Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The prior addition of non-aggregating concentrations of the divalent cation ionophore, A-23187, causes human platelets to aggregate in response to a subsequent addition of the 2',3'-dialdehyde and 2',3'-dialcohol derivatives of ADP (oADP and or ADP). Previous studies [Pearce et al. (1978) Eur. J. Biochem. 88, 543--555] have shown that these derivatives act as partial agonists at the platelet ADP receptor inducing only the transition from discoid to globular morphology ('shape change'). A secretion response is also observed on addition of a low concentration of ionophore A-23187 prior to orADP. These responses are not observed if ionophore A-23187 is added prior to the 2',3'-dialdehyde and 2',3'-dialcohol derivatives of ATP (oATP and or ATP) and are markedly inhibited by prior addition of the ADP antagonist, adenosine 5'-[beta, gamma-methylene]triphosphate. 2. The aggregation response to oADP in the presence of ionophore A-23187 is reduced but not eliminated by addition of 3 mM EGTA when studies are performed in heparinised platelet-rich plasma. Additions of 3 mM EGTA in citrated platelet-rich plasma, or of 4 mM EDTA in either system completely inhibits this response. Inhibitors which are reported to elevate the intracellular concentration of adenosine 3':5'-monophosphate (cyclic AMP) or to prevent Ca2+ movement also inhibit the aggregation response to oADP which is observed in the presence of ionophore A-23187. 3. Prior addition of inhibitors of adenylate cyclase fails to cause an aggregation response to subsequent addition of oADP or orADP. Certain of these inhibitors enhance and prolong the shape change response to oADP or orADP but only at concentrations an order of magnitude in excess of those required to antagonise inhibition by agents such as prostaglandin E1, which act by increasing the concentration of cyclic AMP. 4. The concentration of prostaglandin E1, adenosine or papaverine required to inhibit shape change induced by oADP is one to two orders of magnitude lower than that required to inhibit shape change induced by ADP. 5. Prior addition of oADP decreases the lag phase in the response of human platelets to arachidonate while also increasing the concentration required to observe half-maximal response, and causing a decrease in the extent of the response. Prior addition of oATP also diminishes the extent of this response and increases the concentration of arachidonate required but has no effect on the lag phase. 6. The data suggest that oADP and orADP are capable only of acting as partial agonists at the ADP receptor because of a defective ability to increase cytosolic Ca2+ concentration. The defect is rectified by the presence of low concentrations of ionophore A-23187, which promotes mobilisation of Ca2+ from an intracellular store. The results do not appear consistent with the thesis that a decrease in platelet cyclic AMP is an initiating event in aggregation induced by ADP, but do support a model which implicates cyclic AMP in depletion of cytosolic Ca2+.
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PMID:Factors influencing the response of human blood platelets to analogues of ADP which may act as partial agonists at the ADP receptor. 11 May 86

The effects of extracellular divalent cations on the responses of human platelets to adenosine 5'-diphosphate (ADP) and on its inhibition by the competitive antagonist adenosine 5'-triphosphate (ATP) were investigated. Two responses were studied, shape change and the inhibition of prostaglandin E1 (PGE1)-stimulated adenylate cyclase, and experiments were carried out in the presence of divalent cations (Ca2+ and Mg2+, 1 mM) or in their absence. For each response there was a small leftward shift of the concentration-response curve to ADP in the absence of divalent cations compared to that in their presence, and this leftward shift disappeared when the results were plotted in terms of ADP3- rather than total ADP concentration. The shape change results were, however, complicated by a reduction in the maximal response to ADP in the absence of divalent cations. For each response there was also a marked increase in the pA2 value of ATP in the absence of divalent cations compared to that in their presence, and this difference disappeared if the results were calculated in terms of ATP4- instead of total ATP. These results suggest that the human platelet ADP receptor, in common with other receptors for adenine nucleotides, recognises predominantly the uncomplexed forms of ADP and ATP as ligands.
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PMID:Effects of extracellular divalent cations on responses of human blood platelets to adenosine 5'-diphosphate. 794 29

