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)

Four cyclic-nucleotide phosphodiesterase (PDE) genes belonging to the PDE4 family (PDE4A, 4B, 4C and 4D) have been identified. All four isogenes, including several deletions and alterations of the amino, carboxyl and central catalytic domains, were expressed in insect cells. Lysates were characterised for enzyme activity by using the Km for substrate and the EC50 for activation by the cofactor Mg2+. The catalytic domain alone appears to be sufficient for the normal enzymatic function of PDE4 proteins. Substrate affinity varied by less than 2-fold between catalytic-domain forms of the PDE4A, 4B and 4D isogenes and the long forms (PDE4A5, PDE4B1 and PDE4D3). The affinity for Mg2+ varied by less than 4-fold between long and catalytic-domain forms of PDE4A and 4B. The catalytic-domain form of PDE4D, however, had a 12-fold lower affinity for Mg2+ that was restored by including a portion of the amino-terminal domain, upstream conserved region-2 (UCR2). This result suggests that the Mg2+-binding site of PDE4D involves the UCR2 region. Inhibition of the PDE4 proteins by synthetic compounds is apparently affected differently by the domains. For PDE4B, the catalytic domain is sufficient for interactions with the inhibitors studied: IBMX, trequinsin, rolipram, TVX 2706, RP 73401 and RS-25344. For PDE4D the catalytic-domain form is less sensitive than the long form to inhibition by RS-25344, rolipram and TVX 2706, by 1463-, 11-and 12-fold, respectively. Addition of UCR2 to the catalytic-domain form of PDE4D restored all the lost sensitivities. The catalytic-domain form of PDE4A showed a reduced inhibitor affinity with RS-25344 and TVX 2706 by 77- and 90-fold, respectively. Both catalytic-domain and long forms of PDE4 isogenes interacted with equal affinity with the non-specific inhibitors IBMX and trequinsin, as well as the very potent PDE4-specific inhibitor RP 73401. Other potent and specific PDE4 inhibitors, such as rolipram, RS-25344 or TVX 2706, appear to utilize non-catalytic domain interactions with PDE4D and 4A to supplement those within the catalytic domains. These observations suggest a different relation between amino and catalytic domains in PDE4D relative to PDE4B. We therefore propose a model to illustrate these isogene-specific PDE4 domain interactions with substrate, inhibitors and the co-factor Mg2+. The model for PDE4D is also discussed in relation to changes in the activation curve for Mg2+ and sensitivity to RS-25344 that accompany phosphorylation of the long form by protein kinase A.
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PMID:Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. 972 Jul 65

Theophylline, a drug known to inhibit several classes of adenosine 3'5' cyclic monophosphate (cAMP) phosphodiesterases (PDEs), induces apoptosis in chronic lymphocytic leukemia (CLL) cells. Because the PDE target for theophylline in CLL remains unknown, we examined the ability of isoform-specific PDE inhibitors to increase cAMP levels and induce apoptosis in primary CLL cells. Reverse transcriptase-polymerase chain reaction of purified CLL cDNA amplified transcripts for PDE1B, 4A and 4B. The type 4 PDE inhibitor rolipram but not the type 1 inhibitor vinpocetine increased CLL cAMP levels. Rolipram-inhibitable (type 4) but not calcium-calmodulin augmented (type 1) PDE enzyme activity was detected in CLL samples. In samples from 13 of 14 CLL patients, rolipram induced apoptosis in a dose-dependent fashion over a 48-hour period. Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC) and anti-Ig stimulated CD19(+) B cells were resistant to the induction of apoptosis by rolipram while unstimulated CD19(+) B cells, which had a high basal apoptotic rate, were more sensitive. Rolipram stimulated elevations in cAMP levels in all four of these cell populations, suggesting that they differed in sensitivity to cAMP-induced apoptosis. Consistent with this hypothesis, incubation with the cell permeable cAMP analog dibutyryl-cAMP induced apoptosis in CLL cells and unstimulated B cells but not in IL-2-cultured WMC or anti-Ig stimulated B cells. These data identify PDE4 as a family of enzymes whose inhibition induces apoptosis in CLL cells.
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PMID:Type 4 cyclic adenosine monophosphate phosphodiesterase as a therapeutic target in chronic lymphocytic leukemia. 974 89

