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)

8-(4-Chlorophenyl)thio-cyclic AMP (8-CPT-cAMP), extensively used as selective activator of cyclic AMP-dependent protein kinase, has been found to be a potent inhibitor of the cyclic GMP-specific phosphodiesterase (PDE VA). Indeed, 8-CPT-cAMP (IC50 = 0.9 microM) inhibited PDE VA with a potency identical to that of zaprinast. 8-CPT-cAMP was also metabolized by PDE VA at a rate half that of cyclic GMP. The cyclic GMP-inhibited phosphodiesterase (PDE III) (IC50 = 24 microM) and the cyclic AMP-specific phosphodiesterase (PDE IV) (IC50 = 25 microM) were also inhibited by 8-CPT-cAMP. In contrast, most of the other cAMP-derivative studies showed little inhibition of any phosphodiesterase isoenzyme. These observations provide further reasons why the mechanism of the physiological effects of 8-CPT-cAMP should be interpreted with caution.
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PMID:8-(4-Chlorophenyl)thio-cyclic AMP is a potent inhibitor of the cyclic GMP-specific phosphodiesterase (PDE VA). 133 52

The present studies have examined the regulation of the jun-B early response gene by cyclic AMP (cAMP)-dependent signaling pathways. The 2.0-kb jun-B transcript was at low but detectable levels in uninduced human HL-60 myeloid leukemia cells. In contrast, treatment with 1 mmol/L8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) in the presence of isobutylmethylxanthine, an inhibitor of cAMP-dependent phosphodiesterase, was associated with increases in jun-B transcripts that were maximal by 1 hour and then decreased to near pretreatment levels by 6 hours. Similar findings were obtained with 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) and N6,2'-0-dibutyryladenosine 3',5'-cyclic monophosphate (dBt-cAMP). jun-B transcripts were also increased with other agents that increase intracellular cAMP levels, such as prostaglandin E2 (PGE2) and forskolin. Moreover, inhibition of cAMP-dependent protein kinase by the isoquinolinesulfonamide H-8 blocked 8-Br-cAMP-induced increases in jun-B expression. The results of nuclear run-on assays demonstrate that treatment of HL-60 cells with PGE2, forskolin, 8-Br-cAMP, and dBt-cAMP is associated with increases in the rate of jun-B transcription. The present findings also demonstrate that the related jun-D gene is similarly regulated by a cAMP-dependent pathway. Taken together, these findings suggest that stimulation of cAMP-dependent protein kinase is involved in the induction of jun gene expression in myeloid leukemia cells.
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PMID:Regulation of jun-B expression by a cyclic AMP (cAMP)-dependent mechanism in human myeloid cells. 164 78

We have studied the effects of the membrane-permeant cyclic AMP analogs 8-bromo-cyclic AMP and 8-(4-chlorophenylthio)-cyclic AMP (CPT-cAMP) on the gamma-aminobutyric acidA (GABAA) receptor-mediated chloride current in cultured rat hippocampal neurons. External perfusion with 8-bromo-cyclic AMP or CPT-cAMP caused a reversible, concentration-dependent decrease in the response to GABA. Adding the protein kinase inhibitor H-8 to the perfusing medium or the intracellular recording solution did not affect the response to GABA, which was decreased by CPT-cAMP as before. L858051, a water-soluble derivative of the adenylate cyclase activator forskolin, did not decrease the response to GABA even in the presence of the phosphodiesterase inhibitor 3-isobutylmethylxanthine. External cyclic AMP also caused a reversible, concentration-dependent decrease in the response to GABA with a potency similar to that of 8-Br-cAMP. When cAMP was present in the intracellular recording solution cAMP and CPT-cAMP decreased the response to GABA as before. These experiments suggest that analogs of cAMP decrease GABAA receptor-activated chloride current by acting at an extracellular site.
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PMID:Analogs of cyclic AMP decrease gamma-aminobutyric acidA receptor-mediated chloride current in cultured rat hippocampal neurons via an extracellular site. 169 73