The effects of the P2-purinoceptor antagonist, suramin, on ADP-induced increases in human platelet cytosolic calcium concentration ([Ca2+]i) and inhibition of prostaglandin E1 (PGE1)-stimulated adenylate cyclase activity were investigated. Suramin (50-200 microM) acted as an antagonist of ADP-induced increases in [Ca2+]i, causing parallel, rightward shifts of the log concentration-response curve to ADP with no apparent depression of the maximal response. However, the slope of the Schild plot was 2.3 +/- 0.3, similar to that obtained in previous studies on aggregation, indicating that the antagonism was not simply competitive. The apparent pA2 for suramin, taken from the Schild plot, was 4.63, similar to that for suramin's inhibition of aggregation, which suggests that these two effects are closely related. Suramin was not specific for the ADP receptor, however, as it was also able to inhibit, non-competitively, increases in [Ca2+]i induced by 5-hydroxytryptamine. Suramin (50-400 microM) also inhibited the effect of ADP on PGE1-stimulated accumulation of cyclic AMP, causing parallel shifts of the log concentration-response curve to ADP, with a Schild plot slope of 1.00 +/- 0.10, suggesting competitive antagonism, and a pA2 value of 5.09. Suramin (400 microM) did not reduce the inhibition of cyclic AMP accumulation by adrenaline, although it was able to inhibit the accumulation of cyclic AMP caused by PGE1, again showing that suramin has some non-specific effects. These data suggest that suramin is an antagonist at the platelet ADP receptor mediating increases in [Ca2+]i and inhibition of adenylate cyclase, but that it also shows non-specific effects and can depress platelet responses to other agonists. In addition, the similar pA2 value of suramin for the two effects of ADP does not support suggestion that they are mediated by two different receptors on human platelets.
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PMID:Effects of suramin on increases in cytosolic calcium and on inhibition of adenylate cyclase induced by adenosine 5'-diphosphate in human platelets. 814

Antiplatelet compounds interfere with the platelet activation cascade at different levels. The antiplatelet effect of the thienopyridine, clopidogrel, results from antagonism of a platelet ADP receptor, P2T, resulting in inhibition of platelet activation. This antagonism is non-competitive, irreversible, and results in a 50-70% inhibition of platelet fibrinogen binding. Additionally, clopidogrel may also antagonize the ADP-induced inhibition of adenylate cyclase, possibly resulting in an elevated platelet cyclic adenosine monophosphate level after stimulation by an appropriate agonist, such as prostacyclin. This spectrum of antiplatelet activities is different from that of aspirin. Further, clopidogrel is associated with a reduction in gastrointestinal hemorrhage, making it a valuable therapeutic alternative to aspirin in oral, long-term prevention of atherothrombotic vascular occlusion.
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PMID:Clinical pharmacology of the adenosine diphosphate (ADP) receptor antagonist, clopidogrel. 989 18

U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated human platelets ADP activated p38 MAP kinase in both a time-and concentration-dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate, either alone or together, nor indomethacin blocked ADP-induced p38 kinase activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2, and PGF2alpha, failed to activate p38 kinase in aspirin-treated platelets. Hence, ADP must be generating an agonist, other than thromboxane A2, via an aspirin-sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC (platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist, did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective agonist, alpha, beta-methylene ATP, failed to activate p38 MAP kinase. On the other hand, the P2Y1 receptor selective antagonist, adenosine-2'-phosphate-5'-phosphate inhibited ADP-induced p38 kinase activation in a concentration-dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced generation of the p38 kinase-activating factor. These results demonstrate that ADP causes the generation of a factor in human platelets, which can activate p38 kinase, and that this response is mediated by the P2Y1 receptor. Neither the P2TAC receptor nor the P2X1 receptor has any significant role in this response.
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PMID:The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets. 1075 52

