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

The ecto-5'-nucleotidase activity of rat glomerular mesangial cells increases after exposure to prostaglandin E2 (PGE2) via cAMP stimulation (Savic et al., 1990, Immunology 70, 321). Therefore we examined whether other cAMP-stimulating agents had a similar effect. Forskolin (1 microM), PGE2 (10 microM), and isoproterenol (10 microM), three products stimulating rat mesangial cell adenylate cyclase activity, enhanced cAMP accumulation within 5 min and 5'-nucleotidase activity after a lag time of at least 24 h, 3-Isobutyl-1-methylxanthine (IBMX) and Ro 20-1724, two drugs inhibiting cAMP degradation, also stimulated cAMP accumulation and 5'-nucleotidase activity. The effects of these agents on 5'-nucleotidase activity were additive with those of the three products stimulating adenylate cyclase activity, except for Ro 20-1724 and forskolin which acted synergistically. Cycloheximide, a blocker of protein synthesis, suppressed the cAMP-dependent increase of 5'-nucleotidase activity. Because ecto-5'-nucleotidase activity is a marker of cell differentiation, the effect of the same cAMP-stimulating agents on cell proliferation was also studied. Forskolin, PGE2, and isoproterenol inhibited [3H]thymidine incorporation into rat mesangial cells in a dose-dependent manner. The same effect was obtained with IBMX (100 microM) and Ro 20-1724 (50 microM). Stimulation of 5'-nucleotidase activity and inhibition of [3H]thymidine incorporation occurred over the same range of concentrations for the various agonists tested. Taken together, these results indicate that expression of ecto-5'-nucleotidase in rat mesangial cells is induced by cAMP whatever the reason for its accumulation. The simultaneous inhibition of DNA synthesis may occur independently or be associated with the stimulation of 5'-nucleotidase expression.
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PMID:Cyclic adenosine monophosphate-stimulating agents induce ecto-5'-nucleotidase activity and inhibit DNA synthesis in rat cultured mesangial cells. 165 63

Human adipocytes are of limited viability (7 +/- 2% release of lactate dehydrogenase/h) and contain active ectophosphatases which are capable of sequentially degrading ATP to adenosine. At densities of 30,000-40,000 cells/ml, human fat cell suspensions accumulated adenosine, inosine, and hypoxanthine, and their concentrations were 38 +/- 8, 120 +/- 10, and 31 +/- 7 nmol/liter after 3 h of incubation. Dipyridamole (10 mumol/liter), an inhibitor of nucleoside transport, caused a 5-7-fold increase in adenosine accumulation which was reduced by 85% on inhibition of ectophosphatases by beta-glycerophosphate and antibodies against ecto-5'-nucleotidase or alpha, beta-methylene 5'-adenosine diphosphate (10 mumol/liter), respectively, indicating that most of the adenosine is produced in the extracellular compartment. Accordingly, the spontaneous accumulation of adenosine was reduced beyond 5 nmol/liter on inhibition of ectophosphatase activities or removal of extracellular AMP by AMP deaminase (4 units/ml). Added adenosine (30 nmol/liter) disappeared until its concentration approached 5 nmol/liter. Isoproterenol (1 mumol/liter) had no effect on adenosine accumulation regardless whether purine production from extracellular sources was minimized or not. In contrast to adenosine, the concentrations of inosine and hypoxanthine displayed only a modest decrease (30-50%) on inhibition of ectophosphatase activities. In addition, isoproterenol caused a 2-3-fold increase in inosine and hypoxanthine production which was concentration-dependent and could be inhibited by propranolol. It is concluded that the adenosine that accumulates in human adipocyte suspensions is almost exclusively derived from adenine nucleotides which are released by leaking cells. By contrast, inosine and hypoxanthine are produced inside the cells, and the release of these latter purines appears to be linked to ATP turnover via adenylate cyclase.
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PMID:Purine accumulation in human fat cell suspensions. Evidence that human adipocytes release inosine and hypoxanthine rather than adenosine. 337 46