In the preceding paper (Kehoe, 1985) it was shown that the firing of any one of three neurones (I, II, III) presynaptic to the medial cells of the pleural ganglion of Aplysia californica causes a diminution of the cholinergically controlled K conductance in those cells. Firing of the same three presynaptic neurones was shown here to cause a similar diminution in a depolarization-induced K-dependent conductance in the same post-synaptic cells. The depolarization-induced K conductance was found to disappear when Ca ions were removed from the sea water bathing the ganglion or when the cell was injected with the Ca chelator ethyleneglycol-bis-(beta-aminoethylether)N,N'-tetra-acetic acid (EGTA). The diminution in this Ca-activated, K-dependent current occurred even when the presynaptic neurone was fired a few seconds after the end of the depolarizing voltage step to the post-synaptic neurone, showing that the diminution in K conductance was not an indirect effect of a transmitter-induced diminution in Ca influx during the depolarizing pulse. The two K conductances affected by the 'blocking neurones' could be selectively eliminated. The cholinergic conductance could be blocked by receptor-specific cholinergic antagonists (e.g. 1 mM concentrations of phenyltrimethylammonium (PTMA), choline and tetraethylammonium (TEA]. Even at 10 mM concentrations, none of these compounds (including TEA, which is known to block certain Ca-activated K conductances) had an effect on the depolarization-induced, Ca-activated K conductance studied here. This latter conductance, on the other hand, was selectively blocked by an intracellular injection of EGTA. The three blocking neurones continued to diminish the K conductance (cholinergic or depolarization induced) that remained intact under these different experimental conditions. The depolarization-induced influx of Ca was shown to block the cholinergically controlled K conductance, but Ca was excluded as the possible mediator of the diminution in K conductance caused by the three blocking neurones. An intracellular injection of Ca ions into the medial cells was shown to activate a variety of changes in membrane conductance; in particular, two K-conductance increases: an early, TEA-sensitive one, and a slowly developing, TEA-insensitive one. Both the permeant cyclic AMP analogue p-chlorophenylthioadenosine 3',5'-monophosphate (CPT-cyclic AMP) and the phosphodiesterase inhibitors amino-phylline and isobutyl-1-methylxanthine (IBMX) were shown to block the depolarization-induced K conductance, and to reduce, though not eliminate, the slowly developing K conductance activated by an intracellular injection of Ca.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synaptic block of a calcium-activated potassium conductance in Aplysia neurones. 241 50

The neuroendocrine caudodorsal cells (CDCs) of the pond snail Lymnaea stagnalis release a number of peptides, including the ovulation hormone, caudodorsal cell hormone (CDCH), during a period of high electrical activity (the CDC-discharge). Earlier studies have shown that during the CDC-discharge adenylate cyclase activity is increased, and that the cyclic adenosine monophosphate (cAMP) analogue 8-chlorophenylthio (8-CPT)-cAMP induces exocytosis and release of peptides from the CDCs. Here, we have investigated the role of cAMP, adenylate cyclase and phosphodiesterase in determining the state of excitability of the CDCs. The cAMP analogue 8-CPT-cAMP induced long-lasting discharges in CDCs. Simultaneous inhibition of the phosphodiesterase by 3-isobutyl-1-methylxanthine (IBMX) and activation of the adenylate cyclase by forskolin gave similar results. These agents also induced discharges of CDCs in dissociated cell culture, indicating that the responses to an increase of cAMP were an endogenous property of the cells. The CDC-afterdischarge can be induced by a period of repetitive electrical stimulation. Inhibition of the phosphodiesterase-activity by IBMX did not change the resting membrane potential, but increased the proportion of preparations that responded to this stimulation with an afterdischarge by more than 200%. It is suggested that cAMP-regulating enzymes are involved in stimulus-response coupling of the afterdischarge in CDCs. The induction of an after discharge probably requires both a low phosphodiesterase-activity and the activation of the adenylate cyclase. The low excitability of the CDCs following an afterdischarge might originate from a refractoriness in the activation of the adenylate cyclase.
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PMID:The role of cAMP in regulation of electrical activity of the neuroendocrine caudodorsal cells of Lymnaea stagnalis. 246 19

