Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Heparin was found to be the most potent inhibitor of rat ovarian luteinizing hormone-sensitive adenylate cyclase (I50 = 2 microgram/ml) when compared to other naturally occurring glycosamin oglycans. This inhibition was also apparent when this enzyme was stimulated by follicle-stimulating hormone or prostaglandin E2. Heparin was also found to inhibit glucagon-sensitive rat hepatic adenylate cyclase, and the prostaglandin E1-sensitive enzyme from rat ileum and human platelets. In contrast, heparin stimulated the dopamine sensitive adenylate cyclase from rat caudate nucleus. The sulfated polysugar dextran sulfate exerts similar effects on adenylate cyclase activity of the rat ovary and was shown to inhibit hormone binding to rat ovarian plasma membrane in a manner similar to that exerted by heparin. In contrast to heparin, dextran sulfate inhibited dopamine-sensitive adenylate cyclase from rat caudate nucleus.
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PMID:Modulation of adenylate cyclase activity by sulfated glycosaminoglycans. II. Effects of mucopolysaccharides and dextran sulfate on the activity of adenylate cyclase derived from various tissues. 15 57

Heparin inhibits (I50 = 2 microgram/ml) the activity of luteinizing hormone and human chorionic gonadotropin-stimulated adenylate cyclase in purified rat ovarian plasma membranes. Unstimulated enzyme activity and activity stimulated by NaF, GTP or guanosine 5'-(beta,gamma-imido)triphosphate were inhibited to a lesser extent. Human chorionic gonadotropin binding to this membrane preparation was inhibited by heparin (I50 = 6 microgram/ml). The inhibition with respect to hormone concentration was of a mixed type for hormone binding and adenylate cyclase stimulation. Inhibition by heparin was not eliminated at saturating hormone concentration. The degree of inhibition was unaffected by the order in which enzyme, hormone and heparin were introduced into the assay system. Heparin (3 microgram/ml) did not affect the pH activity relationship of basal and hormone-stimulated adenylate cyclase activity and did not change the dependence of enzyme activity on magnesium ion concentration. The inhibitory action of heparin cannot be solely attributed to interference with either catalysis or hormone binding. The possibility is considered that the highly charged heparin molecule interferes with enzyme receptor coupling, by restricting the mobility of these components or by effecting their conformation.
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PMID:Modulation of adenylate cyclase activity by sulfated glycosaminoglycans. I. Inhibition by heparin of gonadotrophin-stimulated ovarian adenylate cyclase. 21 54

The influences of heparin, dextran and trypan blue on muscarinic receptor binding properties and inhibition of adenylate cyclase were investigated in homogenates of the rat heart. These compounds caused a concentration-dependent enhancement in the specific binding of the muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) when measured at a radioligand concentration of approximately 0.5 nM in magnesium-containing, low ionic strength buffer. The maximal enhancements of [3H]NMS binding were 2.89-, 1.68- and 1.43-fold increases for heparin, dextran and trypan blue, respectively; the EC50 values for this effect were 0.12, 0.033 and 4.6 microM, respectively. The effects of heparin, dextran and trypan blue on [3H]NMS binding were attributed mainly to an increase in the overall affinity of muscarinic receptors for [3H]NMS, and were greatly attenuated by 100 mM NaCl. These effects were qualitatively similar to those produced by GTP. Heparin, dextran and trypan blue also affected the binding of the muscarinic agonist oxotremorine-M in a manner similar to that of GTP; that is, in the presence of these compounds, agonist affinity was decreased. Our experiments also showed that heparin and dextran attenuate the inhibition of adenylate cyclase activity caused by oxotremorine-M in myocardial homogenates without influencing basal adenylate cyclase activity. We conclude that heparin and dextran interfere with the muscarinic receptor-G protein coupling in the rat heart.
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PMID:Heparin, dextran and trypan blue allosterically modulate M2 muscarinic receptor binding properties and interfere with receptor-mediated inhibition of adenylate cyclase. 128 80

Several polyanionic compounds antagonize the interaction between receptors and the G-proteins that regulate adenylate cyclase or K+ channels, possibly by binding to a basic stretch of the receptor that is proposed to mediate its interaction with the G-proteins. We have studied the effects of polyanions on the interaction between the liver alpha 1-adrenoceptor and the G-protein through which it stimulates polyphosphoinositide turnover. Heparin [concn. causing 50% of maximal effect (EC50) = 0.5 microM], Trypan Blue (EC50 7.1 microM) or suramin (EC50 2.1 microM) prevented formation of the high-affinity adrenaline-receptor-G-protein complex without affecting antagonist binding. After alkaline treatment of the membranes, previously reported to cause G-protein removal, binding of agonists was insensitive to both guanine nucleotides and heparin. We conclude that these polyanions uncouple the alpha 1-adrenoceptor from its G-protein, suggesting that similar coupling mechanisms may underlie receptor activation of the G-proteins that activate polyphosphoinositide hydrolysis and those that regulate adenylate cyclase. This action of heparin severely limits its utility as a selective antagonist of the Ins(1,4,5)P3 receptor in intact cells.
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PMID:Heparin and other polyanions uncouple alpha 1-adrenoceptors from G-proteins. 166 87

