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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the involvement of cAMP-dependent protein kinase (A kinase)2 in the inhibition by cilostamide, a specific inhibitor of the low Km cAMP-phosphodiesterase (PDE), on 9,11-epithio-11,12-methanothromboxane A2 (STA2)-induced platelet aggregation. For comparative purposes, the PGE1 analogue, 17S-20-dimethyl-trans-delta 2-PGE1 (OP-1206) was used. OP-1206 (IC50 = 18 +/- 0.55 nM) and cilostamide (IC50 = 40 +/- 4.5 nM) were both potent inhibitors of the platelet aggregation induced by STA2 (1 microM). OP-1206 and cilostamide dose-dependently inhibited elevations in intracellular free Ca2+ ([Ca2+]i) caused by STA2. OP-1206 caused an almost complete inhibition of Ca2+ mobilization, but cilostamide did not prevent the STA2-induced elevation in [Ca2+]i to the same extent as OP-1206, even at a high concentration (greater than 200 nM). Cilostamide did not increase the cAMP level at concentrations (5-100 nm) which affected STA2-induced aggregation. OP-1206 significantly increased cAMP contents in platelets, and the degree of aggregation inhibition by OP-1206 appears to be related to the size of increase in cAMP. OP-1206 increased phosphorylation of the 50,000 mol. wt vasodilator-stimulated phosphoprotein, at concentrations of 7.9-79 nM, which inhibited aggregation induced by STA2. Cilostamide treatment resulted in a marginal increase in the 50,000 mol. wt phosphorylation at concentrations (10-100 nM) which completely inhibited the STA2-induced aggregation. (8R*, 9S*, 11S*)-(-)-9-Hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H, 8H, 11H-2, 7b, 11a-triazadibenzo(a,g)-cycloocta(c,d,e)trinden-1-one (KT-5720), a specific inhibitor of A kinase, not only reversed the inhibition by OP-1206 of STA2-induced platelet aggregation, but also inhibited the OP-1206-induced protein phosphorylation. However, the inhibition by cilostamide of STA2-induced aggregation was not prevented by pretreatment with KT-5720. Inhibition of the STA2-induced aggregation by OP-1206 may be associated with cAMP-dependent protein phosphorylation, while cilostamide may have inhibitory effects on STA2-induced platelet activation through mechanisms other than the activation of A kinase.
...
PMID:Inhibition of platelet aggregation by the cAMP-phosphodiesterase inhibitor, cilostamide, may not be associated with activation of cAMP-dependent protein kinase. 132

A series of new analogues of 1-beta-D-ribofuranosylbenzimidazole 3',5'-phosphate (cBIMP) has been designed according to the properties predicted by the MNDO method, and synthesised from substituted benzimidazoles. Dipole vectors and HOMO and LUMO energies for each benzimidazole base were calculated by the MNDO method and the lipophilicities of the cBIMP derivatives were determined. In general, the cBIMP derivatives activate cAMP-dependent protein kinases I and II and preferentially bind to site B, especially for the type II kinase, with 2-trifluoromethyl-cBIMP and 5,6-difluoro-cBIMP exhibiting the highest site selectivity. Each cBIMP derivative can stimulate cGMP-stimulated cyclic phosphodiesterase (cGS-PDE), with 5,6-dimethyl-cBIMP being as potent as cGMP, and also inhibit cGMP-inhibited phosphodiesterase (cGI-PDE). Only the 2-trifluoromethyl-cBIMP and the Rp-phosphorothioates (cBIMPS) (equatorial P = S) were resistant to hydrolysis by cPDE. The Sp-phosphorothioates were hydrolysed slowly, if at all. In addition to exhibiting a high lipophilicity, the most active compounds for the induction of apoptosis and inhibition of proliferation were also resistant to cPDE (Sp-5,6-dichloro-cBIMPS) and/or were potent activators of cAMP-dependent protein kinase (5,6-dichloro-cBIMP).
...
PMID:Derivatives of 1-beta-D-ribofuranosylbenzimidazole 3',5'-phosphate that mimic the actions of adenosine 3',5'-phosphate (cAMP) and guanosine 3',5'-phosphate (cGMP). 133

