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)

Cyclic nucleotide phosphodiesterase isoenzymes hydrolyse and thus inactivate the intracellular second messengers cyclic AMP and cyclic GMP. Inhibitors of these isoenzymes modulate tissue function by reducing the rate of breakdown of the cyclic nucleotides. Eukaryotic cells contain multiple forms of phosphodiesterase with differing regulatory characteristics and substrate specificities. At present, the majority of the identified isoenzymes can be grouped into five families (PDE I-PDE V). These isoenzymes have differing distributions and play differing relative roles in the hydrolysis of cyclic nucleotides between tissues. Thus, isoenzyme selective inhibitors may selectively modulate tissue function. Drugs which are therapeutically useful in asthma either bronchodilate or reduce the underlying inflammatory condition. Inhibitors of PDE III, PDE IV and PDE V relax airways smooth muscle. Inhibitors of PDE IV attenuate the activation of pro-inflammatory cells, an effect which in some assays is potentiated by additional PDE III inhibition. PDE V inhibition has not been shown to result in potentially useful anti-inflammatory activity. Despite various degrees of tissue selectivity, the possible side effect profile of isoenzyme selective phosphodiesterase inhibitors requires elucidation before these agents can be proposed as selective anti-asthma drugs. However, it is apparent that selective inhibitors of PDE III, PDE IV and PDE V may be useful bronchodilators, whilst PDE IV and PDE III/IV inhibitors also possess potentially useful anti-inflammatory activity. Such compounds require further evaluation in animals and man to clarify their full potential as therapeutic agents for the treatment of asthma.
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PMID:Cyclic nucleotide phosphodiesterase isoenzymes and asthma--outstanding issues. 839 17

Cyclic adenosine monophosphate (cAMP) is an important modulator of platelet responses to agonists. Cyclic nucleotide phosphodiesterase (PDE) controls intracellular cAMP concentrations by hydrolyzing it to AMP. The major PDE activity in platelets is PDE3A (cyclic guanosine monophosphate [cGMP]-inhibited PDE). To obtain structural information on platelet PDE3A, we cloned the enzyme cDNA from a human erythroleukemia cell (HEL) library since the cell line expresses many platelet proteins. This clone consists of 87% of the full-length human myocardial PDE3A cDNA, spanning from nucleotides 456 to 4606, and is identical in sequence. The nucleotide coding for the N terminal 179 amino acid sequence (nt 1-536) as well as four other cDNAs (nt 1459-1632, nt 1765-1986, nt 2152-2538, and nt 2978-3375) obtained by RT-PCR of platelet RNA are also identical to the myocardial sequences, indicating that the HEL, myocardial, and platelet PDE3As are the same. Northern blot analysis of HEL cell RNA detected two mRNAs of 7.5 and 4.4 kb. Four new deletion mutants are reported. PDE 3A delta 1 and PDE 3A delta 2, encoding amino acids 665 to 1141 and amino acids 679 to 1141, respectively, were expressed in a PDE-deficient yeast. They displayed PDE activities of 172 and 79 pmol/mg/min, respectively. PDE 3A delta 3 and PDE 3A delta 4, encoding amino acids 686 to 1141 and 700 to 1141, had no detectable PDE activity. All mutant proteins were expressed as determined by Western blot analysis. These findings localize the PDE3A catalytic domain to within amino acid residues 679 to 1141.
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PMID:Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis. 869 50

Aveolar macrophages (AM) may contribute to airway inflammation via release of superoxide anion (O2-). Elevation of intracellular cyclic adenosine monophosphate (cAMP) levels has been shown to suppress O2- generation, although the exact mechanism is uncertain. To examine the inhibitory effect of cAMP against different stimuli for O2- generation, we compared the effect of cAMP on O2- generation caused by phorbol myristate acetate (PMA), a direct protein kinase C activator, and N-formyl-methionyl-leucyl-phenylalanine (FMLP), which couples its membrane receptor and stimulates guanosine triphosphate binding protein, in guinea pig AM. Cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors or CPT-cAMP, a cAMP analogue, were used in order to increase intracellular cAMP levels. The O2- generation caused by either PMA or FMLP was reduced by cilostazol (PDE 3 inhibitor) and Ro20-1724 (PDE 4 inhibitor), but not by zaprinast (PDE 5 inhibitor). The degree of reduction in O2- generation was not different between PMA and FMLP. Furthermore, CPT-cAMP also reduced PMA- or FMLP-induced O2- generation to a similar degree, although only high concentrations (10(-5) or 10(-4) mol/l) of this agent were effective in producing significant inhibition. A remarkable elevation of the cAMP level is required to produce the inhibitory effect on O2- generation in guinea pig AM. An elevation of cAMP may suppress O2- generation by inhibiting plural sites of the intracellular signaling pathways.
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PMID:Role of cyclic adenosine monophosphate in reducing superoxide anion generation in guinea pig alveolar macrophages. 967 Feb 6