Heparin is known to impair the antiaggregatory effectiveness of prostacyclin (PGI2) for adenosine diphosphate-induced aggregation in citrated platelet rich plasma. Thus porcine mucosal heparin (PMH) from different commercial sources was investigated for its ability to compete with specific platelet prostacyclin binding. In concentrations up to 250 IU/ml PMH itself did not interfere with the binding of 3 X 10(-9) M 9-3H-PGI2-sodium salt to intact washed platelets. The displacement of specifically bound PGI2 observed by PMH (Ki 60 IU/ml) containing 4-chloro-m-cresol (4-CC) was caused by the preservative (Ki 4-CC 3.0 X 10(-4) M). Although 60 IU/ml PMH (free of 4-CC) have been shown to inhibit basal 3 X 10(-5) M forskolin-, and 10(-8)M Iloprost-stimulated adenylate cyclase in platelet membranes (-63%, -62%, -83% respectively), no effect of PMH on 3H-cyclic-AMP formation has been observed when intact platelets were studied by 3H-adenine prelabeling technique. There is also no evidence that the preincubation of PGI2 (5 X 10(-7) M) with 1000 IU/ml PMH might neutralize the effectiveness of this eicosanoid. In contrast, PGI2 preincubated with PMH (10 min, 37 degrees C) caused a more pronounced increase of platelet 3H-cyclic AMP (+65%) compared with PGI2 incubated in 5 X 10(-2) M Tris-HCl, pH 7.4. Thus our data provide no evidence that PMH interferes with i) specific platelet PGI2 binding, ii) PGI2-stimulated cyclic AMP synthesis or iii) neutralizes PGI2 by formation of a biologically less active PGI2-PMH complex.
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PMID:Effects of heparin on prostacyclin binding and platelet adenylate cyclase activity stimulated by iloprost and forskolin. 243 18

Human platelet adenosine-3',5'-cyclic monophosphate (cAMP) levels were determined in platelet rich plasma (PRP) and in washed platelets by a modification of the protein binding assay; the validation of the method is described. Dihydroergotamine (DHE) inhibited epinephrine induced platelet aggregation (ID50 = 2.5 X 10(-7) mol/l), and increased cAMP levels in platelets by an alpha-adrenergic receptor blocking effect, since phentolamine but not propranolol, behaved similarly. The DHE induced cAMP accumulation was correlated to the inhibitory effect on aggregation and showed a characteristic alpha-adrenergic receptor pattern in the presence of alprostadil (PGE1) and epinephrine but not collagen or adenosine diphosphate (ADP). Thrombin induced aggregation was similarly affected by DHE but with 100 times higher concentration. Heparin was found to increase slightly ADP and epinephrine induced aggregation and to decrease cAMP. Also, heparin was found to inhibit thrombin induced platelet aggregation. In washed platelets, the inhibitory effect of thrombin on PGE1 induced cAMP accumulation was counteracted by heparin. This indicates that the binding site of thrombin on platelets is important in the control of adenyl cyclase. Evidence is presented that some of the beneficial synergistic effect of DHE and heparin may consist in the ability of those compounds to produce opposite effects on cAMP system in platelets.
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PMID:Effect of heparin and dihydroergotamine on platelet adenosine-3',5'-cyclic monophosphate. 282 55

The influence of heparin was studied on the inhibitory regulation of adenylate cyclase in human platelet membranes. Heparin blocked the adrenaline-induced inhibition of adenylate cyclase and the stimulation of GTP hydrolysis with half-maximal and maximal efficiency at 0.3 and 1-3 micrograms/ml, respectively. The effect of heparin was reversed by washing the membranes. Heparin did not change the number of alpha-adrenoceptors. In contrast, the affinity of the alpha-adrenoceptor for adrenaline was decreased in the presence of heparin. The pertussis toxin-catalysed ADP-ribosylation of the inhibitory guanine nucleotide-binding Gi-protein was not altered by heparin. Heparin also abolished the inhibition of adenylate cyclase caused by GTP itself. The data indicate that heparin can impair the hormone-induced inhibition of adenylate cyclase and the stimulation of GTP hydrolysis and suggest that the effects of heparin are caused by an action at the Gi-protein of the adenylate cyclase system.
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PMID:Heparin uncouples alpha 2-adrenoceptors from the Gi-protein in membranes of human platelets. 283 29

