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)

The affinities of a series of N6-(omega-aminoalkyl)adenosines as probes for A1 and A2 adenosine receptors were determined in various radioligand binding assays and the intrinsic activities were measured in adenylate cyclase assays. Clear species differences were noticed for A1 receptor affinity of these adenosine receptor agonists, the compounds being more active in calf than in rat brain tissue. The affinity profile within the series was, however, rather similar in both membrane preparations, with N6-9-aminononyladenosine displaying highest affinity. The A2 receptor affinities were comparable to values measured for the A1 receptor in its low affinity state, as assessed with a radiolabelled antagonist in the presence of 1 mM GTP. Calculation of the intrinsic activities of the adenosine analogues from their modulating action on adenylate cyclase showed almost all the compounds to be equally effective to (-)-N6-(R-phenylisopropyl) adenosine, on either A1 or A2 adenosine receptors. N6-3-Aminopropyl- and N6-12-aminododecyladenosine, however, proved to be partial agonists, the first on A1 and the second on A2 adenosine receptors. The data are used as the basis for a discussion of adenosine receptor subtype selectivity and intrinsic activity in general.
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PMID:Influence of the molecular structure of N6-(omega-aminoalkyl)adenosines on adenosine receptor affinity and intrinsic activity. 276 41

In IMR32 neuroblastoma cells, the two adenosine receptor agonists N6-R-phenylisopropyladenosine and 5'-N-ethylcarboxamidoadenosine dose-dependently stimulated membrane adenylate cyclase activity with potencies consistent with the presence of adenosine receptors of the A2-subtype. The S enantiomer of N6-R-phenylisopropyladenosine induced a significantly lower stimulation of adenylate cyclase, accordingly to its lower ability to activate adenosine receptors. These effects were selectively counteracted by the adenosine receptor antagonist theophylline and, conversely, were not affected by the A1-adenosine receptor selective blocker 8-cyclopentyl-1,3-dipropylxanthine. No adenosine receptors belonging to the A1-subtype seem, therefore, to be present in this cell line, as also shown by the lack of inhibitory activity of N6-R-phenylisopropyladenosine on both basal and forskolin-stimulated adenylate cyclase activity. Activation of A2-receptors did not modify intracellular basal calcium levels, did not influence calcium influx through voltage-dependent calcium channels and did not modify calcium influx and redistribution induced by muscarinic receptor activation. Prolonged exposure of cells to either N6-R-phenylisopropyladenosine or 5'-N-ethylcarboxamidoadenosine was associated with a small but significant degree of morphological differentiation, comparable to that induced by dibutyryl cAMP, and therefore presumably related to the prolonged increase of intracellular cAMP levels elicited by the two adenosine agonists. After cellular differentiation induced with either dibutyryl cAMP or 5-bromodeoxyuridine, a selective desensitization of A2-receptor stimulated adenylate cyclase activity was found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptors linked to adenylate cyclase activity in human neuroblastoma cells: modulation during cell differentiation. 277 Oct 50

The aim of the present study was the characterization of adenosine receptors in isolated rat ventricular myocytes. The cAMP-levels of rat ventricular myocytes in the presence of 1 mumol/l isoprenaline were reduced by up to 48% by adenosine analogues; the rank order of potency was: R-N6-phenylisopropyladenosine (IC50 60 nmol/l), 5'-N-ethylcarboxamidoadenosine (IC50 360 nmol/l) and S-N6-phenylisopropyladenosine (IC50 16 mumol/l). The adenosine receptor antagonist XAC ("xanthine amine congener") antagonized the effect of R-N6-phenylisopropyladenosine in a concentration-dependent manner with a Ki-value of 20 nmol/l. The A1 receptor-selective radioligand R-N6-125I-p-hydroxyphenylisopropyladenosine bound to membranes prepared from rat ventricular myocytes in a saturable manner with a Bmax of 17.7 fmol/mg protein and a KD-value of 1.1 nmol/l. Adenosine analogues competed for the binding with the same rank order of potency as for the inhibition of the isoprenaline-induced cAMP-increase. GTP inhibited radioligand binding with an IC50-value of 73 mumol/l. These results suggest the presence of A1 adenosine receptors on rat ventricular myocytes, which mediate an inhibition of adenylate cyclase. The receptors may be responsible for the effects of adenosine and its analogues on the heart.
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PMID:Pharmacological characterization of A1 adenosine receptors in isolated rat ventricular myocytes. 282 48

