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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with atopic dermatitis have abnormal autonomic responses of the arterioles, pilomotor smooth muscle, and sweat glands. Their lesions have been reported to contain increased amounts of the neurohumors, acetylcholine and norepinephrine, as well as increased activity of acetylcholinesterase and catechol-O-methyltransferase. In vitro studies of epidermis show that beta adrenergic agonists fail to evoke the normal inhibition of mitosis of basal cells of patients with atopic dermatitis. Epidermis removed not only from the lesions, but also from normal-appearing skin, responded abnormally. The increase in intracellular levels of cAMP after exposure to catecholamines was similar in normal and atopic epidermis. Lymphocytes and PMN leukocytes isolated from patients with atopic dermatitis show both a decreased physiologic response (glycogenolysis and inhibition of lysosome enzyme release) and a decreased rise in intracellular levels of cAMP upon incubation with beta agonists, but a normal response to PGE1. Cortisol increases the response of lymphocyte adenyl cyclase to both agonists and, in the case of the patients with atopic disease, more than overcomes the depressed response to beta agonists. Because the leukocytes respond normally to PGE1 and because others have reported normal activities of skin and adenyl cyclase, phosphodiesterase, and protein kinases, we conclude that the step responsible for the diminished beta adrenergic response lies antecedent to the catalytic site of adenyl cyclase.
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PMID:Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis. 0 56

Adenosine 3',5'-cyclic monophosphate (cAMP) may be one of the important factors in regulating the expression of many differentiated functions in neuroblastoma cells, but some of these functions can be induced by agents that do not increase the intracellular level of cAMP. An elevation of the intracellular level of guanosine 3',5'-cyclic monophosphate (cGMP) neither induced differentiation nor antagonized the effects of cAMP. Neuroblastoma cells increased the level of cAMP-binding proteins during differentiation, whereas glial cells and L-cells did not. This might have accounted in part for an increase in the intracellular level of cAMP even in the presence of high phosphodiesterase activity in neuroblastoma cells, since the protein-bound with the same proteins, but cAMP had about 10 times higher affinity than did cGMP. cAMP promoted the organization of microtubules and microfilaments necessary for the expression of differentiated phenotypes. The extension of neurites required the synthesis of new protein, but it did not need the synthesis of new RNA. cAMP induced differentiation in neuroblastoma cells by increasing the expression of some genetic information while suppressing the expression of others; e.g., the activities of neural enzymes increased, whereas the synthesis of histone and the phosphorylation of H1-histone markedly decreased in differentiated cells. A hypothesis was offered: An increase in cAMP phosphodiesterase activity as a result of mutation in the regulatory gene for phosphodiesterase in a single, or group of, dividing nerve cell(s) is the primary lesion that leads to malignancy. Based on the concept that selective cytocytoxic drugs should be used with agents that cause differentiation, a new therapeutic approach was suggested for the treatment of neuroblastoma. This involved administration of sodium butyrate followed by L-DOPA or prostaglandin E1 in the presence of cAMP phosphodiesterase inhibitor followed by the less immunosuppressive vincristine and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide.
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PMID:Cyclic nucleotides in the regulation of expression of differentiated functions in neuroblastoma cells. 1 Apr 49

Experiments were made to determine whether cyclic AMP plays a role in transmission at identified dopaminergic synapses in the water snail Planorbis corneus. Intracellular stimulation of a specific dopamine neuron produces direct inhibitory postsynaptic potentials (ipsps) in a number of other neurons. These ipsps, which are mediated by dopamine, were potentiated by as much as 120% by caffeine, theophylline or dibutyryl cyclic AMP, although they were unaffected by cyclic AMP and prostaglandin E1. Caffeine and theophylline also potentiated the inhibitory response to dopamine, applied to the postsynaptic neurons by perfusion or iontophoresis, but the effects were generally much smaller (maximum potentiation 30%). The results provide evidence that postsynaptic cyclic AMP is involved in transmission at these synapses, but that the phosphodiesterase inhibitors may also have a presynaptic effect.
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PMID:Potentiation of dopaminergic transmission by phosphodiesterase inhibitors and cyclic nucleotides. 1 61

Beta-adrenergic agonists, adenosine and prostaglandin E1 increased the level of adenosine 3':5'-monophosphate (cAMP) in glial cultures prepared from rat cerebral cortical tissue. In addition to these physiological effectors, cholera toxin also increased cAMP levels in these cultures. The accumulation of cAMP in response to each of these agen-s, including cholera toxin, was partially blocked (50--80%) by simultaneous alpha-adrenergic receptor stimulation. Basal levels of cAMP were not affected by alpha-adrenergic agonists. These results indicate that in glia, alpha-adrenergic receptors may serve to modulate the level of cAMP which normally accumulates in response to a number of neurohumoral substances. The modulatory effect of alpha-adrenergic agents does not appear to reduce cAMP accumulation by activating phosphodiesterase since the effect was not blocked by a potent inhibitor of this enzymemthe results suggest that the modulatory effect of alpha-adrenergic receptor activation results from an interaction which takes place at some point in between adenylate cyclase-associated-membrane receptors and the enzymatic degradation of cAMP.
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PMID:Alpah-adrenergic receptor modulation of beta-adrenergic, adenosine and prostaglandin E1 increased adenosine 3':5'-cyclic monophosphate levels in primary cultures of glia. 2 89

