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)

HIV infection is associated with qualitative and functional immune deficiencies. It has been shown that the in vitro infection of CD4+ cells with HIV was associated with sustained elevation of cAMP and cGMP. In the present report the role of cAMP on HIV replication in MT-4 cells was investigated. The MT-4 cells were infected with HIV (strain 3b), in the presence or absence of agents that increase intracellular levels of cAMP, through different mechanisms. At selected times postinfection, HIV replication was measured by reverse transcriptase activity or HIV P24Ag in culture supernatants. Forskolin (FK, an activator of adenylate cyclase 1-100 microM), Isobutyl-methylxanthine (IBMX, a phosphodiesterase inhibitor, which indirectly increases intracellular levels of cAMP, 30-100 microM) and dibutyryl (db) cAMP (0.1-10 microM) enhanced HIV replication, in a dose-dependent manner. FK, IBMX, and db cAMP enhanced HIV replication by 2- to 10-fold, 4- to 7-fold, and 2- to 6-fold, respectively. Intracellular levels of cAMP were measured by radioimmunoassay and were also enhanced. Since cAMP exerts its catalytic effects through activation of protein kinase (PK) A the effect of H-8 (a specific inhibitor of the cAMP dependent PK A) on HIV replication was simultaneously examined. The H8 at doses of 0.1 to 10 microns inhibited HIV replication by 25 to 99.9%. Moreover H9 inhibited HIV replication in peripheral blood mononuclear cells by more than 90%. The replication of HIV appears to be a cAMP-dependent event, and PK A could possibly be a target for the development of anti-HIV therapies.
...
PMID:Human immunodeficiency virus replication: modulation by cellular levels of cAMP. 138

Forskolin and milrinone both increase cyclic AMP concentrations to enhance cardiac contractility and cause vascular dilation in vitro and in vivo. However, forskolin acts via direct stimulation of adenylate cyclase while milrinone inhibits phosphodiesterase (PDE-III) activity. The forskolin analog, 7-desacetyl-7-(O-propionyl)-hydroxyl-aminocarbonyl-forskolin (P87-7692) has also been shown to directly stimulate adenylate cylase and increase cyclic AMP production in isolated cardiac tissue; however, the in vivo activity of this compound has not been described. Thus, the purpose of this study was to compare the cardiovascular effects of equivalent doses of these compounds and to further characterize the cardiotonic activity of P87-7692 in the anesthetized dog. It was found that both i.v. (3-30 micrograms/kg) and intracoronary (0.1-30 micrograms) administration of milrinone, forskolin, and P87-7692 caused dose-related positive inotropic, coronary, and peripheral vasodilator effects in anesthetized dogs; however, P87-7692 produced significantly greater and more sustained cardiotonic activity following a single 30-micrograms/kg, i.v., bolus injection when compared to the same dose of milrinone and forskolin. Analysis of the dose-response relationship between the changes in contractile force and heart rate for these compounds revealed that a 50% augmentation in contractile force was associated with increases in heart rate of 2.1% for milrinone, 6.4% for P87-7692, and 13.7% for forskolin. These data indicate an improved separation between the chronotropic and inotropic effects for P87-7692 as compared to forskolin. All three compounds also produced coronary vasodilation in vivo and in vitro; however, P87-7692 consistently showed greater activity relative to the same doses of milrinone and forskolin. Moreover, P87-7692 was significantly (p less than 0.05) more potent at relaxing KC1-precontracted canine coronary rings, with an EC50 of 2.1 x 10(-7) M as compared to 1.1 x 10(-6) M for forskolin and 3.2 x 10(-6) M for milrinone. The results of these studies indicate that structural modification of the forskolin molecule can increase the separation between positive inotropic and chronotropic effects, improve the overall hemodynamic profile, and prolong the duration of cardiotonic activity for this class of compounds.
...
PMID:Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog. 138 77

Odors activate at least two distinct transduction pathways in lobster olfactory receptor cells that, respectively, excite and inhibit the cell. Data presented suggest that odors selectively activate the inhibitory conductance through the second messenger cAMP. Not all cells support both odor-evoked excitatory and inhibitory conductances; in the current investigation, about 50% of the cells tested were inhibited by odors. In the majority of cells that, as a group, support an inhibitory response to odor stimulation, activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine (IBMX) elicits an outward current with a time course similar to that of odor-evoked outward currents. The membrane-permeant cyclic nucleotide analogs 8-Br-cAMP and 8-Br-cGMP have a similar effect. Forskolin and IBMX enhance the magnitude of odor-evoked outward currents when the drug and the odor are copresented to the cell. In contrast, these same drugs have little or no effect on cells that, as a group, fail to support an inhibitory response to odor stimulation. This study provides the first direct evidence implicating cAMP in olfactory transduction in an invertebrate and contrasts with similar studies in vertebrates that have implicated cAMP as a second messenger mediating excitation.
...
PMID:Cyclic nucleotides mediate an odor-evoked potassium conductance in lobster olfactory receptor cells. 138 77