Experiments were conducted using undifferentiated U937 cells, a human monocytic cell line, to establish an in vitro model to examine the hormonal regulation of the cyclic AMP (cAMP)-specific phosphodiesterase (PDE IV). Standard chromatographic techniques, coupled with the use of inhibitors and activators that are selective for various phosphodiesterase (PDE) isozymes, were used to establish the PDE isozyme profile in supernatant fractions of U937 cells. When PDE activity was assessed using 1 microM [3H]cAMP as a substrate, 70 to 90% of the total U937 cell supernatant activity in the major peak eluting from anion-exchange columns was inhibited by 30 microM rolipram, a selective inhibitor of PDE IV. The remaining activity was nearly abolished by 10 microM siguazodan or 10 microM cyclic GMP (cGMP,) selective inhibitors of the cGMP-inhibited PDE. Kinetic analyses of the enzyme activity contained within this major peak of PDE activity revealed a cAMP Km = 3 microM and a rolipram Ki = 0.5 microM, values characteristic of PDE IV. Additional studies revealed the presence of a small amount of Ca++/calmodulin-stimulated PDE, but no cGMP-stimulated PDE or cGMP-specific PDE activity. In an effort to induce PDE activity in intact U937 cells by producing a sustained increase in cAMP content, cells were treated for 4 hr with salbutamol (1 microM), rolipram (30 microM) or a combination of both agents. The combination of salbutamol and rolipram produced a 2- to 3-fold increase in PDE activity in U937 cells; when used alone, rolipram was without effect whereas salbutamol induced an increase that was approximately one-half of that observed with the combination. Isozyme isolation and characterization revealed that the overall elevation of cellular PDE activity could be accounted for by a 2- to 3-fold increase in the Vmax of PDE IV with no change in its Km. The induction of PDE IV by salbutamol was: 1) concentration- and time-dependent; 2) detectable only after prolonged (2-4 hr) agonist exposure; 3) preceded by an increase in cAMP content and an activation of cAMP-dependent protein kinase; 4) mimicked by 8-bromo-cAMP and prostaglandin E2; 5) reversible within 3 hr of salbutamol removal; and 6) abolished by cycloheximide or actinomycin D. Collectively, these results indicate that the major PDE isozyme in the soluble fraction of U937 cells is PDE IV and that the activity of this enzyme is increased markedly in cells after prolonged exposure to agents that increase cAMP content.
...
PMID:Stimulation of beta adrenoceptors in a human monocyte cell line (U937) up-regulates cyclic AMP-specific phosphodiesterase activity. 133 58

Constant exposure of mastocytoma P-815 cells to adenosine 3',5'-cyclic decylphosphoramidate (1), which is permeable to the cell membrane and resistant to the action of phosphodiesterase, caused a dose-dependent (1 to 50 microM) inhibition in the synthesis of DNA and cell proliferation. Pretreating the cells with compound 1 (20 microM, 4 h) caused considerable inhibition of the incorporation of [3H]thymidine ([3H]TdR) into [3H]deoxythymidine 5'-triphosphate ([3H]dTTP) and that of [14C]hypoxanthine into nucleic acid, but not the synthesis of [14C]dTTP from [U-14C]aspartate. These results indicate that compound 1 preferentially inhibits the salvage synthesis of intracellular nucleotides and nucleic acids. Thymidine kinase, a key enzyme in salvage synthesis of nucleotides, was almost undetectable in cells pretreated with compound 1 at 20 microM for 4 h or at 5 microM for 15 h. On the other hand, compound 1 activated partially purified cAMP-dependent protein kinase A from bovine heart. Judging from these observations, it is likely that compound 1 readily permeates the cell membrane, activates cAMP-dependent protein kinase, then inhibits the salvage synthesis of nucleotides and nucleic acids by inhibiting thymidine kinase, which results in the inhibition of cell growth.
...
PMID:Inhibition of salvage synthesis of nucleic acid by adenosine 3',5'-cyclic decylphosphoramidate in mastocytoma P-815 cells. 133 57

