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)

We have cloned a 4.2-kilobase pair (kb) cDNA that encodes the cyclic GMP-stimulated phosphodiesterase (cGS PDE) from a bovine adrenal cortex library. The 921-residue polypeptide deduced from the cDNA nucleotide sequence is nearly identical with the complete amino acid sequence of the cGS PDE purified from a soluble bovine heart extract. Moreover, PPD-S49 cells transfected with the cGS PDE cDNA express a soluble cAMP hydrolytic activity that is enhanced by cGMP. Total RNA isolated from several bovine tissues were screened for cGS PDE transcript by Northern blot analysis. The cGS PDE cDNA appears to hybridize to a single 4.5-4.6-kb mRNA species. Although the cGS PDE mRNA is most abundant in the adrenal cortex, it is also concentrated in the adrenal medulla and heart and in anatomically distinct regions of the brain and kidney. A mRNA species encoding a putative variant cGS PDE isoform was detected by RNase protection. Total RNA isolated from adrenal cortex, adrenal medulla, liver, kidney, trachea, lung, spleen, and T-lymphocytes completely protected a 452-base riboprobe encoding 100 residues of the adrenal cortex cGS PDE amino terminus. In contrast, RNAs isolated from brain (cerebral cortex, hippocampus, and basal ganglia) protected only 268 bases of this riboprobe. The RNase protection pattern of this same probe using heart RNA showed major bands at both 268 and 452 bases, suggesting that two different cGS PDE mRNA species are expressed. These results indicate that the cGS PDE is widely expressed in a variety of tissues. Moreover, these studies suggest that at least one different cGS PDE isoform having a structurally distinct amino-terminal domain is expressed in brain and heart.
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PMID:Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. 165 33

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives was synthesized and evaluated as inhibitors of cAMP hydrolysis by a crude human platelet phosphodiesterase preparation and as inhibitors of ADP- and collagen-induced aggregation of rabbit blood platelets. The parent structure 7a, demonstrated potent inhibitory activity that was enhanced by the introduction of alkyl, alkoxy, or halogen substituents at the 5-, 6-, 7-, and 8-positions. Methylation at N-1 or N-3 produced weaker inhibitors of cAMP PDE and platelet aggregation. 1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-ones (6) were found to be equipotent with their fully oxidized congeners (7). On the basis of platelet inhibitory properties in vitro, efficacy at preventing thrombus formation in animal models of thrombosis, and a favorable hemodynamic profile, 1,3-dihydro-7,8-dimethyl-2H- imidazo[4,5-b]quinolin-2-one (7o, BMY 20844) was selected for advancement into toxicological evaluation and clinical trial. An efficient synthesis of 7o is described.
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PMID:1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation. 165 30

Ligation of the antigen receptors on both T and B lymphocytes induces phosphoinositide (PI) hydrolysis, Ca(2+)-mobilization and protein kinase C activation. The activation of the phosphoinositide-specific phosphodiesterase (PPI-PDE) following crosslinking of surface Ig receptors on B cells is controlled by an uncharacterized guanine nucleotide-regulatory (G) protein. Here we have used permeabilized murine T cells (both resting T cells and a conalbumin-specific CD4-positive T cell clone) to investigate a role for G protein(s) in coupling the TCR to the PPI-PDE. We found that anti-TCR McAb (or processed antigen)-induced PI hydrolysis cannot be uncoupled by permeabilizing T cells, as occurs with classical G protein-linked receptors. Furthermore, the TCR-mediated release of inositol phosphates in permeabilized T cells was not enhanced by non-hydrolyzable analogs of GTP, nor inhibited by GDP analogs. These findings therefore argue strongly against the concept that TCR-mediated PI hydrolysis is G-protein controlled.
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PMID:Antigen receptor-mediated phosphoinositide hydrolysis in murine T cells is not initiated via G-protein activation. 165 2

Many of newly developed positive inotropic agents are phosphodiesterase inhibitors (PDEI). These are (in contrast to the classical, unselective PDEIs) in most cases selective inhibitors of PDE III which is inhibitable by cGMP. The most important action of PDEIs is a receptor-independent increase in intracellular cAMP, resulting from an inhibition of the degradation of cAMP. An increase in intracellular cAMP levels can also be produced by stimulation of adenylate cyclase, which leads to an increase in cAMP formation. Therefore, the effects of beta-adrenoceptor agonists (e. g., isoprenaline) and PDEIs are rather similar. The main effect of cAMP is to increase the slow Ca inward current during the action potential. This leads to an increase in Ca release from intracellular Ca stores, to an increase in the Ca concentration in the vicinity of the contractile proteins and, hence, to a positive inotropic effect. In addition, PDEIs also produce vasodilatation, which might be of even greater importance than the cardiostimulatory effects of these drugs ("inodilators"). However, two potential disadvantages of PDEIs must also be mentioned: 1) increase in beat frequency and tachyarrhythmias that also result from an increase in intracellular cAMP concentration and 2) decrease in effectiveness or tolerance, which might be due to an increase in inhibitory G proteins.
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PMID:[Mechanism of the positive inotropic effect of phosphodiesterase inhibitors]. 165 18

In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).
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PMID:Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus. 165 82

The behavioral effects of specific cAMP phosphodiesterase inhibitors (PDE-I) such as rolipram and structurally related compounds were investigated in mice. Selected PDE-I induced a potent dose-dependent decrease in locomotion and in rearing of mice confronted with a free exploratory procedure, these effects being considered as a behavioral sedation. However, in the light/dark choice test especially conceived to reveal disinhibitory and/or anxiolytic action, they did not show obvious effects. These results suggest that the increase of cAMP probably does not account for our previously observed anxiolytic properties of BW A78U, an adenine derivative PDE-I (20).
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PMID:Behavioral effects of rolipram and structurally related compounds in mice: behavioral sedation of cAMP phosphodiesterase inhibitors. 165 15