1. [3H]-adenosine 3':5'-cyclic monophosphate ([3H]-cyclic AMP) responses were studied in primary cultures of human tracheal smooth muscle cells derived from explants of human trachealis muscle and in short term cultures of acutely dissociated trachealis cells. 2. Isoprenaline induced concentration-dependent [3H]-cyclic AMP formation with an EC50 of 0.2 microM. The response to 10 microM isoprenaline reached a maximum after 5-10 min stimulation and remained stable for periods of up to 1 h. After 10 min stimulation, 1 microM isoprenaline produced a 9.5 fold increase over basal [3H]-cyclic AMP levels. The response to isoprenaline was inhibited by ICI 118551 (10 nM), (apparent KA 1.9 x 10(9) M-1) indicating the probable involvement of a beta 2-adrenoceptor in this response in human cultured tracheal smooth muscle cells. However, with 50 nM ICI 118551 there was a reduction in the maximum response to isoprenaline. Prostaglandin E2 also produced concentration-dependent [3H]-cyclic AMP formation (EC50 0.7 microM, response to 1 microM PGE2 6.4 fold over basal). 3. Forskolin (1 nM - 100 microM) induced concentration-dependent [3H]-cyclic AMP formation in these cells. A 1.6 fold (over basal) response was also observed following stimulation with NaF (10 mM). 4. The nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (0.1 mM) and the type IV, cyclic AMP selective, phosphodiesterase inhibitor rolipram (0.1 mM) both elevated basal [3H]-cyclic AMP levels by 1.8 and 1.5 fold respectively. IBMX (1-100 microM) and low concentrations of rolipram (< 10 microM), also potentiated the response to 1 microM isoprenaline. Inhibitors of the type III phosphodiesterase isoenzyme (SK&F 94120 and SK&F 94836) were without effect upon basal or isoprenaline-stimulated cyclic AMP responses in these cells.5. Carbachol (1 nM-I 00 microM) produced concentration-dependent inhibition of the [3H]-cyclic AMP response to 1 microM isoprenaline in human cultured tracheal smooth muscle cells (IC50 0.24 JM). Carbachol(1 JM) inhibited the [3H]-cyclic AMP response to 1 JM isoprenaline by 60%. This effect of carbachol was itself inhibited by atropine (50 nM) (KA 2.3 x 109 M-') indicating the involvement of a muscarinic receptor.6. These results show that primary cultures of human tracheal smooth muscle cells demonstrate cyclic AMP responses to direct receptor stimulation, adenylyl cyclase activation and inhibition with nonselective and type IV-selective cyclic AMP phosphodiesterase isoenzyme inhibitors, and that the cyclic AMP response to isoprenaline can be inhibited by muscarinic receptor stimulation.
...
PMID:Control of cyclic AMP levels in primary cultures of human tracheal smooth muscle cells. 138 13

The acrosome reaction of spermatozoa appears to be analogous to various somatic cell exocytotic events which involve cascade reactions, i.e., transmission of an external signal across the cell membrane resulting in activation of an "amplifier" enzyme and the generation of a second messenger. Using a synchronous acrosome reaction system (De Jonge et al., J. Androl., 10:232-239, '89a), it was found that analogues of the second-messenger cAMP, dibutyryl cAMP (dbcAMP) and 8-bromo cAMP, stimulated the acrosome reaction of capacitated spermatozoa. Additionally, treatment of spermatozoa with either xanthine or non-xanthine phosphodiesterase inhibitors induced a significant (P less than 0.05) increase in the percent acrosome reaction after a period of capacitation in comparison to untreated controls. These results indicate that analogues of cAMP or inhibitors which prevent cAMP hydrolysis can induce the human sperm acrosome reaction. Subsequent experiments were conducted to test whether the amplifier enzyme in the cascade reaction, adenylate cyclase, has a role in the acrosome reaction. Forskolin, an adenylate cyclase stimulator, caused a significant (P less than 0.01) increase in the percent acrosome reaction in comparison to controls. Modulators of adenylate cyclase--adenosine, 2'-0-methyladenosine, and 2',3'-dideoxyadenosine--significantly (P less than 0.01) inhibited the forskolin-induced acrosome reaction. dbcAMP was able to overcome the inhibition by adenosine. Two inhibitors of protein kinase A, the Walsh inhibitor and H-8, caused a significant (P less than 0.01) inhibition of the dbcAMP-induced acrosome reaction. Finally, in the absence of extracellular calcium, dbcAMP induced a significant (P less than 0.01) increase in the acrosome reaction in contrast to A23187. These results suggest that: 1) a molecular mechanism for the human sperm acrosome reaction involves the cAMP second-messenger system; i.e., activation of adenylate cyclase, the amplifier enzyme that produces cAMP, production of cAMP as a second messenger, and activation of cAMP-dependent kinase A; and that 2) activation of adenylate cyclase occurs after calcium influx.
...
PMID:Modulation of the human sperm acrosome reaction by effectors of the adenylate cyclase/cyclic AMP second-messenger pathway. 165 65

