Platelet activation adenyl cyclase

The intra-platelet levels of cAMP can be stabilized by prostacyclin or its analogues (e.g., iloprost) or by dipyridamole. The former activates adenyl cyclase via a G-protein-coupled receptor the latter inhibits a phosphodiesterase that breaks down cAMP. 

Alkenals, such as 4-hydroxynonenal (Esterbauer, 1985) which is very biologically active, inhibiting platelet aggregation, activating adenyl cyclase activity (Esterbauer, 1985) and is a substrate for glutathione transferases and... 

Prostacyclin (PGI2). Released by endothelium. Activates platelet Gs proteiu-liuked receptors, which in turn activate adenyl cyclase increased levels of cyclic AMP inhibit platelet... 

Activation of Cyclic AMP Generation in Intact Cells - Forskolin activates adenylate cyclase in Intact cells and tissues with similar characteristics as those observed for activation of the enzyme in membranes and solubilized preparations. These Include preparations of rat35 and human36 adipocytes, human platelets,37 tissue slices from brain and other peripheral tissues,3° and various endocrine and secretory tissues.39 Forskolin stimulates adenylate cyclase in S49 lymphoma cells,25 32 j-at astrocytomas.rat pheochromocytoma cells, 2 cultured pituitary cells, 3-48 cardiomyocytes, >30 cultured leydlg cells,31 and cultured kidney cells.32,53 Forskolin increases intracellular cyclic AMP rapidly with an EC50 of about lOpM, and results in elevations of cyclic AMP over basal levels which range between two and fifty-fold, depending on cell type and tissue. 

Forskolin (5-[acetyloxy]-3-ethenyldodecahydro-6,10,10b-trihydroxy-3,4a,7,7,10a-penta-methyl-[3R- 3a-4aP, SP, 6P, 6aa,10a, lOaP, 10ba -lFf-naphtho[2,l-b]pyran-l-one) [66575-29-9] M 410.5, m 229-232°, 228-233°. Recrystd from CfiH6-pet ether. It is antihypertensive, positive ionotropic, platelet aggregation inhibitory and adenylate cyclase activating properties [Chem AbstrS9 1978 244150, de Souza et al. Med Res Rev 3 201 1983]. 

Prostacyclin and its analogues also function by increasing the level of platelet cAMP, presumably by activation of the enzyme adenyl cyclase. A chemically stable analogue of prostacyclin called Iloprost has been effective in preventing consumption of platelets (71). 

Ebstein R, Belmaker R, Grunhaus L, et al Lithium inhibition of adrenaline-stimulated adenylate cyclase in humans. Nature 259 411-413, 1976 Ebstein RP, Hermoni M, Belmaker RH The effect of lithium on noradrenahne-in-duced cyclic AMP accumulation in rat brain inhibition after chronic treatment and absence of supersensitivity. J Pharmacol Exp Ther 213 161-167, 1980 Ebstein RP, Lerer B, Shlaufman M, et al The effect of repeated electroconvulsive shock treatment and chronic lithium feeding on the release of norepinephrine from rat cortical vesicular preparations. Cell Mol Neurobiol 3 191-201, 1983 Ebstein RP, Moscovich D, Zeevi S, et al Effect of lithium in vitro and after chronic treatment on human platelet adenylate cyclase activity prosreceptor modification or second messenger signal amplification. Psychiatry Res 21 221-228, 1987 Eccleston D, Cole AJ Calcium-channel blockade and depressive illness. Br J Psychiatry 156 889-891, 1990... 

Newman ME, Drummer D, Lerer B Single and combined effects of desimipramine and lithium on serotonergic receptor number and second messenger function in rat brain. J Pharmacol Exp Ther 252 826-831, 1990 Newman ME, Lerer B, Lichtenberg P, et al Platelet adenylate cyclase activity in depression and after clomipramine and lithium treatment. Psychopharmacology 109 231-234, 1992... 

Specific binding of PGE2 to a variety of cells correlates with an activation of adenylate cyclase and the accumulation of cAMP. In human adipocytes, PGE2 causes a 15-fold increase in the concentration of cAMP. In platelets, PGI2 rather than PGE2 appears to mediate the increase in cAMP. 

There are three important ADP receptors on the platelet surface (16). The P2X, inotrophic receptor is responsible for rapid influx of calcium into the cytosol. The P2Y, receptor mediates mobilization of calcium through activation of PLC and shape change. The P2Y,2 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease in the cAMP The decrease in cAMP stimulates dephosphorylation of VASP that is closely correlated with the GPIIb/llla activation. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

Anand-Srivastava MB. 1993. Rat platelets from spontaneously hypertensive rats exhibit decreased expression of inhibitory guanine nucleotide regulatory protein relationship with adenylate cyclase activity. Circ Res 173 1032-1039. 

Livingstone, C., A.R. McLellan, M.A. McGregor, A. Wilson, J.M. Connell, M. Small, G. Milligan, K.R. Paterson, and M.D. Houslay. 1991. Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects. Biochim. Biophys. Acta 1096 127-133. 

Hydroxy alkenals affect adenylate cyclase activity and phospholipase C activities reduce cell growth and promote cell differentiation inhibit platelet aggregation block macrophage action block thiol group... 

Huttemann, E, Ukena, D, Lenschow, V, Sdiwabe, U, Adenosine receptors in human platelets Characterization by 3=-Atethylcarboxamido[ H]adenosine binding in relation to adenylate cyclase activity. Nauyn-Schmiedebergs Arch Pharmacol 1984,32S 226-28S. 

Haslam RJ, Vanderwel M. Inhibition of platelete adenylate cyclase by l-0-alkyl-2-0-acetyl-sn-glyceryl-3-fdiosphoryldioline (platdet-activating factor). J Biol Chon 1982 257 6879-6885 Henson PM. Release of vasoactive amine from rabbit platelets induced by sensitized mmoniidear leukocytes and antigens. J Exp Med 1970 131 287-304... 

Maurice DH, HaSLAM RJ. Molecular basis of the synergistic inhibition of platelet function by nihovasodilators and activators of adenylate cyclase inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmcolil 671-681,1991. 

BRASS LF, LAPOSATA M, BANGA HS, RTITENHOUSE SE (1986) Relation of the phosjAoinositide hydrolysis pathway in thrombin-stimulated platelets by a pertussis toxin-senative guanine nucleotide-binding protein. Evaluation of its contribution to platelet activation and comparisons with the adenylate cyclase inhibitory protein, Gi. Journal of Biological Chemistry, 261,16838-16847. 

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