM, Hirata M, Kakizuka A et al. (1993). "Characterization and chromosomal mapping of the human thromboxane A2 receptor gene". J. Biol. Chem. 268 (33): 25253–9. PMID 8227091.
- Funk CD, Furci L, Moran N, Fitzgerald GA (1994). "Point mutation in the seventh hydrophobic domain of the human thromboxane A2 receptor allows discrimination between agonist and antagonist binding sites". Mol. Pharmacol. 44 (5): 934–9. PMID 8246916.
- Schwengel DA, Nouri N, Meyers DA, Levitt RC (1994). "Linkage mapping of the human thromboxane A2 receptor (TBXA2R) to chromosome 19p13.3 using transcribed 3' untranslated DNA sequence polymorphisms". Genomics 18 (2): 212–5. doi:10.1006/geno.1993.1457. PMID 8288221.
- Offermanns S, Laugwitz KL, Spicher K, Schultz G (1994). "G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets". Proc. Natl. Acad. Sci. U.S.A. 91 (2): 504–8. doi:10.1073/pnas.91.2.504. PMC 42977. PMID 8290554.
- Hirata T, Ushikubi F, Kakizuka A et al. (1996). "Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation". J. Clin. Invest. 97 (4): 949–56. doi:10.1172/JCI118518. PMC 507140. PMID 8613548.
- Kinsella BT, O'Mahony DJ, Fitzgerald GA (1997). "The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha". J. Pharmacol. Exp. Ther. 281 (2): 957–64. PMID 9152406.
- Becker KP, Garnovskaya M, Gettys T, Halushka PV (1999). "Coupling of thromboxane A2 receptor isoforms to Galpha13: effects on ligand binding and signalling". Biochim. Biophys. Acta 1450 (3): 288–96. doi:10.1016/S0167-4889(99)00068-3. PMID 10395940.
- Barr CL, Wigg KG, Pakstis AJ et al. (1999). "Genome scan for linkage to Gilles de la Tourette syndrome". Am. J. Med. Genet. 88 (4): 437–45. doi:10.1002/(SICI)1096-8628(19990820)88:4<437::AID-AJMG24>3.0.CO;2-E. PMID 10402514.
- Zhou H, Yan F, Tai HH (2001). "Phosphorylation and desensitization of the human thromboxane receptor-alpha by G protein-coupled receptor kinases". J. Pharmacol. Exp. Ther. 298 (3): 1243–51. PMID 11504827.
- Vezza R, Mezzasoma AM, Venditti G, Gresele P (2002). "Prostaglandin endoperoxides and thromboxane A2 activate the same receptor isoforms in human platelets". Thromb. Haemost. 87 (1): 114–21. PMID 11848439.
- Turek JW, Halmos T, Sullivan NL et al. (2002). "Mapping of a ligand-binding site for the human thromboxane A2 receptor protein". J. Biol. Chem. 277 (19): 16791–7. doi:10.1074/jbc.M105872200. PMID 11877412.
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Prostanoids
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Receptor
(ligands) |
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Enzyme
(inhibitors) |
| Cyclooxygenase |
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| PGD2 synthase |
- Retinoids
- Selenium (selenium tetrachloride, sodium selenite, selenium disulfide)
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| PGE synthase |
HQL-79
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| PGF synthase |
Bimatoprost
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| PGI2 synthase |
Tranylcypromine
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| TXA synthase |
- Camonagrel
- Dazmegrel
- Dazoxiben
- Furegrelate
- Isbogrel
- Midazogrel
- Nafagrel
- Nicogrelate
- Ozagrel
- Picotamide
- Pirmagrel
- Ridogrel
- Rolafagrel
- Samixogrel
- Terbogrel
- U63557A
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| Others |
- Precursors: Linoleic acid
- γ-Linolenic acid (gamolenic acid)
- Dihomo-γ-linolenic acid
- Diacylglycerol
- Arachidonic acid
- Prostaglandin G2
- Prostaglandin H2
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See also: Leukotrienergics
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