Thromboxane receptor
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[5] and was the first eicosanoid receptor cloned.[6] The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.[5]
Gene
The
Heterogeneity
The expression of α and β isoforms is not equal within or across different cell types.
Mice and rats express only the TPα isoform. Since these rodents are used as animal models to define the functions of genes and their products, their failure to have two TP isoforms has limited understanding of the individual and different functions of each TP receptor isoform.[13]
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.[9] For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.[9][14]
| Organ/Tissue | Cells/Cell lines | |
|---|---|---|
| TP Receptor Distribution[9] | Lung, Spleen, Uterus, Placenta, Aorta, Heart, Intestine, Liver, Eye, Thymus, Kidney, Spinal Cord, Brain | Platelets, Blood Monocytes, Glomerular mesangial cells, Oligodendrocytes, Cardiac myocytes, Afferent Sympathetic Nerve Endings in the Heart, 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), astrocytoma cells |
TP receptor ligands
Activating ligands
Standard
Inhibiting ligands
Several synthetic compounds bind to, but do not activate, TP and thereby inhibit its activation by activating ligands. These
Mechanism of cell stimulation
TP is classified as a contractile type of prostenoid receptor based on its ability to contract diverse types of smooth muscle-containing tissues such as those of the lung, intestines, and uterus.[20] TP contracts smooth muscle and stimulates various response in a wide range of other cell types by coupling with and mobilizing one or more families of the G protein class of receptor-regulated cell signaling molecules. When bound to TXA2, PGH2, or other of its agonists, TP mobilizes members of the:[14][21][22]
- a) myosin light chain kinase, Mitogen-activated protein kinases, and Calcineurin;
- b) G12/G13 family which activates Rho GTPases that control cell migration and intracellular organelle movements;
- c) cell signaling pathways (see PKA)
- d) atypical G protein complex Gh/transglutaminase-2-calreticulin which activates phospholipase C, IP3, cell Ca2+ mobilization, protein kinase C, and Mitogen-activated protein kinase but inhibits adenyl cyclase.
Following its activation of these pathways, the TP receptors's cell-stimulating ability rapidly reverses by a process termed
In addition to its ability to down-regulate TPα, the IP receptor activates cell signaling pathways that counteract those activated by TP. Furthermore, the IP receptor can physically unite with the TPα receptor to form an IP-TPα heterodimer complex which, when bound by TXA2, activates predominantly IP-coupled cell signal pathways. The nature and extent of many cellular responses to TP receptor activation are thereby modulated by the IP receptor and this modulation may serve to limit the potentially deleterious effects of TP receptor activation (see following section on Functions).[12][13]
Functions
Studies using animals genetically engineered to lack the TP receptor and examining the actions of this receptor's agonists and antagonists in animals and on animal and human tissues indicate that TP has various functions in animals and that these functions also occur, or serve as a paradigm for further study, in humans.
Platelets
Human and animal
Cardiovascular system
Animal model studies indicate that TP receptor activation contracts vascular smooth muscle cells and acts on cardiac tissues to increase heart rate, trigger
20-Hydroxyeicosatetraenoic acid (20-HETE), a product of arachidonic acid formed by Cytochrome P450 omega hydroxylases,[25] and certain isoprostanes, which form by non-enzymatic free radical attack on arachidonic acid,[17] constrict rodent and human artery preparations by directly activating TP. While significantly less potent than thromboxane A2 in activating this receptor, studies on rat and human cerebral artery preparations indicate that increased blood flow through these arteries triggers production of 20-HETE which in turn binds TP receptors to constrict these vessels and thereby reduce their blood blow. Acting in the latter capacity, 20-HETE, it is proposed, functions as a TXA2 analog to regulate blood flow to the brain and possibly other organs.[15][26] Isoprostanes form in tissues undergoing acute or chronic oxidative stress such as occurs at sites of inflammation and the arteries of diabetic patients.[17] High levels of isoprostanes form in ischemic or otherwise injured blood vessels and acting through TP, can stimulate arterial inflammation and smooth muscle proliferation; this isoprostane-TP axis is proposed to contribute to the development of atherosclerosis and thereby heart attacks and strokes in humans.[17][19]
Lung allergic reactivity
TP receptor activation contracts bronchial smooth muscle preparations obtained from animal models as well as humans and contracts airways in animal models.
Uterus
Along with
Immune system
Activation of TP receptors stimulates vascular endothelial cell pro-inflammatory responses such as increased expression of cell surface adhesion proteins (i.e.
Cancer
Increased expression of cyclooxygenases and their potential involvement in the progression of various human cancers have been described. Some studies suggest that the TXA2 downstream metabolite of these cyclooxygenases along with its TP receptor contribute to mediating this progression. TP activation stimulates tumor cell proliferation, migration, neovascularization, invasiveness, and metastasis in animal models, animal and human cell models, and/or human tissue samples in cancers of the prostate, breast, lung, colon, brain, and bladder.[14][31] These findings, while suggestive, need translational studies to determine their relevancy to the cited human cancers.
Clinical significance
Isolated cases of humans with mild to moderate bleeding tendencies have been found to have mutations in TP that are associated with defects in this receptors binding of TXA2 analogs, activating cell signal pathways, and/or platelet functional responses not only to TP agonists but also to agents that stimulate platelets by TP-independent mechanisms (see Genomics section below).[15]
Drugs in use targeting TP
TP receptor antagonist seratrodast is marketed in Japan and China for the treatment of asthma. Picotamide, a dual inhibitor of TP and TXA2 synthesis, is licensed in Italy for the treatment of clinical arterial thrombosis and peripheral artery disease.[15] These drugs are not yet licensed for use in other countries.