Epithelial cells play a critical role in airway inflammation and have the capacity to produce many inflammatory mediators, including bioactive lipids and proinflammatory cytokines. Intracellular levels of cAMP and cGMP are important in the control of inflammatory cell function. These cyclic nucleotides are inactivated via a family of phosphodiesterase (PDE) enzymes, providing a possible site for drug intervention in chronic inflammatory conditions. We studied the expression of PDE activity in an epithelial cell line (A549) and in primary human airway epithelial cells (HAECs). We measured PDE function using specific inhibitors to identify the PDE families present and used RT-PCR to elucidate the expression of PDE isogenes. Both A549 cells and HAECs predominantly expressed PDE4 activity, with lesser PDE1, PDE3, and PDE5 activity. RT-PCR identified HSPDE4A5 and HSPDE4D3 together with HSPDE7. Inhibition of PDE4 and PDE3 reduced secretion by these cells. Epithelial PDE may be an important target for PDE4 inhibitors in the development of the control of asthmatic inflammation, particularly when delivered via the inhaled route.
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PMID:Phosphodiesterase expression in human epithelial cells. 975 1

Experiments were conducted to determine how selective inhibitors of certain cyclic nucleotide phosphodiesterase (PDE) families, namely CI-930 (PDE3 inhibitor; 3-(2H)-pyridazinone-4,5-dihydro-6-[4-(1H-imidazolyl) phenyl]-5-methyl monohydro chloride) and rolipram (PDE4 inhibitor), may affect human coronary artery smooth muscle cell (HCASMC) proliferation. CI-930- and rolipram-inhibitable PDEs accounted for most of the cyclic AMP hydrolyzing activity in HCASMC. Twenty micromolar CI-930 and 20 microM rolipram used individually attenuated proliferation of HCASMC from some, but not all donors, as measured by flow cytometry. The simultaneous addition of 10 microM CI-930 plus 10 microM rolipram caused greater attenuation. This attenuation represented a reduction of the number of cells entering the S phase of the cell cycle and not merely a delay in cell cycle traverse. No statistically significant elevation of cyclic AMP was detected following the addition of either PDE inhibitor individually, but the combination produced significant elevations. It is concluded that CI-930- and rolipram-inhibitable PDE isozymes are expressed in HCASMC and that selective inhibitors of these isozymes can attenuate HCASMC proliferation. The data suggest that selective PDE inhibitors may prevent restenosis in patients following percutaneous transluminal coronary angioplasty because of their effect on HCASMC proliferation, and they may also be useful in retarding the progression of atherosclerosis in individuals at risk. PDE3 and PDE4 inhibitors in combination are more effective than the inhibitors used individually.
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PMID:Effect of CI-930 [3-(2H)-pyridazinone-4,5-dihydro-6-[4-(1H-imidazolyl) phenyl]-5-methyl-monohydrochloride] and rolipram on human coronary artery smooth muscle cell proliferation. 977 20

Bronchodilatory substances such as the phosphodisterase inhibitor (PDE-I) theophylline stimulate mucociliary activity. With the introduction of selective PDE-Is it has become possible to study the functional importance of each phosphodiesterase enzyme (PDE) concerning the regulation of the ciliary beat. The effects of rolipram (inhibiting a cAMP specific PDE (PDE4), milrinone (inhibiting a cGMP inhibited PDE (PDE3)) and zaprinast (inhibiting a cGMP specific PDE (PDE5)) were investigated in in vitro preparations from the rabbit maxillary sinus and trachea. Ciliary beat frequency (CBF) was measured with a photoelectrical method. In sinus mucosa all three compounds accelerated CBF. Milrinone (10(-5) M) by 22.6 +/- 5.3% (n = 6; P < 0.01), rolipram (10(-5) M) by 29.7 +/- 5.7% (n = 7; P < 0.01), and zaprinast (10(-5) M) by 19.4 +/- 6.3% (n = 6; P < 0.05). In the tracheal specimens at a concentration of 10(-5) M, milrinone accelerated CBF by 27.5 +/- 9.0% (n = 7; < 0.05), rolipram by 11.6 +/- 2.8% (n = 6; P < 0.05) and zaprinast by 24.3 +/- 5.3% (n = 7; P < 0.01). Comparison of the effects in the upper and lower airways showed that at concentrations of 10(-5) and 10(-4) M rolipram was more effective in the upper than in the lower airways. The reverse was true of milrinone which concentrations of 10(-7) and 10(-6) M had a significant effect in tracheal specimens but not in sinus specimens. Zaprinast was equally effective in both the upper and lower airways. It is concluded that in both the upper and lower airways selective PDE-Is have an accelerating effect on the CBF that may be beneficial in the treatment of airway diseases.
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PMID:The effect of selective phosphodiesterase inhibitors on mucociliary activity in the upper and lower airways in vitro. 979 93

