Disease relevance of TBXA2R

• Synthetic peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone suppress transcription by promoter 3 of the human thromboxane A2 receptor gene in human erythroleukemia cells [1].
• TBXA2R thus has a significant prognostic value in clinical breast cancer [2].
• Cloning and pharmacologic characterization of a thromboxane A2 receptor from K562 (human chronic myelogenous leukemia) cells [3].
• Decrease in thromboxane A2 receptor expression by differentiation with dibutyryl cyclic AMP in 1321N1 human astrocytoma cells [4].
• The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries [5].

High impact information on TBXA2R

• Northern blot analysis and nucleotide sequences of the two clones suggest that an identical species of the thromboxane A2 receptor is present in platelets and vascular tissues [6].
• Two isoforms of the human TXA2 receptor have been cloned; one from placenta and the other from endothelium, here referred to as TXR alpha and TXR beta, respectively [7].
• TXA2 receptor antagonists block the activity of both TXA2 and PGH2 on platelets and the vessel wall [8].
• Thromboxane synthase inhibitors suppress TXA2 formation and increase the synthesis of the antiaggregatory prostaglandins PGI2 and PGD2; however, accumulated PGH2 may interact with the platelet and vessel wall TXA2 receptor, thus reducing the antiplatelet effects of this class of drug [8].
• Peptide mapping studies of in vivo phosphorylated TXA2 receptors demonstrated cGMP mediates phosphorylation of the carboxyl terminus of the TXA2 receptor [9].

Chemical compound and disease context of TBXA2R

• The results suggest that 1321N1 human astrocytoma cells differentiated with dbcAMP show impaired TXA2 receptor-mediated phosphoinositide hydrolysis and Ca2+ mobilization, due to the decrease in TXA2 receptor number [4].
• 15-deoxy Delta12,14-prostaglandin J2 suppresses transcription by promoter 3 of the human thromboxane A2 receptor gene through peroxisome proliferator-activated receptor gamma in human erythroleukemia cells [10].
• CONCLUSION: TxA2 receptor-mediated vasoconstriction is reduced in the fetal vasculature of placentae from women with pre-eclampsia, possibly to compensate for the increased levels of TxA2 seen in these conditions [11].
• These results suggest that phosphatidylcholine-specific phospholipase C and protein kinase C, but not phosphatidylinositol-specific phospholipase C, are involved in TXA2 receptor-mediated MAPK activation in 1321N1 human astrocytoma cells [12].
• Antagonists of the TXA2 receptor and/or TXA2 synthesis in vivo have been associated with selective improvement in renal vascular tone and preservation of GFR during experimental endotoxemia in several mammalian species [13].

Biological context of TBXA2R

• TBXA2R was localized to chromosome 19 by PCR amplification in a series of monochoromosomal human/rodent somatic cell hybrids [14].
• Transient expression of the HEL cell TXA2 receptor cDNA and radioligand binding studies with the agonist 125I-BOP showed a single class of binding sites with an affinity comparable to a low affinity platelet TXA2 receptor [15].
• These findings may provide useful information for conducting mutagenesis and reveal the molecular mechanism how the human TXA2 receptor interact with G alpha 13 to activate intracellular signaling [16].
• RESULTS: The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma [17].
• OBJECTIVE: To determine whether IL-5 (T-746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma [17].

Anatomical context of TBXA2R

• Using a series of 13-azapinane TXA2 analogs, which discriminate between TXA2 receptor subtypes in platelets and vascular smooth muscle, we found that the cloned HEL cell TXA2 receptor is characteristic of a platelet type TXA2 receptor and that its binding characteristics are different from those of vascular smooth muscle cells [15].
• Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma [17].
• Further evidence for functional coupling of G13 to TXA2 receptors was provided in studies where solubilized platelet membranes were subjected to immunoaffinity chromatography using an antibody raised against native TXA2 receptor protein [18].
• 1. 5-HT and the prostanoid TP receptor agonists, U46619 and I-BOP, constricted the human umbilical artery with pEC50 values of 7.3+/-0 [19].
• Thromboxane A2 receptor signaling inhibits vascular endothelial growth factor-induced endothelial cell differentiation and migration [20].