The influence of nonmetabolizable adenosine analogs on cAMP production was investigated in preovulatory rat granulosa cells. 5'-(N-ethyl)Carboxamido-adenosine (NECA), a stimulatory A2-adenosine receptor agonist, stimulated cAMP accumulation, and NECA and 2-chloro-adenosine also potentiated the response to FSH. The adenosine receptor antagonist 8-phenyltheophylline antagonized the effect of NECA, shown by a shift in the dose-response curve to the right. The stimulatory effect of NECA was also seen in an ovarian membrane preparation, where NECA stimulated adenylate cyclase in both the presence and absence of FSH. The stimulatory effect of NECA was also decreased by 8-phenyltheophylline in this preparation. The A1-receptor agonists N6-(R-phenyl-isopropyl)-adenosine (R-PIA) and N6-(S-phenyl-isopropyl)-adenosine (S-PIA) both inhibited FSH-stimulated cAMP accumulation. The inhibitory effects of R-PIA and S-PIA, but not the stimulatory effects of NECA, could be counteracted by dipyridamole, a nucleoside transport inhibitor. Furthermore, R-PIA and S-PIA inhibited adenosine uptake into granulosa cells. Thus, the inhibitory effects of R-PIA and S-PIA are not likely to be mediated via membrane-bound inhibitory A1-adenosine receptors. Neither the stimulatory effects of NECA nor the inhibitory effects of R- and S-PIA could be attributed to changes in ATP levels, since the ATP levels were unaffected by these analogs. The results of this study indicate the existence of stimulatory A2-adenosine receptors in preovulatory rat granulosa cells and suggest a membrane-associated modulatory role of adenosine in preovulatory granulosa cells.
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PMID:Adenosine receptor-mediated effects by nonmetabolizable adenosine analogs in preovulatory rat granulosa cells: a putative local regulatory role of adenosine in the ovary. 282 14

1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation.
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PMID:Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP. 283 71

Human platelet membranes were solubilized with the zwitterionic detergent CHAPS (3-[3-(cholamidopropyl)-dimethylammonio]-1-propanesulfonate) and the solubilized extract subjected to gel filtration. Binding of the adenosine receptor agonist [3H]NECA (5'-N-ethylcarboxamidoadenosine) was measured to the eluted fractions. Two [3H]NECA binding peaks were eluted, the first of them with the void volume. This first peak represented between 10% and 25% of the [3H]NECA binding activity eluted from the column. It bound [3H]NECA in a reversible, saturable and GTP-dependent manner with an affinity of 46 nmol/l and a binding capacity of 510 fmol/mg protein. Various adenosine receptor ligands competed for the binding of [3H]NECA to the first peak with a pharmacological profile characteristic for the A2 adenosine receptor as determined from adenylate cyclase experiments. In contrast, most adenosine receptor ligands did not compete for [3H]NECA binding to the second, major peak. These results suggest that a solubilized A2 receptor-Gs protein complex of human platelets can be separated from other [3H]NECA binding sites by gel filtration. This allows reliable radioligand binding studies of the A2 adenosine receptor of human platelets.
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PMID:Separation of solubilized A2 adenosine receptors of human platelets from non-receptor [3H]NECA binding sites by gel filtration. 283 89

Effects of adenosine analogues on adenylate cyclase activity in preovulatory rat ovarian membranes were studied. Adenosine analogues stimulated adenylate cyclase activity in the following rank order of potency: NECA (5'-(N-ethyl)carboxamidoadenosine) greater than 2-chloroadenosine greater than N6-(R-phenylisopropyl)-adenosine greater than N6-(S-phenylisopropyl)adenosine. The apparent EC50 for NECA was 0.28 microM. The adenosine receptor antagonist 8-phenyltheophylline (10 microM) displaced the dose-response curve for NECA to the right, increasing the EC50 for NECA about one order of magnitude. NECA also additively increased maximally FSH-stimulated adenylate cyclase activity. These results suggest that adenosine stimulates adenylate cyclase in rat ovarian membranes via adenosine receptors of the A2 type.
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PMID:Evidence for A2 adenosine receptor-mediated effects on adenylate cyclase activity in rat ovarian membranes. 283 46