Activation of cAMP-dependent protein kinase (kinase A) has recently been shown to enhance responses evoked by stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured hippocampal pyramidal neurons. Here we report results of experiments designed to determine if activation of the cAMP cascade potentiates synaptic strength in field CA1 of rat hippocampal slices. We find that bath application of the direct adenylate cyclase activator forskolin (50 microM) enhances the field excitatory postsynaptic potential (EPSP) slope and population spike amplitude evoked by stimulation of Schaffer/commissural afferents. This effect is potentiated by the phosphodiesterase inhibitor and adenosine receptor antagonist 3-isobutyl-1-methylxanthine (IBMX). The enhancement produced by forskolin is suppressed in the presence of adenylate cyclase inhibitors and is not mimicked by the inactive forskolin analogue 1,9-dideoxyforskolin, indicating that, indeed, activation of adenylate cyclase mediates the effects of forskolin in field CA1. Our observations support the idea that changes in intracellular cAMP levels can modulate synaptic efficacy of excitatory glutamatergic synapses in the mammalian hippocampus.
...
PMID:Modulation of synaptic efficacy in field CA1 of the rat hippocampus by forskolin. 137 10

cAMP regulates the maturation of many biochemical processes that occur during normal lung development, including the changing levels of surfactant proteins and phospholipids. We examined the effect of cAMP on the beta-adrenergic receptor concentration in the developing human lung. Isobutylmethylxanthine, a cAMP phosphodiesterase inhibitor, increased both the tissue cAMP content and beta-adrenergic receptor concentration in treated explants above those in untreated explants. 8-Bromo-cAMP treatment also elevated the beta-adrenergic receptor concentration of lung explants compared to that in untreated controls. These data indicate the ability of elevated cAMP to increase the beta-adrenergic receptor concentration. Both lung cAMP and beta-adrenergic receptor concentrations increase spontaneously in culture. To test for a possible causal relationship, we cultured explants with protein kinase inhibitors. We found that H-8, a preferential inhibitor of the cAMP-dependent protein kinase [protein kinase-A (PKA)], but not H-7, which inhibits PKA and protein kinase-C with similar potency, blocked the spontaneous rise in beta-adrenergic receptor concentration in human fetal lung explants, indicating that PKA activity is required for this rise in beta-adrenergic receptor concentration. Type II cells isolated from cultured lung treated with H-8 had fewer beta-adrenergic receptors than cells isolated from untreated explants. These studies show that cAMP increases the beta-adrenergic receptor concentration in human fetal lung and specifically in type II cells through a PKA-dependent mechanism, consistent with a role for cAMP in beta-adrenergic receptor regulation during normal lung development.
...
PMID:Cyclic adenosine 3',5'-monophosphate increases beta-adrenergic receptor concentration in cultured human fetal lung explants and type II cells. 137 64

1. Messenger RNAs for the subunits of the muscle nicotinic acetylcholine receptor (nAChR) were expressed in Xenopus oocytes. A two-electrode voltage clamp was used to measure the acetylcholine (ACh)-induced macroscopic currents. In addition, patch-clamp techniques were used to study nAChR channels in whole cells and in outside-out patches excised from BC3H-1 cells and in patches from oocytes. The single-channel and macroscopic currents were modified by compounds that are usually used to study protein phosphorylation. 2. IBMX (3-isobutyl-1-methylxanthine) is a phosphodiesterase inhibitor. Because it elevates the intracellular concentration of adenosine 3',5'-cyclic monophosphate (cAMP), IBMX is often used to indirectly activate cAMP-dependent protein kinase. H-7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] is mainly used as a rather nonspecific inhibitor of protein kinase activity. Both IBMX and H-7 directly inhibit ACh-induced currents independent of their action on phosphorylation. This direct effect of these compounds is similar to the previously reported inhibition of nAChRs and K+ channels by forskolin, which is commonly used to elevate intracellular cAMP. 3. Macroscopic currents induced in the oocytes by 50 microM ACh had an average peak current of 605 nA, and the currents decayed biexponentially with tau of 15 and 225 s. When 300 microM H-7 was added simultaneously with the ACh, the average peak current was 228 nA and the tau were 1 and 108 s. When 500 microM IBMX was added simultaneously with the ACh, the average peak current was 308 nA and the tau were 9 and 237 s. H-7 and IBMX decreased the peak current induced by ACh, and the compounds increased the decay rate of the current. Under these experimental conditions, the IC50 for reduction of peak amplitude at -30 mV was 160 microM for H-7 and 475 microM for IBMX. 4. H-7 preferentially inhibits the open conformation of the nAChR channel, but there is also some inhibition of the closed channel. The inhibition is voltage dependent: inhibition decreases e-fold per 34 mV depolarization. H-7 does not become trapped within the closed channel and does not significantly alter desensitization under our experimental conditions. 5. H-7 and IBMX interrupt or terminate single-channel openings in membrane patches excised from oocytes or BC3H-1 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Nicotinic acetylcholine receptors are directly affected by agents used to study protein phosphorylation. 138 18

