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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 and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.
The TP receptor is a G-protein coupled receptor coupled to the G protein Gq. 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. The gene responsible for the thromboxane receptor, TBXA2R is found on chromosome 19 and spans 15 kilobases.
Molecular biology findings have provided definite evidence of human TP receptor subtypes. 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. The first 328 amino acids are the same for both isoforms, but the β isoform exhibits an extended C-terminal cytoplasmic domain. Both isoforms functionally couple to a Gq protein leading to the phospholipase C activation, calcium release and activation of protein kinase C. Nevertheless, they couple oppositely to adenylate cyclase. TPα activates adenylate cyclase while TPβ inhibits this enzyme. Intrareceptor differences in C-terminal tail sequence also allow for significant differences in their ability to internalize in response to agonist exposure. 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.
The expression of α and β isoforms is not equal within or across different cell types. 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. The β isoform is expressed in human endothelium.
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. For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.
|TP Receptor Distribution||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)|
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.
|Biological roles of TXA2/TP receptor|
Inflammatory lung disease
Sickle cell disease
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
TP receptor has been the easiest of the prostanoids receptors to block. 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. TP receptor antagonists have been evaluated as potential therapeutic agents for asthma, thrombosis and hypertension. Some studies have in fact revealed that TP receptor antagonists are more effective than thromboxane synthase inhibitors.
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