1 Heparin can produce platelet aggregation in vitro and in vivo; it has been proposed that this may be due to the reported inhibition of the prostaglandin E(1) (PGE(1))-stimulated adenylate cyclase of the platelet by heparin.2 The effect of heparin on the cyclic adenosine 3',5'-monophosphate (cyclic AMP) response to PGE(1) was measured in intact and broken platelets both in vitro and in platelets obtained from normal subjects during intravenous infusion with herapin.3 In platelet lysates, heparin produced a dose-related inhibition of PGE(1)-stimulated adenylate cyclase. The maximum response to PGE(1) was reduced, with half-maximal inhibition occurring at 3 mug/ml heparin. This inhibition could be prevented by protamine sulphate.4 Heparin did not affect PGE(1)-stimulated cyclic AMP production in intact platelets either in vitro or in platelets taken during the infusion of 5,000iu heparin over 2h to 2 normal volunteers. Similarly, preincubation of platelets with heparin for up to 3h at 37 degrees C did not affect platelet adenylate cyclase.5 The effects of heparin were very similar to those of fluoride on the platelet adenylate cyclase: heparin and fluoride increased basal enzyme activity slightly (3-4 fold) but their effects were not additive; both inhibited the response to PGE(1) by approximately 50% when added directly to the assay and the inhibitory effects of the two were not additive; preincubation of membranes with either heparin or fluoride produced an irreversible state of inhibition.6 As heparin inhibits PGE(1)-stimulated adenylate cyclase activity only in broken platelets, we suggest that the aggregatory effects of heparin are probably independent of any action on cyclic AMP production.
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PMID:Inhibition of prostaglandin E1-responsive platelet adenylate cyclase by heparin: a study of the mechanism of inhibition and its relevance to platelet aggregation. 724 63

The high-affinity receptor for melatonin is coupled to a pertussis toxin-sensitive, inhibitory guanine nucleotide regulatory protein, Gi, which mediates inhibition of adenylate cyclase activity in the chick and other species. Heparin has been found to uncouple alpha 2-adrenoceptors from a similar Gi; therefore it was of interest to examine the effect of this agent on melatonin binding and signal transduction in chick brain. In competition studies, melatonin inhibited the binding of 2-[125I]iodo-melatonin with high- and low-affinities of KH = 20 pM and KL = 15 nM, respectively. In the presence of heparin (100 units/ml), a single site with an affinity of about 6 nM was detected. The monovalent cations, Na+ and Li+, produced a greater rightward shift of the agonist competition curve than heparin and converted all high-affinity sites to a low affinity of approximately 15-18 nM. In saturation studies, heparin reduced the affinity of high-affinity sites and caused a significant decrease in the density of low-affinity sites. In keeping with its ability to reduce high-affinity binding, heparin blocked melatonin's inhibitory effect on forskolin-stimulated adenylate cyclase activity in chick brain synaptosomal membranes. These findings indicate that heparin impairs the coupling between the melatonin receptor and Gi, with a consequent decrease in binding affinity and a loss of receptor-mediated signalling.
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PMID:Heparin inhibits melatonin binding and signal transduction in chick brain. 792 Sep 73

1. We have characterized the 5-hydroxytryptamine (5-HT)-induced calcium signalling in endothelial cells from the human pulmonary artery. Using RT-PCR we show, that of all cloned G-protein coupled 5-HT receptors, these cells express only 5-HT1D beta, 5-HT2B and little 5-HT4 receptor mRNA. 2. In endothelial cells 5-HT inhibits the formation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) via 5-HT1D beta receptors but fails to activate phosphoinositide (PI) turnover. However, the latter pathway is strongly activated by histamine. 3. Despite the lack of detectable inositol phosphate (IP) formation in human pulmonary artery endothelial cells, 5-HT (pD2 = 5.82 +/- 0.06, n = 6) or the selective 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (pD2 = 5.66 +/- 0.03, n = 7) elicited transient calcium signals comparable to those evoked by histamine (pD2 = 6.44 +/- 0.01, n = 7). Since 5-HT2A and 5-HT2C receptor mRNAs are not detectable in pulmonary artery endothelial cells, activation of 5-HT2B receptors is responsible for the transient calcium release. The calcium transients are independent of the inhibition of adenylate cyclase, since DOI does not stimulate 5-HT1D beta receptors. 4. Both, the 5-HT- and histamine-stimulated calcium signals were also observed when the cells were placed in calcium-free medium. This indicates that 5-HT triggers calcium release from intracellular stores. 5. Heparin is an inhibitor of the IP3-activated calcium release channels on the endoplasmic reticulum. Intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block 5-HT-induced calcium signals, whereas it abolished the histamine response. This supports the conclusion that the 5-HT-induced calcium release is independent of IP3 formation. 6. Unlike the histamine response, the 5-HT response was sensitive to micromolar concentrations of ryanodine and, to a lesser extent, ruthenium red. This implies that 5-HT2B receptors trigger calcium release from a ryanodine-sensitive calcium pool. 7. It has been postulated that cyclic ADP-ribose (cADPR) is a soluble second messenger which activates ryanodine receptors. However, calcium signals similar to the 5-HT response could not be elicited by intracellular infusion with cADPR. Furthermore, the subsequent application of 5-HT or DOI elicited a calcium signal that was not affected by the above pretreatment. 8. We conclude that human 5-HT2B receptors stimulate calcium release from intracellular stores through a novel pathway, which involves activation of ryanodine receptors, and is independent of PI-hydrolysis and cADPR.
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PMID:5-HT2B receptor-mediated calcium release from ryanodine-sensitive intracellular stores in human pulmonary artery endothelial cells. 888


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