Low concentrations of sodium nitroprusside (0.2 and 1 microM) relaxed carbachol-induced tone of the rat anococcygeus but did not affect the content of either cGMP or cAMP; higher concentrations (10,100 and 1000 microM) produced greater relaxation (greater than 60%) and a rise in cGMP but not cAMP. In the presence of the cGMP-phosphodiesterase inhibitor M&B 22948 (10 microM), 1 microM sodium nitroprusside produced greater relaxation and a selective increase in cGMP. Forskolin (0.5-250 microM) caused relaxation and a selective increase in cAMP; the concentration-response relationships of the two effects were similar. Non-adrenergic, non-cholinergic (NANC) field stimulation (10 Hz; 20 s trains) reduced tone by 52% but had no effect on cyclic nucleotide content; in the presence of 10 microM M&B 22948 or 1 microM sodium nitroprusside, NANC stimulation produced a greater degree of relaxation and increased cGMP but not cAMP content. The results show that NANC stimulation acts like sodium nitroprusside, causing a selective increase in cGMP, and this supports the proposal that NANC transmission in the rat anococcygeus involves an endogenous nitrate; the possibility that multiple pools of cGMP exist in the anococcygeus is discussed.
...
PMID:Cyclic nucleotide content of the rat anococcygeus during relaxations induced by drugs or by non-adrenergic, non-cholinergic field stimulation. 167 36

We investigated the involvement of second messenger systems in the control by pituitary cytotropic factor (CTF) of tyrosine hydroxylase (TH) expression in primary cultures of hypothalamic cells. Forskolin, an activator of adenylyl cyclase, as well as Sp-cAMP[S] [(Sp)-cyclic adenosine 3',5'-monophosphothioate], a cAMP agonist, and theophylline, an inhibitor of phosphodiesterase activity, stimulate the secretion of dihydroxyphenylalanine (DOPA) and dopamine (DA), suggesting a role for cAMP-dependent protein kinase in the secretion of catecholamines by hypothalamic dopaminergic cells. When cells were cultured with either CTF or forskolin for 14 days, a progressive increase in the secretion of DOPA and DA was observed throughout the period of incubation. At the end of the 2-week culture period, the amount of TH in the cells, determined by immunoblot analysis, was appreciably increased compared to controls. When the cells were analyzed immunocytochemically for TH, the TH-positive cells that had been incubated with CTF or forskolin for 2 weeks were found to have neurites that appeared larger than those of TH-positive cells in the controls. The diameters of the perikarya of TH-positive cells in cultures incubated with CTF also appeared larger than the controls. After incubation of hypothalamic cells with CTF for 96 h, the amount of TH mRNA in the cultures was significantly increased. When membranes isolated from PC12 cells were incubated for 10 min with 50 microM forskolin, the specific activity of adenylyl cyclase was increased 20-fold; CTF had no effect on adenylyl cyclase activity of PC12 cell membranes. Yet, CTF significantly (P less than 0.001) stimulated the secretion of DOPA and DA by PC12 cells. When hypothalamic cells were incubated with both forskolin and CTF, using doses of each that stimulated maximal secretion, the secretion of DOPA and DA was equal to sum of the secretions with each stimulant alone. These additive actions of forskolin and CTF and the failure of CTF to activate adenylyl cyclase in membranes of PC12 cells suggest that forskolin and CTF stimulate catecholamine secretion by hypothalamic dopaminergic cells through different mechanisms, perhaps through different protein kinases. When hypothalamic cells were incubated with CTF and W-7 [N-(6-aminohexyl)5-chloro-1-naphthalenesulfonamide], an inhibitor of calmodulin, the secretion of DOPA was significantly (P less than 0.001) less than that in cultures that were not incubated with W-7. The findings of this study suggest that TH expression in hypothalamic dopaminergic cells is controlled by redundant protein kinases, including cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase.
...
PMID:Tyrosine hydroxylase expression in hypothalamic cells: analysis of the roles of adenosine 3',5'-monophosphate- and Ca2+/calmodulin-dependent protein kinases in the action of pituitary cytotropic factor. 168 36