Two unrelated patients with a congenital bleeding diathesis associated with a severe defect of the platelet ADP receptor coupled to adenylate cyclase (P2(CYC)) have been described so far. In one of them, platelet secretion was shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granule stores, thromboxane A(2) production, and ADP-induced primary wave of aggregation) have a moderate defect of P2(CYC). Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for normal platelet secretion, and PSD patients may be heterozygotes for the congenital severe defect of P2(CYC). In this study, we describe 2 new related patients with a severe defect of P2(CYC) and the son of one of them, who is to be considered an obligate heterozygote for the defect. The 2 patients with the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack of inhibition of adenylate cyclase by ADP, and a deficiency of platelet-binding sites for [(33)P]2 MeS-ADP (240 and 225 sites per platelet; normal range, 530 to 1102). The son of one of them had a mildly prolonged bleeding time and abnormalities of platelet aggregation and secretion similar to those found in patients with PSD. In addition, his platelets showed a moderate defect of binding sites for [(33)P]2 MeS-ADP (430 sites per platelet) and of adenylate cyclase inhibition by ADP. This study of a family with the platelet disorder characterized by a defect of the platelet P2(CYC) receptor supports our hypothesis that the full complement of the platelet ADP receptors is essential for normal platelet secretion and that some patients with the common, ill-defined diagnosis of PSD are actually heterozygous for the defect.
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PMID:Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2CYC receptors. 1107 62

Four patients with a previously unrecognized congenital disorder of platelet function have recently been described. Their platelets aggregate very poorly to exogenous ADP. The abnormality is likely due to a severe defect of the platelet ADP receptor that is coupled to adenylate cyclase, as suggested by the following findings: 1) ADP does not normally lower cAMP levels of PGE1-treated platelets; 2) platelet shape change induced by ADP is normal; 3) the binding of [radiolabelled]ADP to formalin-fixed platelets or of the ADP analogue [radiolabelled]2-MeS-ADP to fresh platelets is severely defective. Since all patients that have been described were born from consanguineous parents, the condition seems to be inherited as an autosomal recessive trait. Platelets of an obligate heterozygote have intermediate binding sites for 2-M eS-ADP, undergo a normal primary wave of aggregation induced by exogenous ADP, but do not normally secrete the content of their granules when stimulated by release-inducing agonists. Studies of normal platelets treated with acetylsalycilic acid revealed that ADP potentiates platelet secretion directly, and that the full complement of its platelet receptors appears to be necessary for this function.
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PMID:Hereditary defect of the platelet ADP receptor(s). 1679 95

We have previously shown that ADP-induced thromboxane generation in platelets requires signalling events from the G(q)-coupled P2Y1 receptor (platelet ADP receptor coupled to stimulation of phospholipase C) and the G(i)-coupled P2Y12 receptor (platelet ADP receptor coupled to inhibition of adenylate cyclase) in addition to outside-in signalling. While it is also known that extracellular calcium negatively regulates ADP-induced thromboxane A2 generation, the underlying mechanism remains unclear. In the present study we sought to elucidate the signalling mechanisms and regulation by extracellular calcium of ADP-induced thromboxane A2 generation in platelets. ERK (extracllular-signal-regulated kinase) 2 activation occurred when outside-in signalling was blocked, indicating that it is a downstream event from the P2Y receptors. However, blockade of either P2Y1 or the P2Y12 receptors with corresponding antagonists completely abolished ERK phosphorylation, indicating that both P2Y receptors are required for ADP-induced ERK activation. Inhibitors of Src family kinases or the ERK upstream kinase MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] abrogated ADP-induced ERK phosphorylation and thromboxane A2 generation. Finally ADP- or G(i)+G(z)-induced ERK phosphorylation was blocked in the presence of extracellular calcium. The present studies show that ERK2 is activated downstream of P2Y receptors through a complex mechanism involving Src kinases and this plays an important role in ADP-induced thromboxane A2 generation. We also conclude that extracellular calcium blocks ADP-induced thromboxane A2 generation through the inhibition of ERK activation.
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PMID:Regulation and functional consequences of ADP receptor-mediated ERK2 activation in platelets. 1729 99