Associations of TBXA2R with chemical compounds

• Both statins significantly reduced IP receptor-mediated cyclic AMP generation and intracellular calcium ([Ca(2+)](i)) mobilization in a time and concentration dependent manner but had no effect on signalling by the non-isoprenylated beta(2) adrenergic receptor or by the human prostanoid-TP receptor isoforms [21].
• The alpha, but not the beta, isoform of the human thromboxane A2 receptor is a target for prostacyclin-mediated desensitization [22].
• 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 [23].
• Activation of human platelets by thrombin and the thromboxane A2 receptor agonist U46619 lead to phosphorylation of Galpha12 and Galpha13 [24].
• Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases [25].

Physical interactions of TBXA2R

• These results suggest TXA2 receptor polymorphism strongly interacts with IL-4R alpha polymorphism as a major determinant of high serum immunoglobulin E levels in AD [26].
• The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family [27].

Regulatory relationships of TBXA2R

• In separate experiments, it was found that the TXA2 receptor agonist U46619 stimulated [35S]guanosine 5'-O-(3-thiotriphosphate) incorporation into G13 alpha-subunit [18].
• Thromboxane A2 (TXA2) synthetase inhibitor and TXA2R inhibitor R68070 were able to inhibit platelet aggregation induced by CD69 stimulation, indicating that TXA2 was the main mediator of the response [28].
• The thromboxane A2 receptor activates mitogen-activated protein kinase via protein kinase C-dependent Gi coupling and Src-dependent phosphorylation of the epidermal growth factor receptor [29].
• These results suggest that glibenclamide also reduced the endothelin-1-induced contractions by inhibiting a thromboxane A2 receptor-mediated component of the contraction elicited by this peptide [30].

Other interactions of TBXA2R

• Characterization of the cloned HEL cell thromboxane A2 receptor: evidence that the affinity state can be altered by G alpha 13 and G alpha q [15].
• Linkage mapping places TBXA2R closest to the anonymous marker D19S120, with a maximal LOD = 19.55, at a theta = 0.05 in the CEPH panel of DNAs [14].
• AD patients with both TXA2 receptor 795TT genotype and the IL-4R alpha Ile50/Ile50 genotype showed the greatest immunoglobulin E concentrations [26].
• A similar differential expression pattern was seen in tumours from patients with different prognosis, in that patients with predicted poor prognosis had higher, but not statistically different, levels of TBXA2R, and significantly lower levels of TBXAS1 (p = 0.008) [2].
• Reconstitution of thromboxane A2 receptor-stimulated phosphoinositide hydrolysis in isolated platelet membranes: involvement of phosphoinositide-specific phospholipase C-beta and GTP-binding protein Gq [31].

Analytical, diagnostic and therapeutic context of TBXA2R

• We amplified a 573-nucleotide fragment of the transcribed 3' untranslated region of the TBXA2R gene using the polymerase chain reaction (PCR) and the published cDNA sequence [14].
• Levels of TBXA2R and TBXAS1 transcripts were quantified using quantitative real-time RT-PCR analysis and correlated with clinical/pathological information including nodal status, grade, prognosis and long term survival (median follow-up period 120 months) [2].
• Finally, Kaplan-Meier survival analysis has shown that patients with high levels of TBXA2R had significantly shorter disease free survival (103.8 (79.1-128.5) months) compared with those with low levels (123.7 (112.0-135.3)) months, p = 0.043 [2].
• The alpha subunit of Gq/ll bound to TXA2-receptor was reduced by the differentiation, determined by immunoblotting after immunoprecipitation with an anti-TXA2-receptor antibody [4].
• Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT) [32].

References