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-(p-Chlorophenylthio)-cGMP (8-pCPT-cGMP) and 8-bromo-cGMP were compared with respect to their chemical and biological properties in order to evaluate their potential as selective activators of cGMP-dependent protein kinase (cGMP-PK; EC 2.7.1.37) in intact human platelets. 8-pCPT-cGMP, 8-Br-cGMP and cGMP were shown to be potent and selective activators of purified bovine lung cGMP-PK and of cGMP-PK present in human platelet membranes when compared with the activation of cAMP-dependent protein kinase (cAMP-PK; EC 2.7.1.37). 8-pCPT-cGMP was not hydrolysed by the purified cGMP-stimulated phosphodiesterase (cGS-PDE), cGMP-inhibited phosphodiesterase (cGI-PDE) and Ca(2+)-calmodulin-dependent phosphodiesterase (CaM-PDE), whereas cGMP and, to a lesser extent, 8-Br-cGMP were hydrolysed by all three types of 3',5' cyclic nucleotide phosphodiesterases (EC 3.1.4.17) examined. Also, 8-pCPT-cGMP was not hydrolysed by a human platelet homogenate which contains a high level of the cGMP-specific cGMP-binding phosphodiesterase (cGB-PDE). Additionally, 8-pCPT-cGMP did not activate the cGS-PDE or inhibit the cGI-PDE, whereas half-maximal inhibition of cGI-PDE occurred at 8 microM 8-Br-cGMP. The apparent lipophilicity of 8-pCPT-cGMP was higher than that of 8-Br-cGMP. Extracellular application of 8-pCPT-cGMP to intact human platelets reproduced the pattern of protein phosphorylation induced by sodium nitroprusside (SNP), a cGMP-elevating inhibitor of platelet activation. Quantitatively, 8-pCPT-cGMP was more effective than 8-Br-cGMP in inducing phosphorylation of the 46/50 kDa vasodilator-stimulated phosphoprotein, a major substrate of cGMP-PK in intact platelets. As observed with SNP, pretreatment of human platelets with 8-pCPT-cGMP prevented the aggregation induced by thrombin. The results suggest that 8-pCPT-cGMP is a very potent and selective activator of cGMP-PK in cell extracts and in intact human platelets and, in this respect, is superior to 8-Br-cGMP and other cGMP analogs used for intact cell studies. The data also suggest that inhibition of platelet activation in intact human platelets by nitrovasodilators is mediated by cGMP-PK.
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PMID:Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-para-chlorophenylthio-cGMP. 132 24

Treatment of membranes from guinea-pig peritoneal eosinophils with deoxycholate and NaCl solubilized greater than 95% of the particulate cyclic AMP-specific phosphodiesterase (PDE IV). Solubilized PDE IV was at least 10 times more potently inhibited by selective PDE IV inhibitors (e.g. rolipram, denbufylline) than bound enzyme. Vanadate/glutathione complex (V/GSH) activated membrane-bound PDE IV and also increased potencies of these same inhibitors by at least 10-fold. Neither solubilization nor V/GSH markedly influenced the inhibitory activities of non-selective inhibitors (e.g. trequinsin, dipyridamole). Inhibitor effects on solubilized PDE IV and cyclic AMP accumulation in intact cells were strongly correlated. These results suggest a biologically important site on eosinophil PDE IV which is concealed or partially concealed in freshly prepared membranes and is exposed by solubilization or V/GSH.
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PMID:Effects of solubilization and vanadate/glutathione complex on inhibitor potencies against eosinophil cyclic AMP-specific phosphodiesterase. 132 25

Positive inotropic effects of phosphodiesterase inhibitors like 3-isobutyl-1-methylxanthine (IBMX), pimobendan, adibendan, milrinone, saterinone, and enoximone are greatly diminished in isolated heart muscle preparations from human failing myocardium as compared to nonfailing myocardium. This is accompanied by a reduced increase in cAMP content in intact isometrically contracting human trabeculae. With anion exchange chromatography four peaks of phosphodiesterase activities (PDE I-IV) could be separated from both nonfailing and failing human myocardium. Substrate specificity, Km, and Vmax were similar in nonfailing and failing myocardium. Furthermore, the PDE inhibitors investigated exhibited similar IC50-values in both tissues, indicating that the sensitivity of the enzymes from nonfailing and failing tissue was unchanged. Thus, changes in PDE are probably not responsible for the reduced positive inotropic and cAMP-increasing effects of PDE inhibitors in human failing heart muscle preparations. Instead, an increase in signal transducing inhibitory G-proteins may keep the adenylyl cyclase at reduced activity, resulting in an attenuated formation of cAMP, even in the presence of PDE inhibitors.
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PMID:Phosphodiesterase inhibition and positive inotropy in failing human myocardium. 132 66