Calmodulin-dependent phosphodiesterase was purified to apparent homogeneity from the total calmodulin-binding fraction of bovine heart in a single step by immunoaffinity chromatography. The isolated enzyme had significantly higher affinity for calmodulin than the bovine brain 60-kDa phosphodiesterase isozyme. The cAMP-dependent protein kinase was found to catalyze the phosphorylation of the purified cardiac calmodulin-dependent phosphodiesterase with the incorporation of 1 mol of phosphate/mol of subunit. The phosphodiesterase phosphorylation rate was increased severalfold by histidine without affecting phosphate incorporation into the enzyme. Phosphorylation of phosphodiesterase lowered its affinity for calmodulin and Ca2+. At constant saturating concentrations of calmodulin (650 nM), the phosphorylated calmodulin-dependent phosphodiesterase required a higher concentration of Ca2+ (20 microM) than the nonphosphorylated phosphodiesterase (0.8 microM) for 50% activity. Phosphorylation could be reversed by the calmodulin-dependent phosphatase (calcineurin), and dephosphorylation was accompanied by an increase in the affinity of phosphodiesterase for calmodulin.
...
PMID:Phosphorylation and characterization of bovine heart calmodulin-dependent phosphodiesterase. 164 4

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.
...
PMID:Regulation of jun-B expression by a cyclic AMP (cAMP)-dependent mechanism in human myeloid cells. 164 78

Compounds containing the imidazoquinoline nucleus are a new class of potent, broad-spectrum inhibitors of platelet aggregation. This report describes studies with a simply-substituted imidazoquinoline (BMY 20844) and several new ether-linked side chain derivatives (BMY 21638 and BMY 43351). These compounds are potent inhibitors of platelet cAMP phosphodiesterase (IC50 values: BMY 20844, 1.3 X 10(-8); BMY 21638, 2 X 10(-10); and BMY 43351, 1 X 10(-10) M, measured using 0.15 microM cAMP) but have little effect on platelet homogenate cGMP phosphodiesterase (IC50 greater than 10(-5) M). Inhibition of different cAMP phosphodiesterase isozymes was tested to determine if the compounds inhibited similar isozymes in other tissues. Rabbit heart cAMP phosphodiesterase isozymes were resolved by ion-exchange chromatography and three peaks of activity were obtained. BMY 20844 inhibited only fraction III (a "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase) with an IC50 value of 5 X 10(-8) M. These compounds also inhibited canine cardiac sarcoplasmic reticulum membrane-bound "cGMP-inhibitable, low Km" cAMP-specific phosphodiesterase with virtually the same potency as inhibition of cAMP phosphodiesterase in platelet homogenate. In washed platelets these compounds elevated cAMP levels and activated the platelet cAMP dependent protein kinase. Activation of cAMP-dependent protein kinase was determined by cAMP-dependent protein kinase ratio measurements and phosphorylation of intracellular proteins. These studies suggest that this potent new class of agents inhibits platelet phosphodiesterase activity in intact platelets causing an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and stimulate protein phosphorylation. This mechanism is, at least in part, responsible for the ability of these compounds to prevent platelet aggregation and thrombosis in experimental animal models.
...
PMID:Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets. 164 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---