Various receptor-linked cyclic AMP systems were measured in rat neostriatum 2--14 days after selective destruction of neuronal cell bodies and dendrites by micro-injection of 3 microgram of kainic acid. Basal adenylate cyclase activity was reduced by up to 56% in the injected side and the sensitivity to dopamine was abolished. Up to 84% of cyclic nucleotide phosphodiesterase activity, hydrolyzing either cyclic AMP or cyclic GMP, was destroyed by kainic acid injection. Specific binding of [3H]etorphine and [3H]spiroperidol was reduced by up to 62% in the injected side, while non-specific binding was unchanged. All of these changes were time-dependent, and were greatest 7--14 days after kainic acid treatment. On the other hand, intrastriatal kainic acid injection caused no change in the steady-state concentration of cyclic AMP in striatal slices, or in the in vivo cyclic AMP content in the striatum of rats killed by microwave irradiation. Receptor-mediated increases in cyclic AMP accumulation in striatal slices were either unchanged or markedly potentiated by kainic acid treatment. The maximum response to adenosine was unchanged, while the response to isoprenaline was increased up to 3.7-fold, the response to dopamine increased up to 6.7-fold, and the response to PGE1 increased up to 30-fold. The effect of dopamine in kainic acid-treated striatal slices was no longer blocked by fluphenazine, but was blocked by propranolol, suggesting an interaction of dopamine with a beta-adrenoceptor in kainic acid-treated slices. The results suggest differential cellular localizations of the various receptor-linked cyclic AMP systems in rat neostriatum. Some dopamine and opiate receptors, as well as most of the phosphodiesterase activity, are associated with local neuronal elements, while beta-adrenoceptor, adenosine and PGE1 alterations in cyclic AMP are not. The potentiation of the beta-adrenoceptor and PGE1 responses suggests that they may occur in glial cells. In addition, the pool of adenylate cyclase destroyed by kainic acid appears to make little contribution to normal levels of cyclic AMP in the tissue.
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PMID:Receptor-linked cyclic AMP systems in rat neostriatum: differential localization revealed by kainic acid injection. 2 87

The accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in guinea-pig macrophages exposed to the adenylate cyclase (AC) stimulators prostaglandin E1 (PGE1) and isoproterenol (IP), was markedly enhanced by pretreatment of the cells with colchicine, vinblastine, and podophyllotoxin--agents which prevent microtubule assembly. The same agents did not augment basal cAMP levels. The facilitating effect of the drugs on the response to PGE1 and IP developed both in the absence and presence of a phosphodiesterase (PDE) inhibitor. The same drugs also enhanced the accumulation of cAMP induced by cholera toxin (CT) but the presence of a PDE inhibitor was required for such enhancement to become evident. Pretreatment of macrophages with cytochalasin B, an agent interfering with microfilament function, had no effect on the responsiveness of the cells to AC stimulators. The microtubule stabilizer, deuterium oxide (D2O) partially reversed the colchicine effect. Microtubule disrupting drugs did not block the release of cAMP from the cells into the surrounding medium. Macrophages incubated as monolayers or in suspension showed the same degree of increased responsiveness to stimulators after preexposure to colchicine. Preincubation with the ionophore A23187, which elevates the intracellular concentration of Ca2+, also enhanced the stimulation of AC by PGE1 and IP. Microtubule disrupting agents did not potentiate AC activity in broken cell preparations, whether added to the intact cells before disruption or directly to the enzyme assay mixture, nor did they affect PDE activity of macrophage sonicates. Moderate enhancement of PGE1-induced cAMP formation was also seen in colchicine- and vinblastine-treated lymphocytes. It was concluded that microtubules control the activity of AC by restricting the mobility of membrane receptors. Disruption of microtubules by drugs results in the removal of such restraints and an augmented chance of productive interactions between receptors and catalytic units of AC.
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PMID:Enhancement of macrophage adenylate cyclase by microtubule disrupting drugs. 4 91