1. The effect of amrinone, milrinone and of three milrinone analogues was tested on spontaneous chronotropic and inotropic activity of guinea-pig isolated atria, on the activity of cGMP-inhibited phosphodiesterase (cGI-PDE) from guinea-pig heart and on specific binding of N6-cyclohexyl[3H]adenosine ([3H]CHA) to Ri adenosine receptors in guinea-pig atria. 2. The Ki-values towards [3H]CHA binding to Ri receptors were linearly related to the EC50S for the increase in force of contraction but not to the EC50S for the increase in frequency of the atria. The Ki values towards cGI-PDE were linearly related to the EC50S for the positive chronotropic effect.
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PMID:Antagonism towards endogenous adenosine and inhibition of cGI-PDE in the cardiac effects of amrinone, milrinone and related analogues. 132 70

Partially degenerate oligonucleotides based on peptide sequence were used to isolate cDNA to a 63-kDa bovine brain calmodulin-stimulated phosphodiesterase (CaM-PDE) isozyme. A 412-base pair polymerase chain reaction fragment was obtained and used along with the oligonucleotides to isolate several cDNAs each encoding sequence identical to known peptide sequences from the 63-kDa CaM-PDE. The largest cDNA contained a full-length open reading frame (ORF) encoding a 534 amino acid, 61,005-dalton protein. It had 59% amino acid identity to the 61-kDa bovine brain CaM-PDE and included a carboxyl-terminal conserved domain containing the PDE catalytic domain consensus sequences. The NH2-terminal region fits the criteria for a calmodulin-binding domain. When its expression was driven by a cytomegalovirus promoter on a pCDM8 vector in COS-7 cells, the cDNA encoded a catalytically active, calmodulin-stimulated PDE. Northern analysis of RNA from several tissues with a probe containing much of the conserved PDE catalytic domain showed only a single band of 4.0 kilobases. Hybridization was seen in mRNA from several regions of the central nervous system with the greatest signal in basal ganglia. Strong signals also were seen in other tissues including kidney papilla and adrenal medulla. Antisense RNA probes were used in RNase-protection assays to look for evidence of multiple 63-kDa CaM-PDE transcripts. A catalytic domain probe was fully protected by RNA from cerebral cortex, basal ganglia, cerebellum, hippocampus, adrenal medulla, and kidney papilla. However, a probe to the NH2-terminal region was fully protected only by brain and adrenal medullary RNA indicating the likelihood of one or more isozyme(s) divergent in this region in the kidney papilla.
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PMID:Molecular cloning of cDNA encoding a "63"-kDa calmodulin-stimulated phosphodiesterase from bovine brain. 132 31

Foetal calf serum (FCS) and platelet-derived growth factor (PDGF)-stimulated incorporation of [3H]thymidine into pig aortic smooth muscle cell (ASMC) DNA was decreased by agents that either stimulated the synthesis (forskolin) or inhibited the breakdown (3-isobutyl-1-methylxanthine, IBMX) of cAMP. FCS-stimulated incorporation of [3H]thymidine into DNA was also reduced by selective inhibitors of cAMP-specific phosphodiesterase (PDE IV) (Ro-20-1724, rolipram) and cGMP-inhibited cAMP PDE (PDE III) (SK&F 94836). IBMX, Ro-20-1724, rolipram and SK&F 94836 enhanced forskolin inhibition of DNA synthesis. Alone, rolipram was a relatively weak inhibitor of FCS-induced ASMC DNA synthesis (IC25 greater than 20 microM); however, in the presence of a threshold concentration of SK&F 94836 (20 microM), the potency of rolipram increased (IC25 = 4 microM), suggesting synergy in the actions of PDE III and PDE IV inhibitors. SK&F 94836 and rolipram elicited 30% and 37%, respectively, reductions in FCS-induced ASMC proliferation and potentiated the inhibitory actions of forskolin. PDE III and PDE IV inhibitors alone, exerted minimal effects on ASMC cAMP levels after a short term (10 min) or long-term (2 or 24 hr) exposure, but enhanced forskolin-induced accumulation of cAMP. ASMC spontaneously released cAMP into the extracellular medium, a process that was increased by forskolin. PDE III and PDE IV inhibitors had no effect alone on cAMP extrusion but enhanced the effect of forskolin. Exposure of ASMC to forskolin or SK&F 94836 for 15 min increased the activity ratio (AR) of cAMP-dependent protein kinase from 0.05 to 0.17 and 0.23, respectively. Ro-20-1724, alone, did not affect cAMP-dependent protein kinase but enhanced the stimulatory effect of forskolin (AR = 0.37) and SK&F 94836 (AR = 0.27). Agents that increased cGMP synthesis (glycerol trinitrate, atrial natriuretic factor) or decreased its hydrolysis by selectively inhibiting cGMP-specific PDE (PDE V) (zaprinast) exerted no effects on FCS- or PDGF-stimulated [3H]thymidine incorporation into DNA either alone or in combination. The cytosolic fraction of pig ASMC contained four cyclic nucleotide PDEs which were categorized as PDE V, Ca2+/calmodulin-stimulated PDE (PDE I), PDE III and PDE IV. PDE I and III activities were also associated with the particulate fraction. The results demonstrate that inhibitors of PDEs III and IV alone or in combination with forskolin, reduce ASMC DNA synthesis and proliferation, through an action likely to involve elevation of intracellular cAMP. In contrast, inhibition of cGMP hydrolysing PDE subtypes (I and V) exerted no effect on DNA synthesis in this cell type.
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PMID:Inhibition of pig aortic smooth muscle cell DNA synthesis by selective type III and type IV cyclic AMP phosphodiesterase inhibitors. 132 64