Cyclic nucleotide phosphodiesterase (PDE) is an important regulator of the cellular concentrations of the second messengers cyclic AMP (cAMP) and cGMP. Insulin activates the 3B isoform of PDE in adipocytes in a phosphoinositide 3-kinase-dependent manner; however, downstream effectors that mediate signaling to PDE3B remain unknown. Insulin-induced phosphorylation and activation of endogenous or recombinant PDE3B in 3T3-L1 adipocytes have now been shown to be inhibited by a dominant-negative mutant of the serine-threonine kinase Akt, suggesting that Akt is necessary for insulin-induced phosphorylation and activation of PDE3B. Serine-273 of mouse PDE3B is located within a motif (RXRXXS) that is preferentially phosphorylated by Akt. A mutant PDE3B in which serine-273 was replaced by alanine was not phosphorylated either in response to insulin in intact cells or by purified Akt in vitro. In contrast, PDE3B mutants in which alanine was substituted for either serine-296 or serine-421, each of which lies within a sequence (RRXS) preferentially phosphorylated by cAMP-dependent protein kinase, were phosphorylated by Akt in vitro or in response to insulin in intact cells. Moreover, the serine-273 mutant of PDE3B was not activated by insulin when expressed in adipocytes. These results suggest that PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B.
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PMID:Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. 1045 75

cGMP has been implicated in the regulation of many essential functions in the brain, such as synaptic plasticity, phototransduction, olfaction, and behavioral state. Cyclic nucleotide phosphodiesterase (PDE) hydrolysis of cGMP is the major mechanism underlying the clearance of cGMP and is likely to be important in any process that depends on intracellular cGMP. PDE9A has the highest affinity for cGMP of any PDE, and here we studied the localization of this enzyme in the rat brain using in situ hybridization. PDE9A mRNA is widely distributed throughout the brain with varying regional expression. The pattern of PDE9A mRNA expression closely resembles that of soluble guanylyl cyclase (sGC) in the rat brain, suggesting a possible functional association or coupling of these two enzymes in the regulation of cGMP levels. Most of the brain areas expressing PDE9A mRNA also contain neuronal nitric oxide synthase (NOS), the enzymatic source of NO and the principal activator of sGC. PDE9A is the only cGMP-specific PDE with significant expression in the forebrain, and as such is likely to play an important role in NO-cGMP signaling.
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PMID:Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain. 1169 17

Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-alpha is thought to be one of the mechanisms by which TNF-alpha induces insulin resistance. Ceramide is the suggested second messenger of TNF-alpha action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C(2)-ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 micromol/l C(2)-ceramide (N-acetyl-sphingosine) resulted in a time-dependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C(2)-ceramide, in a time- and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 micromol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes.
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PMID:C(2)-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes. 1187 60

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes are key proteins regulating intracellular cyclic nucleotide turnover and thus smooth muscle tension. Several in vitro studies have indicated that the cyclic GMP and cyclic AMP-mediated signaling may play a role in the control of human ureteral muscle. The aim of the present study was to evaluate the functional effects of PDE5 inhibitors sildenafil (Sil), vardenafil (Var) and tadalafil (Tad), as well as nitric oxide (NO)-donating agent sodium nitroprusside (SNP) and non-selective muscarinic antagonist butylscopolamine (BSC) on the tension induced by KCl and the turnover of cyclic nucleotides in isolated human ureteral smooth muscle. In vitro relaxant responses of human ureteral smooth muscle to the PDE5 inhibitors mentioned above were investigated using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by means of specific radioimmunoassay following incubation of the tissue with Sil, Var, Tad and SNP. The tension induced by KCl of the ureteral tissue was dose dependently reversed by the drugs with the following rank order of efficacy: SNP > Var >or= Sil > Tad > BSC. R(max) values ranged from 25 +/- 9% (SNP) to 5 +/- 3% (BSC). Relaxant responses were paralleled by threefold to fourfold increase in tissue levels of cGMP. Our results indicate that PDE5 inhibitors can reverse the tension of isolated human ureteral smooth muscle via cGMP-mediated pathways. Nevertheless, further studies are indicated in order to evaluate as to whether there might be a use for PDE5 inhibitors in the treatment of ureteral stone disease.
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PMID:In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. 1710 58