1. The decreased response to beta-adrenoceptor stimulation seen in heart failure may be related to a defect in cyclic AMP production. The inotropic effects of the selective phosphodiesterase (PDE) III inhibitors, SK&F 94120 and SK&F94836, and the non-selective PDE inhibitor, 3-isobutyl-l-methylxanthine (IBMX), alone and when combined synergistically with isoprenaline, were studied in control and beta-adrenoceptor-desensitized ventricular myocytes. 2. Myocytes isolated from noradrenaline-treated guinea-pigs had a reduced maximum response to isoprenaline compared with control animals (60.0 +/- 2.5%, n = 42 vs 79.5 +/- 1.7% maximum calcium: n = 46, P < 0.001). Together with an approximately 20 fold increase in the isoprenaline EC50, this is indicative of beta-adrenoceptor desensitization as a result with chronic infusion with noradrenaline. 3. The maximum inotropic response of IBMX was depressed following noradrenaline treatment, from 74.9 +/- 4.6% (n = 7) in control, to 61.7 +/- 2.70% (n = 6), as a percentage of maximum calcium in noradrenaline-treated guinea-pig ventricular myocytes (P < 0.02). The pD2 value for IBMX was also reduced (P < 0.02). No significant differences in the inotropic effects of SK&F94120 and SK&F94836 were seen between control and beta-adrenoceptor desensitized myocytes. 4. Threshold inotropic concentrations of SK&F94120 and SK&F94836 caused a five fold decrease in the EC50 of control myocytes for isoprenaline, and an 11 fold decrease in the noradrenaline-treated guinea-pig ventricular myocytes. 5. The maximum response to isoprenaline in myocytes isolated from normal guinea-pigs was unaffected by PDE inhibition; either at threshold or maximum inotropic concentrations, or by CPT cyclic AMP, an analogue of cyclic AMP.6. A significant potentiation of the maximum isoprenaline response by threshold inotropic concentrations was observed with SK&F 94120 (P<0.05), but not with IBMX or SK&F 94836, in myocytes isolated from noradrenaline-treated guinea-pig hearts. This potentiation, however, did not completely restore the response to levels seen in control myocytes.7. The extent of potentiation of the maximum isoprenaline response by maximum inotropic concentrations of either IBMX or CPT cyclic AMP, was no greater than that by threshold concentrations of IBMX, in myocytes isolated from noradrenaline-treated guinea-pig hearts.8. In cardiac myocytes isolated from the explanted hearts of 16 patients with heart failure, threshold concentrations of IBMX and SK&F 94120 decreased the isoprenaline EC50 by a factor of four and six,respectively, but potentiation of the maximum isoprenaline response occurred only with SK&F 94120.The attenuated isoprenaline response was increased from 60.3 +/- 4.5% to 74.3 +/- 4.2% as a % maximum calcium (P<0.05, n = 6), but remained substantially lower than the 116 +/- 7% (P<0.001, n = 6) seen in myocytes isolated from non-failing hearts.9. We conclude that the reduced maximum contraction amplitude with isoprenaline in cardiac myocytes from either patients in end-stage failure, or noradrenaline-treated guinea-pigs, is partly but not solely due to insufficient cyclic AMP levels, since inhibition of cyclic AMP degradation does not result incomplete reversal of the beta-adrenoceptor desensitization.
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PMID:Incomplete reversal of beta-adrenoceptor desensitization in human and guinea-pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors. 769 63

We examined effects of a novel antidiabetic agent, racemic englitazone (CP 68,722, Pfizer), on normal rat hepatocytes in vitro. For optimal effects, CP 68,722 must be preincubated for approximately 20 minutes. CP 68,722 inhibited the actions of glucagon on glycogenolysis (measured by monitoring cyclic adenosine monophosphate [cAMP] levels, phosphorylase activation, and glucose output) and gluconeogenesis (from 14C-lactate). Since CP 68,722 was able to attenuate the ability of glucagon to increase cAMP levels, this may account for part of its inhibitory actions on glycogenolysis and gluconeogenesis. The observation that CP 68,722 also inhibits the ability of the cAMP analog, 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic monophosphate (8 CPT cAMP), to stimulate phosphorylase a is consistent with an effect of CP 68,722 to activate cAMP-dependent phosphodiesterase. The ability of vasopressin (an agonist known to stimulate glycogenolysis via a Ca(2+)-dependent mechanism) to stimulate phosphorylase a was slightly inhibited by CP 68,722. Another site of action of CP 68,722 was to inhibit hormonal-mediated Ca2+ influx, an effect that would decrease intracellular free calcium ([Ca2+]i), thereby inhibiting the actions of the Ca(2+)-dependent hormones such as alpha 1-adrenergic agonists and vasopressin, agents known to promote glucose output from the liver. In summary, CP 68,722 inhibits glucagon-stimulated glycogenolysis and gluconeogenesis in hepatocytes by a mechanism that may include activation of cAMP phosphodiesterase and inhibition of Ca2+ influx.
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PMID:Actions of the novel antidiabetic agent englitazone in rat hepatocytes. 824 73

