Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology.
Thromboxane A(2) (TXA(2)), an unstable arachidonic acid metabolite, elicits diverse physiological/pathophysiological actions, including platelet aggregation and smooth muscle contraction. TXA(2) has been shown to be involved in allergies, modulation of acquired immunity, atherogenesis, neovascularization, and metastasis of cancer cells. The TXA(2) receptor (TP) communicates mainly with G(q) and G(13), resulting in phospholipase C activation and RhoGEF activation, respectively. In addition, TP couples with G(11), G(12), G(13), G(14), G(15), G(16), G(i), G(s) and G(h). 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 Asp(193) is a key amino acid. There are two alternatively spliced isoforms of TP, TPalpha and TPbeta, which differ only in their C-terminals. TPalpha and TPbeta 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, TXA(2) synthase inhibitors and TP antagonists. Some flavonoids of natural origin also have TP receptor antagonistic activity. Recent advances in TP research have clarified TXA(2)-mediated events in detail, and further study will supply more beneficial information about TXA(2) pathophysiology.
Nakahata
Norimichi
N
Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-0815, Japan.
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D019204:GTP-Binding Proteins