Changes in intracellular and extracellular rat mast cell adenosine 3':5' monophosphate (cAMP) concentrations during stimulation of histamine release by 48/80 were studied. There was a rapid and progressive fall in intracellular cAMP beginning within 10 sec after the addition of 48/80. The lowest cAMP values were obtained at 10 min, with return to control levels by 30 min. The fall in cAMP was dose-related with progressive decreases in 10-min cAMP measurements as the 48/80 concentration was increased from 0.25 to 1.00 mug/ml. There was a graded increase in histamine release over the same concentration range. Attempts to demonstrate significant amounts of cAMP in the medium during 48/80 stimulation were unsuccessful, indicating that the changes in cAMP intracellularly are not due to altered cellular permeability. There was a general correlation between the ability of pharmacologic agents to sustain high intracellular levels of cAMP in the presence of 48/80, and inhibition of histamine release. Theophylline (20 mM) which increased cAMP levels 2- 3-fold prevented a detectable decrease in cAMP after 1 mug/ml 48/80 (measured at 10 min) and almost completely inhibited histamine release. Prostaglandin E1 (27 muM) also raised cAMP levels, decreased the 48/80-induced fall in cAMP (by 42%). Epinephrine increased mast cell cAMP levels, but did not prevent the subsequent 48/80-induced decrease in cAMP and did not inhibit histamine release. Carbamylcholine (1 nM), adenine (1 muM), and diazoxide (10 muM) lowered mast cell cAMP and potentiated 48/80 induced release. In view of previous studies from this laboratory indicating that 48/80 stimulates mast cell phosphodiesterase, it seems likely that the 48/80-induced fall in cAMP is due, at least in part, to increased cAMP destruction. Since agents which prevent the fall in cAMP inhibit histamine release, it is apparent that cAMP is an important part of the control mechanism of histamine secretion. On the other hand, it cannot be concluded that a decrease in cAMP alone is sufficient to produce a response since carbamylcholine, diazoxide, and adenine which lower cAMP do not alter histamine release unless 48/80 is also present.
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PMID:Modulation of cyclic AMP in purified rat mast cells. II. Studies on the relationship between intracellular cyclic AMP concentrations and histamine release. 4 64

Concentrations of cyclic AMP (cAMP) were increased in isolated renal cortical tubules from hamsters by both parathyroid hormone (PTH) and prostaglandin E1 (PGE1) with maximal effects of PGE1 being 6-8 fold greater than those of PTH during a 10 min period. However, cAMP concentrations in cells treated with 1-methyl-3-isobutylxanthine (MIX) were increased with maximal concentrations of either hormone to the same degree. Similar effects of both hormones were observed on adenylate cyclase activity in renal homogenates. Simultaneous addition of hormones produced changes in both cAMP concentrations in intact tubules as well as adenylate cyclase activity of homogenates which were not completely additive. Degradation of cAMP, estimated in intact tubules as the difference in cAMP levels in the presence and absence of MIX, was increased by both hormones, however, changes were 2-3 fold greater in tubules exposed to PTH than to PGE1. Neither hormone directly altered cAMP phosphodiesterase (PDE) activity in either 30,000 x g supernatant or pellets from renal cortical homogenates. The results suggest that both hormones increase the production of cAMP in renal cortical tubules and may share a common target cell type in this response. Degradation of cAMP, however, is differentially effected by the two hormones, probably reflecting differences exerted on intracellular mechanisms regulating the enzymatic hydrolysis of cAMP.
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PMID:Metabolism of cyclic AMP in isolated renal tubules: effects of prostaglandins and parathyroid hormone. 8 2

Local administration of PGE1 to pre-formed inflammatory granulomata of rats results in a decrease of granulomatous tissue and reduction of prostaglandin concentrations in granulomatous exudates. Under the same experimental conditions, a similar correlation between these two effects is observed with dibutyryl cyclic-AMP. An anti-granuloma effect is also achieved with the phosphodiesterase inhibitors, IBMX and RA-233, but not with theophylline, a rather feeble inhibitor of this enzyme. The present findings provide further support for the concept that elevation of cyclic-AMP in cell population(s) within granuloma is a promising line for pharmacological suppression of inflammatory tissue proliferation.
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PMID:Mimickry of anti-granuloma effect of prostaglandin E by dibutyryl cyclic-AMP and some phosphodiesterase inhibitors. 9 15

(-)-trans-delta 1-Tetrahydrocannabinol (delta 1-THC) antagonized the cyclic AMP responses of WI-38 fibroblasts to both prostaglandin E1 (PGE1) and catecholamines. Both cellular cyclic AMP accumulation and cyclic AMP escape to the incubation medium were reduced, but the reduction of escape was much more dramatic at all concentrations of the drug. Conversely, long term incubations of cells with delta 1-THC alone resulted in substantial accumulations of cyclic AMP in the incubation medium. This effect was potentiated by the phosphodiesterase inhibitor 1-methyl, 3-isobutylxanthine and appeared to result from weak agonist activity of the cannabinoid as determined by a) stimulation of radioactivity incorporated into cyclic AMP using 3H-adenine prelabelled cells, and b) a rapid and pronounced increase in the activity ratio of cellular protein kinase. The antagonistic effect of delta 1-THC on the cellular response to PGE1 was greater in preconfluent cells than in confluent monolayers. Further, the increased sensitivity of preconfluent cultures to delta 1-THC was associated with the appearance of cytoplasmic vacuoles in the perinuclear region of the cells. Cannabidiol acted similar to delta 1-Thc in affecting cyclic AMP metabolis whereas cannabinol and cannabicyclol showed mixed effects on the various parameters studied.
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PMID:Effects of delta 1-tetrahydrocannabinol on cyclic AMP in cultured human diploid fibroblasts. 9 29


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