1. The effects of the phosphodiesterase inhibitors theophylline and isobutylmethylxanthine (IBMX) on baseline and voltage-activated Cl- conductance (gCl) of toad skin were compared with those of the potent 2-chlorophenylthio analogue of cAMP (CPT-cAMP). 2. Using intact and split skins of Bufo viridis we confirmed that theophylline and IBMX raised the voltage-activated gCl with a pattern identical to that seen under control conditions. This effect was small or missing if gCl was already high in the control. 3. CPT-cAMP, in contrast, increased the Cl(-)-specific conductance by up to 6 mS cm-2 at short circuit. The characteristic time-dependent, slow activation of gCl by serosa-positive clamp potentials was completely lost under these conditions. 4. Coinciding with the loss of voltage activation of gCl the plateau value of the Lorentzian component of fluctuation in current at serosa-positive clamp potentials decreased by almost 50%. The corner frequencies were not notably different. 5. After CPT-cAMP, the sigmoidal voltage-conductance relation that is characteristic of control conditions or after theophylline disappeared; the patterns were variable and incompatible with voltage activation. 6. The voltage-activated gCl under control conditions and with theophylline was blocked by mucosal NO3-, I- or SCN-, the last two being almost equally effective. In the presence of CPT-cAMP, mucosal NO3- had minimal influence on tissue conductance, whereas the effects of I- and SCN- were essentially unchanged. Br- on the mucosal side could substitute for Cl- under all conditions. 7. The results suggest that protein phosphorylation by supramaximal concentrations of cAMP induces maximal conductance through anion-specific routes, while the voltage sensitivity of this pathway is lost. The effects of theophylline and IBMX on the voltage-activated Cl-conductance of toad skin cannot be explained solely by inhibition of the phosphodiesterase.
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PMID:Effects of cyclic AMP and theophylline on chloride conductance across toad skin. 858 95

A shadow passing overhead acts as a danger stimulus and elicits an escape response in the crab Chasmagnathus that habituates promptly and for a long period. Robust retention is shown at 24 h after 15 trials of shadow presentation or at 120 h after 30 trials, but no significant retention is disclosed at 24 h after 5 trials or at 72 h after 15. A cocktail of the cAMP membrane permeable analog 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), plus the phosphodiesterase inhibitor isobutyl methylxanthine (IBMX), was given by systemic administration. Pretraining injection of the cocktail (25 or 50 microM, 15 min before a 5-trial session) failed to affect short-term habituation, but induced significant retention when tested at 24 h. This facilitatory effect was not shown when a lower dose (5 microM) was used. A post-training injection of 25 microM, immediately after a 5- or 15-trial session, induced retention when tested at 24 or 72 h, respectively. Thus, the administration of CPT-cAMP + IBMX during acquisition of a habituated response or immediately after, improves long-term habituation, a result supporting the view that an increase in the cAMP level is one of the steps in long-term memory consolidation.
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PMID:Acute administration of a permeant analog of cAMP and a phosphodiesterase inhibitor improve long-term habituation in the crab Chasmagnathus. 880 Jun 48

Addition of 8-bromo-adenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) or 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) to hepatocytes at the time of plating enhanced the acquisition of beta-adrenoceptors that occurs spontaneously upon culturing as primary monolayers. This effect was partially suppressed by the phosphodiesterase inhibitor isobutyl methylxanthine, and was mimicked by 8-bromo-AMP, 8-bromo-adenosine, and the adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine. Agents that elevated the intracellular level of cAMP, such as glucagon and forskolin, and Sp-8-bromo-adenosine 3',5'-monophosphorothioate (Sp-8-bromo-cAMPS), a cAMP analogue that is resistant towards metabolic breakdown, did not significantly enhance beta-adrenoceptor expression when used alone, but glucagon enhanced the effect of 8-bromo-adenosine. 8-bromo-cAMP and 8-bromo-adenosine decreased cellular ATP-levels. These observations suggest that the enhanced beta-adrenoceptor acquisition was mediated mainly through the action of metabolites of 8-bromo-cAMP and 8-CPT-cAMP, although there may be a cAMP-mediated component in the effect. Several mechanisms, including depletion of ATP, are probably involved, and might affect beta-adrenoceptor degradation.
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PMID:8-bromo-cAMP and 8-CPT-cAMP increase the density of beta-adrenoceptors in hepatocytes by a mechanism not mimicking the effect of cAMP. 884 Oct 91


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