Thromboxane receptor activation

Thromboxane receptor Inhibits TxA2 receptor-associated G protein activation... 

Recently, it was shown that the thromboxane receptor itself is a substrate ofcGMP-PK and cAMP-PK in HEK293 cells, HEL cells, or with purified enzymes in vitro. Phosphorylation of its cytoplasmic carboxyterminal domain prevented the thromboxane receptor from coupling to and activating G-proteins [36, 37]. For intact platelets, TxA2 receptor phosphorylation has not yet been shown, however, it would provide another explanation for the inhibition of PLC activation and subsequent intracellular Ca2+ elevation and granule secretion in response to cyclic nucleotides. 

Aimstrong RA, Jones RL, Wilson NH. Ligand binding to thromboxane receptors on human platelets correlation with biological activity. Br J Phannacol 1983 79 953-64... 

A direct effect of AmB on cell function was suggested by in vitro experiments, which demonstrated a vasoconstrictor action of AmB in perfused afferent arterioles and isometrically contracting rings of rabbit aorta or renal artery, effects which were prevented in Ca -free medium and by Ca" " channel blockers or theophylline [103]. Thus, AmB-induced reductions in RBF or GFR are not secondary to activation of TGF, but due to its direct vasoconstrictor effect. A role for thromboxane A2 has also been suggested based upon partial inhibition of the AmB-induced vasoconstriction and reduction in GFR by pretreatment with ibuprofen or a thromboxane receptor antagonist [104]. 

In both series almost equipotent activities were observed for thromboxane receptor antagonism and thromboxane synthase inhibition (IC50 = 2-30 nM). Upon oral administration to guinea pigs the enantiomers inhibited the ex vivo U-46619-induced platelet aggregation with potencies similar to that of the corresponding racemates. This indicates... 

Fitzgerald, D.J., Doran, J., Jackson, E. and FitzGerald, G.A. (1986). Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo. ]. Clin. Invest., 77, 496-502... 

Ogletree, M., Allen, G., O Keefe, E., Liv, K. and Hedberg, A. (1986). Activities of various prostanoids at thromboxane receptors revealed by selective receptor antagonists Studies in human platelets and several rat and guinea-pig smooth muscles. In 6th International Conference on Prostaglandins, p. 350. (Fondazione Giovanni Lorenzini)... 

A more active thromboxane receptor agonist was found in the 9a-homo-9,l 1-epoxy-5,13-prostadienoic acid analogue, SQ 26,538. This compound was 200 times more potent than arachidonic acid in inducing platelet aggregation but was onl> 1/10 as potent as PGH2. This effect was not blocked by inhibitors of cyclo-oxygenas< or of thromboxane synthetase [241]. 

Sugawara A, Uruno A, Kudo M, et al. Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Spl in vascular smooth muscle cells. J Biol Chem 2002 277 9676-9683. 

The formation of a platelet aggregate requires the recruitment of additional platelets from the blood stream to the injured vessel wall. This process is executed through a variety of diffusible mediators which act through G-protein-coupled receptors. The main mediators involved in this process are adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin (factor Ila). These mediators of the second phase of platelet activation are formed in different ways. While ADP is secreted from platelets by exocytosis, the release of TXA2 follows its new formation in activated platelets. Thrombin can be formed on the surface of activated platelets (see Fig. 2). 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

CoUagen-induced activation of a platelet phospholipase A2 by increased levels of cytosolic Ca results in hberation of arachidonic acid from platelet phospho-hpids, leading to the formation of thromboxane A2 (Chapter 23), which in turn, in a receptor-mediated fashion, can further activate phospholipase C, promot-ing platelet aggregation. 

---