The animal cyclic nucleotide phosphodiesterases (PDEs) comprise at least seven subtypes, PDE1-7, which differ from each other in domain organization and primary function, and they diverged from an ancestral gene by gene duplication and domain shuffling during animal evolution. To obtain rough estimates for the divergence times of these subtypes, cloning of PDE cDNAs from Ephydatia fluviatilis (freshwater sponge) by RT-PCR was carried out. We obtained four cDNAs, EFPDE1, EFPDE2, EFPDE3, and EFPDE4, which are possibly homologs of the vertebrate PDE1, PDE2, PDE3, and PDE4, respectively, judging from the sequence similarity, domain organization, and branching pattern in the phylogenetic tree. The phylogenetic tree of the PDE family revealed that most gene duplications and domain shufflings that gave rise to different subtypes had been completed in the early evolution of animals before the separation of sponges and eumetazoans.
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PMID:Ancient gene duplication and domain shuffling in the animal cyclic nucleotide phosphodiesterase family. 980 Nov 41

Cyclic AMP (adenosine 3':5'-cyclic monophosphate, cAMP) is an intracellular second messenger that mediates the actions of endogenous hormones and neurotransmitters and also of drugs such as beta-adrenoceptor agonists. The presence of functional beta-adrenoceptors on human airway epithelial cells has been demonstrated but the expression of the cAMP-metabolizing enzyme, cyclic nucleotide phosphodiesterase (PDE) in these cells has not been studied. We investigated the profile of activity of the different PDE isoenzymes in lysates of a pulmonary epithelial cell line, A549, and of human bronchial epithelial (HBE) cells grown in primary culture. The effects of non-selective and isoenzyme-selective PDE inhibitors on beta-agonist-induced elevations in intracellular cAMP concentrations and the production of interleukin (IL) 8 and prostaglandin (PG) E2 was also investigated. A549 cells expressed a high level of PDE4, lower levels of PDE1 and PDE3, and minor PDE5 activity. Primary HBE cultures expressed PDE4 and PDE1 activity at approximately equal levels with small additional PDE3 and PDE5 activities. The total PDE activity of the HBE cells was approximately nine-fold lower than that of A549 cells. The beta-adrenoceptor agonist salbutamol, caused a slow, concentration-dependent increase in intracellular cAMP levels in HBE cells which was not affected by a non-selective PDE inhibitor, IBMX (100 microM), or by a selective PDE4 inhibitor, rolipram (100 microM). Zardaverine, a dual-selective PDE3/PDE4 inhibitor, had no effect on cAMP levels at 10 microM but did cause a significant enhancement of salbutamol-induced elevations at 100 microM (150+/-36 pmol/10(5) cells at 10 microM salbutamol vs. 64+/-25 pmol/10(5) cells in the absence of zardaverine; n=3,P<0.01). Neither basal nor tumour necrosis factor alpha (10 ng/ml)-induced IL8 secretion was affected by salbutamol (10 microM) in the absence or presence of IBMX (100 microM). Salbutamol (10 microM), alone or in the presence of IBMX (100 microM) or rolipram (100 microM), also failed to affect basal or bradykinin (1 microM)-induced PGE2 release. Zardaverine (100 microM) caused a significant increase in basal PGE2 release but this was not enhanced in the presence of salbutamol (10 microM) and was not related to changes in cAMP levels. We conclude that HBE cells express a low total PDE activity, made up predominantly of PDE1 and PDE4 isoenzymes, and that intracellular cAMP levels in HBE cells are not related to the production of IL8 or PGE2.
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PMID:Cyclic nucleotide phosphodiesterase in human bronchial epithelial cells: characterization of isoenzymes and functional effects of PDE inhibitors. 980 63