Cyclic nucleotide phosphodiesterase 10A (PDE10A) is a member of phosphodiesterase families that degrade cAMP and/or cGMP in distinct intracellular sites. PDE10A has a dual activity on hydrolysis of both cAMP and cGMP, and is prominently expressed in the striatum and the testis. Previous studies suggested that PDE10A is involved in regulation of locomotor activity and potentially related to psychosis, but concrete physiological roles of PDE10A remains elusive yet. In this study, we genetically inactivated PDE10A2, a prominent isoform of PDE10A in the brain, in mice, and demonstrate that PDE10A2 deficiency results in increased social interaction without any major influence on different other behaviors, along with increased levels of striatal cAMP. We also demonstrate that PDE10A2 is selectively distributed in medium spiny neurons, but not interneurons, of the striatal complex. Thus, our results establish a physiological role for PDE10A2 in regulating cAMP pathway and social interaction, and suggest that cAMP signaling cascade in striatal medium spiny neurons might be involved in regulating social interaction behavior in mice.
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PMID:Increased social interaction in mice deficient of the striatal medium spiny neuron-specific phosphodiesterase 10A2. 1808 67

Cyclic nucleotide phosphodiesterase (PDE) isoforms can influence disease pathogenesis and be novel therapeutic targets. Because lower cAMP levels may contribute to the decreased apoptosis that occurs in chronic lymphocytic leukemia (CLL), we assessed the expression levels of PDE isoforms in peripheral blood mononuclear cells (PBMC) of healthy adults and patients with CLL. We found a unique PDE mRNA signature in CLL: higher levels than in normal PBMC of PDE7B (increased approximately 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximately 30-fold). Increased PDE7B mRNA in CLL correlates with a 10-fold-higher expression of PDE7B protein and results in an increased contribution of PDE7 to total PDE activity. Consistent with the higher level of PDE7B expression, inhibitors of PDE7 (BRL-50481, IR-202) and a dual PDE4/PDE7 inhibitor (IR-284) selectively increase apoptosis in CLL cells compared with normal PBMC or B cells. Apoptosis of CLL cells promoted by inhibitors of PDE7 and PDE4/7 is attenuated by PKA inhibition, occurs via a mitochondrial-dependent process, and is associated with increased cAMP accumulation and down-regulation of the antiapoptotic protein survivin and of PDE7B. The increase in PDE7B expression and PDE7 inhibitor-promoted apoptosis implicates PDE7B as a drug target in CLL. Our findings identify a unique PDE signature in CLL and illustrate the utility of broad analyses of PDE isoform expression in human disease.
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PMID:Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. 1903 55

The nitric oxide (NO) signaling pathway plays a critical role in auditory signal conversion and transduction. Cyclic nucleotide phosphodiesterase (PDE), an important component of the NO signaling pathway, has not been identified in the cochlea. Using cross-species comparison, homologous sequences of human and mouse Pde coding sequences were searched in a guinea pig genomic database and conserved homologous exons were found between human and mouse homologous sequences. Based on reverse-transcription PCR of these conserved regions, six partial Pde cDNAs were detected in the cochlea: CpPde3a, CpPde4d, CpPde8a, CpPde8b, CpPde9a, and CpPde11a. The identity rates of the six partial Pde cDNA sequences between guinea pig and human range from 83.8 to 95.5% and those of the peptide sequences range from 85.6 to 100%. The identity rates of the six Pde cDNA sequences between guinea pig and mouse range from 80.6 to 93.0% and those of peptide sequences range from 79.5 to 99.2%. The results demonstrate that multiple Pde genes are expressed in the cochlea, suggesting a NO pathway in the auditory system. Insights into this pathway will help to develop new therapeutic drugs on auditory abnormalities.
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PMID:Identification of novel cyclic nucleotide phosphodiesterase gene cDNAs in the cochlea of guinea pig (Cavia porcellus) through conserved homologous sequences. 1970 92


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