Four cAMP phosphodiesterase (cAMP-PDE) genes (ratPDE1, ratPDE2, ratPDE3, and ratPDE4) are expressed in the rat testis (Swinnen et al., PNAS USA 1989; 86:5325). Since multiple ratPDE1 and ratPDE2 mRNAs were present in male germ cells, their developmental expression was investigated by using purified spermatogenic cell populations. RatPDE1 mRNAs (4.0 and 2.8 kb) were found to be abundant in pachytene spermatocytes. RatPDE1 mRNA levels were decreased in round spermatids and absent from condensing spermatids/residual bodies. However, multiple ratPDE2 mRNAs (4.0, 3.5, 3.1, 2.8, and 2.4 kb) were abundant in round spermatids, and lower amounts were present in condensing spermatids/residual bodies. Transcripts related to ratPDE2 were also present in mouse round spermatids. Chromatography of germ cell cytosol identified two peaks of cAMP-PDE activity. Whereas peak A was evident in all germ cell populations examined, peak B was present in pachytene spermatocytes and round spermatids, but was at the limit of detection in condensing spermatids/residual bodies. The large decrease in peak B activity in condensing spermatids/residual bodies may be related to the drop in ratPDE1 mRNA levels observed during spermatogenesis. The sustained peak A activity in condensing spermatids/residual bodies coincides with the presence of ratPDE2 mRNA in these cells and suggests that the ratPDE2 enzyme may function during spermiogenesis and in spermatozoa.
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PMID:Unique adenosine 3',5' cyclic monophosphate phosphodiesterase messenger ribonucleic acids in rat spermatogenic cells: evidence for differential gene expression during spermatogenesis. 132 99

The phenolic preservative, methylparaben (MPB), has in the past been demonstrated to harbour definite pharmacological effects. In an attempt to examine the possible central effects of MPB, notably on cyclic nucleotides and cyclic nucleotide phosphodiesterase (PDE; EC 3.1.4.17), rats were orally treated with the drug (0.4% in rat food) for 3 weeks with cortex extracts being used for the various determinations. Three isozymes were identified by DEAE-cellulose anion exchange chromatography, namely the calmodulin/calcium-stimulated form or PDE I (peak I), the cGMP-stimulated form or PDE II (peak II), and an independent form not affected by either calmodulin or cGMP also known as PDE IV (peak III). The presence of MPB induced a significant decrease in cortical cAMP, as well as strongly stimulating the activity of PDE IV (peak III). In addition, a small, yet significant, increase in cGMP levels was observed. Since no increase in cGMP hydrolysis was observed, we conclude that chronic ingestion of MPB induces a preference for cAMP hydrolysis, which was confirmed by the increase in PDE IV (peak III) activity. PDE IV is a membrane-bound, low Km PDE exhibiting high selectivity for cAMP hydrolysis. While there was an increase in cGMP, we failed to observe an increase in the activity of the cGMP-stimulated PDE (PDE II). These data are discussed with reference to the possible membrane effects of MPB allowing it to alter both the kinetic properties of PDE IV with the resultant effects on cAMP, as well as a means whereby it may activate guanyl cyclase and increase cGMP.
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PMID:Central effects of the preservative, methylparaben. In vivo activation of cAMP-specific phosphodiesterase and reduction of cortical cAMP. 132 56

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

Previous evidences reported by us and by other authors revealed the presence of IgG in sera of Schistosoma mansoni-infected patients to immunodominant antigens which are enzymes. Besides their immunological interest as possible inductors of protection, several of these enzyme antigens might be also interesting markers of infection in antibody-detecting immunocapture assays which use the intrinsic catalytic property of these antigens. It was thus thought important to define some enzymatic and immunological characteristics of these molecules to better exploit their use as antigens. Four different enzymes from adult worms were partially characterized in their biochemical properties and susceptibility to react with antibodies of infected patients, namely alkaline phosphatase (AKP, Mg2+, pH 9.5), type I phosphodiesterase (PDE, pH 9.5), cysteine proteinase (CP, dithiothreitol, pH 5.5) and N-acetyl-beta-D-glucosaminidase (NAG, pH 5.5). The AKP and PDE are distinct tegumental membrane-bound enzymes whereas CP and NAG are soluble acid enzymes. Antibodies in infected human sera differed in their capacity to react with and to inhibit these enzyme antigens. Possibly, the specificity of the antibodies related to the extent of homology between the parasite and the host enzyme might be in part responsible for the above differences. The results are also discussed in view of the possible functional importance of these enzymes.
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PMID:Parasite enzymes as a tool to investigate immune responses. 134 26


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