Treatment of quiescent MG-63 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) or platelet-derived growth factor (PDGF) stimulates the rapid accumulation of c-myc RNA. We have now determined that a similar effect can be induced by cAMP. Treatment with forskolin (an activator of adenylate cyclase), IBMX (a phosphodiesterase inhibitor), PGE1, and isoproterenol stimulated accumulation of both cAMP and c-myc RNA, but no increase in either cAMP or c-myc RNA was seen with the inactive forskolin analog 1,9-dideoxyforskolin. Forskolin and IBMX acted synergistically in stimulating accumulation of both cAMP and c-myc RNA. However, three lines of evidence indicated that PDGF action is not mediated by cAMP. First, PDGF treatment caused no elevation of cAMP within 1 h, even in the presence of IBMX. Second, the kinetics of c-myc RNA elevation after treatment with PDGF or forskolin were similar, ruling out delayed onset of cAMP stimulation. Finally, simultaneous treatment with forskolin and the calcium ionophore A23187 enhanced the elevation of c-myc RNA levels; no such effect was seen with PDGF. We had previously shown that PDGF action is not affected by prior treatment of MG-63 cells with TPA, a treatment which desensitizes the c-myc response to TPA. Similarly, TPA pretreatment had minimal effect on forskolin or IBMX-induced c-myc expression. These data suggest that cAMP, phorbol esters, and PDGF act independently to stimulate c-myc RNA expression in MG-63 cells. However, nuclear runoff experiments and RNA half-life measurements demonstrated that PDGF, phorbol ester, and cAMP all act to increase the transcription of the MYC gene.
...
PMID:Platelet-derived growth factor-stimulated c-myc RNA accumulation in MG-63 human osteosarcoma cells is independent of both protein kinase A and protein kinase C. 168 64

The present investigation was undertaken to examine the possible role of cAMP in PTH-stimulated prostaglandin (PG) production in organ cultures of neonatal mouse parietal bones. Cultures were treated with PTH, forskolin, isobutylmethylxanthine (IBMX), and 8-bromo-cAMP (8BrcAMP). We found that similar concentrations of PTH stimulate cAMP formation and increase PG production in this culture system. Forskolin, a direct activator of adenylate cyclase, was also a potent stimulator of cAMP and PG production. The effect was dose dependent, with a maximum at 10(-5) M. The time courses for PTH- and forskolin-stimulated PG production were similar, and there was a close and similar correlation between cAMP production at 15 min and PGE2 production at 6 h for both agents. An increase in PG production was also observed when IBMX, which elevates cAMP levels in cells by inhibiting cAMP phosphodiesterase, or the cAMP analog 8BrcAMP was added to the cultures. In addition, IBMX enhanced the PGE2 responses to PTH, forskolin, and 8BrcAMP. These findings indicate that stimulation of PG production by PTH may be mediated by cAMP.
...
PMID:Evidence that adenosine 3',5'-monophosphate mediates hormonal stimulation of prostaglandin production in cultured mouse parietal bones. 168 90

At the initial phase of cell differentiation in mouse neuroblastoma (N18) induced by dibutyrylcyclic AMP (dbcAMP), an additional site of histone H1 was extensively phosphorylated. Forskolin and various phosphodiesterase inhibitors also induced both cell differentiation and H1 phosphorylation at the identical site. The phosphorylation preferentially occurred in a single H1 subtype (H1c) among the five (H1a-e) fractionated by high performance liquid chromatography. The three H1 subtypes of N18 (H1c, H1d, and H1e) were phosphorylated in vitro, and their amino acid sequences of the phosphopeptides were identical to the known sequence of rabbit H1 peptides containing a serine 37 residue. However, the amount of H1a and H1b phosphorylations was negligible. The serine residue was replaced by threonine residue in H1a, and H1b did not have a homologous peptide. The tryptic phosphopeptides of H1 in N18 were identical to that in rat liver H1 induced by glucagon (Langan, T.A. (1969) Proc. Natl. Acad. Sci. USA 64, 1276-1283). The results indicate that 1) the response of H1 subtypes to cAMP-dependent protein kinase in vivo and in vitro is H1 subtype-specific, and 2) the H1c phosphorylation may play an important role in the restrictive area of chromatin in both cell differentiation and hormonal stimulation mediated by cAMP.
...
PMID:Subtype-specific cyclic AMP-dependent histone H1 phosphorylation at the differentiation of mouse neuroblastoma cells. 169 Jul 30


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

---