Thromboxane A2: Physiology/pathophysiology, cellular signal transduction and pharmacology

Thromboxane A2 (TXA2), an unstable arachidonic acid metabolite, elicits diverse physiological/pathophysiological actions, including platelet aggregation and smooth muscle contraction. TXA2 has been shown to be involved in allergies, modulation of acquired immunity, atherogenesis, neovascularization, and metastasis of cancer cells. The TXA2 receptor (TP) communicates mainly with Gq and G13, resulting in phospholipase C activation and RhoGEF activation, respectively. In addition, TP couples with G11, G12, G13, G14, G15, G16, Gi, Gs and Gh. TP is widely distributed in the body, and is expressed at high levels in thymus and spleen. The second extracellular loop of TP is an important ligand-binding site, and Asp193 is a key amino acid. There are two alternatively spliced isoforms of TP, TPα and TPβ, which differ only in their C-terminals. TPα and TPβ communicate with different G proteins, and undergo hetero-dimerization, resulting in changes in intracellular traffic and receptor protein conformations. TP cross-talks with receptor tyrosine kinases, such as EGF receptor, to induce cell proliferation and differentiation. TP is glycosylated in the N-terminal region for recruitment to plasma membranes. Furthermore, TP conformation is changed by coupling to G proteins, showing several states of agonist binding. Finally, several drugs modify TP-mediated events; these include cyclooxygenase inhibitors, TXA2 synthase inhibitors and TP antagonists. Some flavonoids of natural origin also have TP receptor antagonistic activity. Recent advances in TP research have clarified TXA2-mediated events in detail, and further study will supply more beneficial information about TXA2 pathophysiology.