PTH-induced phosphaturia is exerted in part by cAMP added to the renal tubular lumen under the influence of the hormone. Modulation of renal phosphate transport by luminal cAMP requires degradation of the nucleotide into adenosine by brush-border membrane ectoenzymes, among them ecto-5'-nucleotidase (5'-NU). Hormonal modulation of 5'-NU activity was evaluated in cultured opossum kidney cells. PTH (1-100 nM) stimulated 5'-NU in a time-, concentration-, and protein synthesis-dependent manner. The effect of PTH-(1-34) was mimicked by PTH-(3-34), which does not activates adenylate cyclase, and by phorbol 12-myristate 13-acetate (PMA), but not by forskolin or (Bu)2cAMP. Down-regulation or pharmacological inhibition of protein kinase-C (PKC) abolished the effect of PTH fragments and PMA. PTH fragments increased intracellular Ca2+ and translocated PKC activity to the membrane. PTH or PMA did not affect 5'-NU messenger RNA content. Inhibition of sodium-phosphate cotransport by extracellular cAMP was decreased by 5'-NU inhibition and was magnified by PTH. These results indicate that 1) PTH stimulates 5'-NU activity in renal proximal tubular cells in a manner involving PKC activation and de novo protein synthesis; and 2) this effect participates in PTH modulation of renal phosphate transport.
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PMID:Parathyroid hormone stimulates ecto-5'-nucleotidase activity in renal epithelial cells: role of protein kinase-C. 786 81

Plasma membranes from liver of control rats or from chemical-induced hepatoma were prepared. The basal activity of adenylate cyclase was increased significantly in the rat plasma membranes of DEN-induced hepatoma compared to normal tissue. The glucagon-induced response on the cellular effector systems via guanine nucleotide-binding regulatory proteins (G proteins) was inhibited in hepatoma plasma membranes. These findings suggest that in hepatoma membranes, unlike normal hepatic membranes, the response to hormonal stimuli through regulatory G proteins results in a loss of response to glucagon, as well as to GTP plus glucagon or to GTP gamma S. However, the activating effects of forskolin, which catalyses the formation of cyclic AMP from ATP acting on the catalytic subunit, were to some extent retained. The methyltransferase-I behaved in the opposite direction to the adenylate cyclase, showing a decreased activity in hepatoma plasma membranes compared to control membranes. In contrast, the activity of the ecto-5'-nucleotidase was significantly increased in hepatoma. These enzymatic changes have been found to influence the membrane fluidity and to be responsible for the ultrastructural modifications of hepatoma plasma membranes which are induced by chemical carcinogens.
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PMID:Enzymatic, biophysical and ultrastructural changes of plasma membranes in chemical-induced rat hepatoma. 856 46

Neurotransmitter release and the role of adenosine in its regulation has been investigated for more than twenty years, and it is now widely accepted that adenosine tonically inhibits the release of excitatory neurotransmitters. This effect of adenosine is operated by an A1 adenosine receptor. Since activation of this receptor could inhibit Ca2+ conductance, increase K+ conductance, inhibit adenylate cyclase or phospholipase C, it is not clear if there is only one mechanism or several mechanisms operated by adenosine to inhibit neurotransmitter release, and in that case, what is the relative importance of each mechanism. The mechanism by which adenosine inhibits evoked synchronous transmitter release might be different from that used by the nucleoside to inhibit spontaneous asynchronous release. In some systems adenosine triphosphate per se acts like adenosine and inhibits neurotransmitter release. However, in most cases the inhibitory effect of this adenine nucleotide depends upon its hydrolysis into adenosine by a cascade of ectoenzymes, the last step being mediated by ecto-5'-nucleotidase.
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PMID:Purinergic inhibition of neurotransmitter release in the central nervous system. 877 40