Catecholamines and adenosine have a stimulating effect on the process of dedifferentiation of cultured iris epithelial cells (IECs) from the adult newt Notophthalmus viridescens. Micromolar concentrations of adrenergic ligands such as isoproterenol, norepinephrine, and epinephrine induced marked morphological alterations culminating in the stellate configuration and depigmentation of IECs. Dopamine at 100 microM or higher induced the morphological response, while serotonin was ineffective. The morphological change was transient, requiring 80-90 min for maximum induction, and only a fraction of the cells was responsive. The response was blocked by beta-adrenergic antagonists, such as propranolol and alprenolol, but not by alpha-adrenergic blockers. Adenosine at 10 microM, or higher, also induced morphological alterations of IECs. The effect of adenosine was partially blocked by various adenosine receptor antagonists. The effect of isoproterenol and norepinephrine on the induction of morphological alterations was potentiated by adenosine. The release of melanosomes from IECs was increased in the presence of catecholamines and adenosine. Catecholamines and adenosine at 10 microM increased the intracellular levels of cAMP of dedifferentiating dorsal irides. The increase in cAMP levels induced by isoproterenol was inhibited by propranolol and the adenosine receptor antagonist 5'-deoxy-5'-methyl thioadenosine (MTA) partially blocked the effect of adenosine. Our results suggest that adrenergic hormones may be coupled to a beta-adrenergic adenylate cyclase system. The presence of an adenosine receptor is also suggested by the results. Our data strongly support previous work in which cAMP and substances related to it induced morphological alterations and depigmentation of IECs. It is proposed that catecholamines and adenosine may participate in the regulation of dedifferentiation during the transdifferentiation of IECs into lens cells.
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PMID:The effect of catecholamines and adenosine on the induction of morphological alterations and depigmentation of newt iris epithelial cells in vitro. 285 Feb 51

5'-N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than adenosine greater than (-)-N6-(R-phenyl-isopropyl)-adenosine [(-)-R-PIA] greater than (+)-N6-(S-phenyl-isopropyl)-adenosine [(+)-S-PIA] inhibited in vitro human platelet aggregation in a dose-dependent fashion. 6-nitrobenzylthioinosine and dipyridamole, which inhibit adenosine uptake, and erythro-9-(2-hydroxy-3-nonyl)-adenine, which blocks adenosine metabolism, did not impair the inhibition induced by NECA and adenosine. 8-phenyltheophylline and theophylline, two competitive antagonists of adenosine receptors, blocked the inhibition of platelet aggregation caused by NECA and adenosine. NECA greater than 2-chloroadenosine greater than adenosine greater than (-)-R-PIA greater than (+)-S-PIA increased platelet cyclic adenosine monophosphate (cAMP) levels in a dose-dependent fashion. A significant linear correlation (r = 0.70, p less than 0.001) was found between the increase of platelet cAMP and the inhibition of platelet aggregation induced by adenosine and its analogs. 8-phenyltheophylline, which is a competitive antagonist of adenosine in platelets, also blocked the cAMP accumulation caused by NECA. These data suggest that NECA and other adenosine analogs activate a specific cell surface adenylate cyclase-linked adenosine receptor whose properties are similar to those of an adenosine A2/Ra receptor.
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PMID:Functional and biochemical evidence of a specific adenosine A2/Ra receptor on human platelets. 285 Jun 3

Changes in cyclic AMP concentrations were studied in intact PC12 pheochromocytoma cells exposed to a variety of treatments. A marked increase was triggered by N-(L-2-phenylisopropyl)adenosine, the activator of an adenosine receptor, whereas a decrease (observed even after phosphodiesterase blockade) was induced by carbachol, working through a muscarinic receptor inhibited by the selective muscarinic blocker pirenzepine, only at high concentration (Ki 450 nM). A decrease in cyclic AMP was also induced by clonidine, an alpha 2-adrenergic-receptor agonist. Both the alpha 2-adrenergic and the muscarinic inhibitions were prevented by pretreatment of the cells with pertussis toxin, and were unaffected by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate. The latter drug caused a decrease in the resting cyclic AMP concentrations, and a potentiation of the increase induced by adenosine-receptor activation. Except for clonidine, all these treatments were found to be effective in both growing PC12 cells and, although to a smaller degree, in cells that had stopped growing and had acquired a neuron-like phenotype after prolonged treatment with nerve growth factor (NGF). Neither forskolin (a direct activator of adenylate cyclase) nor the activation of adenosine and alpha-adrenergic receptors was able to modify the resting cytosolic Ca2+ concentration [Ca2+]i in PC12 cells. Likewise, the K+-induced [Ca2+]i transients were unchanged after these treatments, whereas the transients induced by carbachol through the activation of a muscarinic receptor highly sensitive to pirenzepine were moderately potentiated by forskolin (and, to a lesser degree, by the adenosine analogue) and attenuated by clonidine. These results characterize in further detail the spectrum and the mutual interrelationships of the intracellular signals induced by receptor activation in PC12 cells, also as a function of the NGF-induced differentiation.
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PMID:Second-messenger generation in PC12 cells. Interactions between cyclic AMP and Ca2+ signals. 285 Jul 95


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