Thromboxane receptor

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a is_associated_with::protein that in humans is encoded by the TBXA2R is_associated_with::gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first is_associated_with::eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

The TP receptor is a is_associated_with::G-protein coupled receptor coupled to the is_associated_with::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 is_associated_with::gene responsible for the thromboxane receptor, TBXA2R is found on is_associated_with::chromosome 19 and spans 15 is_associated_with::kilobases.

Heterogeneity
is_associated_with::Molecular biology findings have provided definite evidence of human TP receptor subtypes. The originally cloned TP from is_associated_with::placenta (343 amino acids in length) is known as the α isoform, and the splice variant cloned from is_associated_with::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 is_associated_with::phospholipase C activation, calcium release and activation of is_associated_with::protein kinase C. Nevertheless, they couple oppositely to is_associated_with::adenylate cyclase. TPα activates is_associated_with::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 is_associated_with::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, is_associated_with::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 is_associated_with::endothelium.

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. For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.

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.

Antagonists
TP receptor has been the easiest of the prostanoids receptors to block. Several laboratories have synthesized and developed TP receptor antagonists such as is_associated_with::Seratrodast (AA-2414), is_associated_with::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 is_associated_with::asthma, is_associated_with::thrombosis and is_associated_with::hypertension. Some studies have in fact revealed that TP receptor antagonists are more effective than is_associated_with::thromboxane synthase inhibitors.