Clinical trials
While functional roles for TP receptor signaling in diverse homeostatic and pathological processes have been demonstrated in animal models, in humans these roles have been demonstrated mainly with respect to platelet function, blood clotting, and hemostasis. TP has also been proposed to be involved in human: blood pressure and organ blood flow regulation; essential and pregnancy-induced hypertension; vascular complications due to sickle cell anemia; other cardiovascular diseases including heart attack, stroke, and peripheral artery diseases; uterine contraction in childbirth; and modulation of innate and adaptive immune responses including those contributing to various allergic and inflammatory diseases of the intestine, lung, and kidney.[9] However, many of the animal model and tissue studies supporting these suggested functions have yet to be proven directly applicable to human diseases. Studies to supply these proofs rest primarily on determining if TP receptor antagonists are clinically useful. However, these studies face issues that drugs which indirectly target TP (e.g. Nonsteroidal anti-inflammatory drugs that block TXA2 production) or which circumvent TP (e.g. P2Y12 antagonists that inhibit platelet activation and corticosteroids and cysteinyl leukotriene receptor 1 antagonists that suppress allergic and/or inflammatory reactions) are effective treatments for many putatively TP-dependent diseases. These drugs are likely to be cheaper and may prove to have more severe side effects that TP-targeting drugs.[14] These considerations may help to explain why relatively few studies have examined the clinical usefulness of TP-targeting drugs. The following translation studies on TP antagonists have been conducted or are underway:[27][19]
- In a non-randomized, uncontrolled examination, 4 weeks of treatment with TP receptor antagonist AA-2414 significantly reduced bronchial reactivity in asthmatic patients. A follow-up ).
- A phase 3 study, TP antagonist Terutroban was tested against aspirin as a preventative of recurrent as well as new ischemia events in patients with recent strokes or transient ischemic attacks. The study did not meet its primary end points compared to aspirin-treated controls and was stopped; patients on the drug experienced significant increases in minor bleeding episodes.
- A study comparing the safety and efficacy of TP antagonist ridogrel to aspirin as adjunctive therapy in the emergent treatment of heart attack with the clot dissolving agent streptokinase found that ridogrel gave no significant enhancement of clot resolution but was associated with a lower incidence of recurrent heart attack, recurrent angina, and new strokes without causing excess bleeding **complications.
- TP antagonist Ifetroban is in phase 2 clinical development for the treatment of kidney failure.
In addition to the above TP antagonists, drugs that have dual inhibitory actions in that they block not only TP but also block the enzyme responsible for making TXA22, Thromboxane-A synthase, are in clinical development. These dual inhibitor studies include:[15]
- A long-term study in diabetic patients compared dual inhibitor picotamide to aspirin for improving ischemia symptoms caused be peripheral artery diseases found not difference in primary end points but also found that picotamide therapy significantly reduced cardiovascular mortality over a 2-year trial.
- A phase 2 clinical trial of Dual inhibitor Terbogrel to treat vasoconstriction was discontinued due to its induction of leg pain.
- Dual inhibitor EV-077 is in clinical phase II development.
Genomics
Several isolated and/or inherited cases of patients suffering a mild to moderately severe bleeding diathesis have been found to be associated with mutations in 'the 'TBXA2R gene that lead to abnormalities in the expression, subcellular location, or function of its TP product. These cases include:[15][32]
- A missense mutation causing tryptophan (Trp) to be replaced by cysteine (Cys) as its 29th amino acid (i.e. Trp29Cys) yields a TP which is less responsive to stimulation by a TP agonist, less able to activate its Gq G protein target, and poorly expressed at the cell's surface. Some or perhaps all of these faults may reflect the failure of this mutated TP to form TP-TP dimers.
- An Asn42Ser mutation yields a TP that remains in the cell's Golgi apparatus and fails to be expressed at the cell surface.
- An Asp304Asn mutation yields a TP that exhibits decreased binding and responsiveness to a TP agonist.
- An Arg60Leu mutation yields a TP that is normally expressed and normally binds a TP agonist but fails to activate its Gq G protein target.
- A missense mutation that replaces thymine (T) with guanine (G) as the 175 nucleotide (c.175C>T) in the TBXA2R gene as well as Cc87G>C and c.125A>G mutations yield TP's that are poorly expressed.
- A c.190G>A mutation yields a TP that binds a TP agonist poorly.
- A guanine (G) duplication at the 167th nucleotide causes a Frameshift mutation (c.165dupG) at amino acid #58 to yield a poorly expressed TP mutant.
- urticarialin a Korean test group.
- SNP variant rs768963 in TBX2R was associated with increased frequency of large artery atherosclerosis, small artery occlusion, and stroke in two separate studies of Chinese test groups. In one of the latter groups, the T-T-G-T haplotype of C795T-T924C-G1686A-rs768963 was significantly less frequent in patients suffering stroke. SNP variant rs13306046 exhibited a reduction in microRNA-induced repression of TBXA2R gene expression and was associated with decreased blood pressure in a Scandinavian Caucasian test group.
See also
References
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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. S2CID 260320877.
- 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. S2CID 4368702.
- 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. 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. 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. 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. 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. 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. 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. 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. S2CID 7488221.
- 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. PMID 11877412.
External links
- "Prostanoid Receptors: TP". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.