Salt sensitivity affects a fraction of hypertensive and normotensive subjects, but biochemical markers that target salt-sensitive individuals are not available at present. The aim of these studies was to establish if calmodulin-phosphodiesterase (CaM-PDE) activator (J Clin Invest 82: 276, 1988) and platelet cyclic nucleotides could serve as potential markers of salt sensitivity. The results demonstrated that CaM-PDE activator was increased in the heart of Dahl salt-sensitive rats (DS/JR) compared to Dahl salt-resistant (DR/JR) animals fed a 1% sodium diet. Normotensive male Wistar rats given a low (0.15%) or high (3.5%) sodium diet from age 7 weeks to 11 weeks presented significant increases (p less than 0.01) of three parameters: blood pressure (from 106 +/- 4 to 128 +/- 8 mmHg); platelet aggregation in response to ADP and thrombin; and CaM-PDE activator levels (from 1.57 +/- 0.14 to 2.8 +/- 0.18). Basal as well as stimulated cyclic nucleotide levels were significantly reduced in rats fed the high sodium diet. Since the degree of stimulation by the agonists was unaltered, the results are compatible with augmented PDE activity. These preliminary data suggest that CaM-PDE activator should be explored as a potential marker of salt sensitivity.
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PMID:Cyclic nucleotides and calmodulin-phosphodiesterase activator: potential biochemical markers of salt sensitivity. 166 35

The levels of the retinal mRNAs encoding opsin, the alpha subunit of rod transducin (T alpha), S-antigen (S-ag) and the gamma subunit of rod-specific cGMP-phosphodiesterase (cGMP-PDE) were measured in rats reared in cyclic light or darkness and after adaptation for different periods of time to the opposite light environment. We found that rats changed from cyclic light to darkness, gradually increased their retinal content of opsin and T alpha mRNAs but decreased their levels of S-ag mRNA. The reverse results were obtained when rats were changed from darkness to cyclic light. In contrast, the levels of retinal cGMP-PDE gamma mRNA remained unchanged in animals adapted to either of the two rearing light conditions. Our results indicate that some mRNAs encoding proteins associated with the cGMP cascade are responsive to environmental lighting and may be involved in the long term light or dark adaptive processes.
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PMID:Levels of mRNA encoding proteins of the cGMP cascade as a function of light environment. 166 39

Metabolism of cGMP is critically important for the functioning of phototransduction in the mammalian retina. In rod and cone photoreceptors, two types of antagonistic enzymes, guanylate cyclases and cGMP phosphodiesterases, carefully balance the available amount of the intracellular messenger. Guanylate cyclase produces cGMP and phosphodiesterase rapidly hydrolyzes cGMP upon bleaching of the photopigment. Regulation of their activity in light and dark, influence of Ca++, and feed-back mechanisms are currently under intense investigation. A molecular analysis on both the gene and protein levels will contribute significantly to our understanding of their respective roles in phototransduction. The two types of enzymes have been characterized molecularly to a very different extent. Rod phosphodiesterase was purified to homogeneity almost fifteen years ago, but photoreceptor guanylate cyclase has evaded all attempts for molecular characterization. Characterization of retinal guanylate cyclase cDNA(s), however, will most likely be achieved in the near future. Cone PDE was shown to be a distinct enzyme, different from, but related to, the rod enzyme. Molecular cloning has provided sequence information of two of the three subunits of rod PDE; the small inhibitory subunit has been expressed in bacterial expression vectors, giving us an elegant tool for exploring mechanisms of activation and inhibition. The gene encoding the alpha subunit was shown to be a member of a large gene family of cyclic nucleotide phosphodiesterases, present in many eucaryotes ranging from unicellular organisms (yeast) to mammals. While much has been achieved, many questions remain to be answered. The beta subunit of rod phosphodiesterase has evaded complete molecular characterization, and its origin (one gene and posttranslational modification of the gene product generating alpha and beta, alternative splicing, or two separate genes with distinct gene products) has not been elucidated. Mechanisms of interaction of subunits, activation and inhibition, the active site(s) of the enzyme are undefined. Virtually nothing is known about the molecular organization of the photoreceptor guanylate cyclase(s). Recent cloning of two apparently unrelated mammalian guanylate cyclases, however, containing a common homologous domain signals increasingly rapid progress in this field.
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PMID:The molecular genetics of retinal photoreceptor proteins involved in cGMP metabolism. 167 36

Effects of Ro 20-1724, a selective inhibitor of soluble cGMP-insensitive type IV phosphodiesterase, on the force and cAMP levels were compared with those of 3-isobutyl-1-methylaxanthine, a non-selective inhibitor, in the rat ventricular myocardium. Ro 20-1724 scarcely affected the basal force of contraction and cAMP levels, whereas it enhanced the positive intropic effect and cAMP accumulation induced by isoproterenol more effectively than 3-isobutyl-1-methylxanthine. These results imply that inhibition of the soluble cGMP-insensitive type IV PDE by Ro 20-1724 may be crucially involved in the regulation of myocardial contractility through the interaction with cAMP generation in the rat ventricular myocardium.
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PMID:Differential effects of Ro 20-1724 and isobutylmethylxanthine on the basal force of contraction and beta-adrenoceptor-mediated response in the rat ventricular myocardium. 168 99


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