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFalpha) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFalpha production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFalpha production with an ED50 of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFalpha production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFalpha production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 microgram) inhibited intralesional concentrations of interleukin-4 (55%; P <.01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFalpha production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.
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PMID:SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo. 980

Type IV phosphodiesterase (PDE4) inhibitors may be useful in several diseases in which catecholamine infusions are commonly used, including asthma, sepsis, and multiple organ failure. To determine whether type IV phosphodiesterase inhibitors alter baseline or catecholamine-induced changes in cardiac function or both, we examined the effects of Ro 20-1724 (PDE4 inhibitor) on several cardiac-performance parameters in the absence and presence of norepinephrine, epinephrine, isoproterenol, and dobutamine infusions (3, 1, 0.1, and 3 microg/kg/min, respectively). Male Sprague-Dawley rats received either Ro 20-1724 (10 microg/kg/min; n = 7) or vehicle (n = 6). After a left ventricular catheter was placed and connected to a heart-performance analyzer, each animal received each of the four catecholamines in randomized order (10 min per catecholamine with a 30-min washout period between infusions). In the absence of catecholamines, Ro 20-1724 significantly but mildly (i.e., <10%) increased heart rate but did not alter significantly any other measured cardiac parameter. In addition, Ro 20-1724 did not significantly alter norepinephrine-, epinephrine-, or dobutamine-induced changes in cardiac-performance parameters. There was, however, a significant attenuation of the isoproterenol-induced increase in a single measure of cardiac contractility (maximum dP/dt normalized to pressure). PDE4 inhibition does not cause significant cardiac toxicities in rats, both in the absence and presence of catecholamines. Our data suggest that PDE4 inhibitors may be safely used in critically ill patients receiving catecholamines. A clinical trial of this family of drugs in patients with critical illness is now being planned.
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PMID:Effects of type IV phosphodiesterase inhibition on cardiac function in the presence and absence of catecholamines. 982 51

The inhibitory effect of 2-phenyl-4-quinolone (YT-1) on respiratory burst in rat neutrophils was investigated, and the underlying mechanism of action was assessed. YT-1 caused a concentration-dependent inhibition of the rate of O2.- release from rat neutrophils in response to formylmethionyl-leucyl-phenylalanine (fMLP), but not to phorbol 12-myristate 13-acetate (PMA), with an IC50 value of 60.7+/-8.2 microM. A comparable effect was also demonstrated in the inhibition of O2 consumption. Unlike superoxide dismutase, YT-1 had no effect on O2.- generation in the xanthine-xanthine oxidase system and during dihydroxyfumaric acid autoxidation. The fMLP-induced inositol trisphosphate (IP3) formation was unaffected by YT-1. In addition, YT-1 did not affect the initial spike of [Ca2+]i, but it accelerated the rate of [Ca2+]i decline in cells in response to fMLP. YT-1 was found to have little effect on the activity of neutrophil cytosolic protein kinase C (PKC). YT-1 increased the cellular cyclic AMP level, while having no effect on the cyclic GMP level. In addition, YT-1 increased neutrophil cytosolic protein kinase A (PKA) activity, but had no direct effect on the enzyme activity of pure porcine heart PKA. When neutrophils were treated with (8R,9S,11S)-(-)-9-hydroxy-9-hexoxycarbonyl-8-methyl-2,3,9,10-tetra hydro-8,11-epoxy- 1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinde n-1-one, (KT 5720), a PKA inhibitor, the inhibition of O2.- generation by YT-1, as well as by prostaglandin E1 (PGE1) and dibutyryl cyclic AMP, was attenuated effectively. YT-1 did not activate the adenylate cyclase associated with neutrophil particulate fraction but inhibited the cytosolic phosphodiesterase (PDE) activity in a concentration-dependent manner. Neutrophils treated with YT-1 had a more pronounced increase in cellular cyclic AMP level by PGE1. Moreover, the ability of PGE1 to inhibit the respiratory burst in neutrophils was greatly enhanced by YT-1. These results suggest that the increase in cellular cyclic AMP levels by YT-1 through the inhibition of PDE (probably PDE4 isoenzyme) activity is involved in its inhibition of fMLP-induced respiratory burst in rat neutrophils.
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PMID:Involvement of cyclic AMP generation in the inhibition of respiratory burst by 2-phenyl-4-quinolone (YT-1) in rat neutrophils. 982 85


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