At the neuromuscular junction and possibly also at the synaptic level in the brain, the main sequence of events (see Fig. 5) that involves purines in modulation of ACh release includes the following observations: (1) storage of ATP and its release either together with, or independently of acetylcholine. ATP is also released from the post-junctional component. Adenosine as such is released either from the motor nerve terminals or from the post-junctional component. (2) There is extracellular hydrolysis of ATP to adenosine, which is the active substance to modulate transmitter release. The key enzyme in the conversion of AMP into adenosine is the ecto 5'-nucleotidase. When ecto-5'-nucleotidase is not available (e.g. in cholinergic nerve terminals of the cerebral cortex) ATP as such exerts the neuromodulatory role normally fulfilled by adenosine. (3) Both the inhibition and the excitation induced by adenosine on ACh release in the rat is inactivated through up-take and deamination. (4) Adenosine-induced inhibition of ACh release is mediated via A1 receptors and the excitation via A2a receptors. The A2a receptors are positively coupled to the adenylate cyclase/cyclic AMP system, whereas the presynaptic A1 receptors (a) may be negatively linked to adenylate cyclase and (b) to phospholipase C, and, upon stimulation, (c) increase potassium conductance and (d) decrease calcium conductance. (5) Activation of A2a receptors is essential for substances that facilitate ACh release (e.g. CGRP, forskolin) to exert their effects, as well as for induction of nicotinic autofacilitatory receptor desensitization. (6) There are interactions between A1 and A2a receptors. Thus, the net adenosine neuromodulatory response is the resultant, at each moment, of the relative degree of activation of each one of these receptors. This relative activation depends upon the intensity (frequency, pulse duration) of stimulation of the motor nerve terminals. (7) Adenosine released as such seems to preferentially activate A1 receptors, whereas the adenosine formed from metabolism of adenine nucleotides prefers to activate the A2a receptors. In conclusion, to find out precisely what occurs with ACh in transmitting its message at the synaptic level, one has to consider the subtle ways used by purines to modulate the ACh response. It therefore appears of interest that pharmacological and therapeutic strategies use this knowledge to approach cholinergic transmission deficiencies based upon reduction of ACh release.
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PMID:Purinergic regulation of acetylcholine release. 900 12

It is well known that cAMP, an important intracellular second messenger, is released from many cells upon adenylate cyclase stimulation. Cell surface bound phosphodiesterase together with ecto-5'-nucleotidase may convert the extracellular cAMP to adenosine, which may stimulate in a paracrine and/or autocrine manner cells expressing P1 receptors. In this issue of the British Journal of Pharmacology, Chiavegatti et al. demonstrate the existence of an extracellular cAMP-adenosine cascade in skeletal muscle cells which suggests a link between adrenergic stimulation of contraction, elevated cAMP formation and release and exercise hyperaemia.
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PMID:cAMP: fuel for extracellular adenosine formation? 1815 64

Platelets play a critical role in homeostasis and blood clotting at sites of vascular injury, and also in various ways in innate immunity and inflammation. Platelets are one of the first cells to accumulate at an injured site, and local release of their secretome at some point initiate an inflammatory cascade that attracts leukocytes, activates target cells, stimulates vessel growth and repair. The level of exogenous ATP in the body may be increased in various inflammatory and shock conditions, primarily as a consequence of nucleotide release from platelets, endothelium and blood vessel cells. An increase of ATP release has been described during inflammation and this compound presents proinflammatory properties. ADP is a nucleotide known to induce changes in platelets shape and aggregation, to promote the exposure of fibrinogen-binding sites and to inhibit the stimulation of adenylate cyclase. Adenosine, the final product of the nucleotide hydrolysis, is a vasodilator and an inhibitor of platelet aggregation. There is a group of ecto-enzymes responsible for extracellular nucleotide hydrolysis named ectonucleotidases, which includes the NTPDase (nucleoside triphosphate diphosphohydrolase) family, the NPP (nucleoside pyrophosphatase/phosphodiesterase) family and an ecto-5'-nucleotidase. Therefore, we have aimed to investigate the effect of lipopolysaccharide endotoxin from Escherichia coli on ectonucleotidases in platelets from adult rats in order to better understand the role of extracellular adenine nucleotides and nucleosides in the maintenance of blood homeostasis in inflammatory processes. LPS administered in vitro was not able to alter the ATP, ADP, AMP and rho-Nph-5'-TMP hydrolysis of platelets from untreated rats in all concentrations tested (25-100 microg/ml). There was a significant decrease in ATP, ADP, AMP and rho-Nph-5'-TMP hydrolysis in rat platelets after 48 hours of LPS exposure (2 mg/Kg, i.p.). ATP and ADP hydrolysis has been reduced about 28% whereas it has been observed a significant 30% and 26% decrease on AMP and rho-Nph-5'-TMP hydrolysis. Platelet aggregation and platelet number have shown a significant decrease in LPS-treated rats (40% and 55%, respectively) when compared to control group. These results suggest that changes observed in platelet count and, consequently, in nucleotidase activities from circulatory system could alter extracellular nucleotide and nucleoside levels, which might modulate the inflammatory process.
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PMID:Endotoxemia alters nucleotide hydrolysis in platelets of rats. 1923 49