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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This work supports the idea that PDEA is bound and stored in brain particulate fraction. The release of PDEA into cytosol where the activator-sensitive PDE is located, is the first event in the process of the regulation of cAMP metabolism and inactivation. PDEA is released by cAMP-dependent phosphorylation of the activator-binding sites. This process is Ca2+ independent and does not occur in the presence of cGMP and cGMP-dependent phosphorylation. The free, soluble PDEA activates the high Km PDE in the presence of micromolar concentrations of Ca2+. This protein decreases severalfold the Km for cAMP of the high Km activator-sensitive PDE. PDEA regulates cAMP metabolism when the concentration of cAMP is elevated by a transsynaptic activation of adenylate cyclase. The rate of synthesis and the release of PDEA might be a part of the process of receptor sub- and supersensitivity, which has been reported during denervation or as a result of chronic treatment with drugs.
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PMID:A neurobiological role for a protein activator of cyclic nucleotide phosphodiesterase. 1 21

The activity of 2-bromo-alpha-ergokryptine (bromocriptine) (5 mg kg-1, i.p.) on adenylate cyclase and on phosphodiesterase (PDE-PDE II) of rat striatum, has been examined both in vitro and in vivo. In vitro and in vivo bromocriptine stimulated adenylate cyclase activity, but reduced the stimulating effect of dopamine on adenylate cyclase activity. Bromocriptine showed a dose-dependent biphasic action on phosphodiesterases in vitro while in vivo it stimulated them. The results obtained proved bromocriptine to have an agonist-antagonist action at striatal dopamine receptor level, with a relevant effect on the cAMP system.
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PMID:Effects of bromocriptine on adenylate cyclase and phosphodiesterase activities of rat striatum. 2 11

A variety of human diploid fibroblasts released large amounts of cAMP to the medium in a time-dependent fashion concomitant with stimulation of the cells by agonists of the adenylate cyclase. In WI-38 cells increased medium cAMP levels were detectable as quickly as increased cellular levels. Escape was not secondary to serum deprivation nor cell injury. It occurred in defined media, and was pH and temperature dependent. Elevated rates of escape were maintained for up to 24 hours after stimulation. A variety of PDE inhibitors reduced the rate of escape. A rough proportionality existed between the potencies of the compounds as potentiators of PGE1 increased cellular cAMP levels on the one hand and as inhibitors of escape on the other. In the case of IBMX, the inhibition of escape was transient, the most pronounced effect being during the first 5 minutes of incubation. In addition, a variety of compounds without significant acute effects on cellular cAMP levels inhibited escape.
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PMID:The escape of cyclic AMP from human diploid fibroblasts: general properties. 8 40

The correlations between the relaxing effect of papaverine derivatives, inhibition of low Km-phosphodiesterase (cAMP-PDE = EC 3.1.4.17) activity and cyclic 3',5'-AMP (cAMP) levels in isolated rabbit ileum were investigated. There was a strong correlation between the relaxing effect, inhibition of PDE activity and cAMP content for eupaverine, ethylpapaverine and papaverine. Eupaverine was the most effective relaxing agent (I50 = 7.5 muM) and the most potent inhibitor of PDE activity (Ki = 0.6 muM), followed by ethylpapaverine (I50 = 10 muM;Ki 0.8 muM) and papaverine (I50 = 20 muM;Ki = 2 muM). In contrast, there was a strong relaxing effect (I50 = 6 muM) but only slight inhibition of PDE activity (Ki = 350 muM) by tetrahydropapaveroline (THP). The adenylate cyclase stimulating effect of THP which was shown by others is most likely the reason for comparatively higher cAMP levels, which were found to be elevated about seven times over basal levels of 0.35 nmoles/g wet weight, and effective relaxation. Relaxation could be induced by exogenously added cAMP (I50 = 45 muM) and dibutyryl-cAMP (I50 = 450 muM). Our results support the assumption that smooth muscle relaxation in rabbit ileum is mediated by cAMP. Some of these observations have been published in abstract form (Schulz and Berndt, 1972).
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PMID:Influence of papaverine derivatives on phosphodiesterase activity, cyclic 3',5'-AMP levels and relaxing effect on rabbit ileum. 18 61

The experiments presented in this paper examine the mechanisms underlying the ability of cannabinoids to alter the in vivo levels of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in mouse brain. It was found that changes in cyclic AMP levels are a composite result of direct actions of cannabinoids on adenylate cyclase (EC 4.6.1.1) activity and indirect actions involving the potentiation or inhibition of biogenic amine induced activity of adenylate cyclase. Furthermore, the long-term intraperitoneal administration of 1-(--)-delta-tetrahydrocannabinol to mice produced a form of phosphodiesterase (EC 3.1.4.17) in the brain whose activity is not stimulated by Ca2+, although its basal specific activity is similar to that of control animals. In vitro, the presence of the cannabinoids caused no significant changes in activity of brain PDE at the concentrations tested. Some correlations are presented which imply that many of the observed behavioral and physiological actions of the cannabinoids in mammalian organisms may be mediated via cyclic AMP mechanisms.
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PMID:Cannabinoid effects on adenylate cyclase and phosphodiesterase activities of mouse brain. 19 79

The orally-effective antiallergic compound [N-(2-oxo-3,5,7-cycloheptatrien-1-yl)] aminooxoacetic acid ethyl ester (AY-25,674) exhibited a potency equivalent to or 3 times less than theophylline in inhibiting guinea-pig lung and beef heart PDE, respectively, AY-25,674 did not affect the basal activity of guinea-pig lung adenyl cyclase. Although part of the antiallergic activity of AY-25,674 may be due to the ability to elevate cyclic AMP levels by PDE inhibition, other modes of action appear to be of greater relevance.
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PMID:Effects of [N-(2-oxo-3,5,7-cycloheptatrien-1-yl)] aminooxoacetic acid ethyl ester (AY-25,674) on cyclic 3',5'-nucleotide formation and phosphodiesterase activity. 21 16

We have previously reported that Trypanosoma cruzi infection of endothelial cells results in alterations in the metabolism of Ca2+, inositol triphosphate (IP3), and prostacycline (PGI2). In this report, we demonstrate that infection also alters the metabolism of cAMP. Infection of endothelial cells does not significantly alter beta-adrenergic receptor density or affinity, adenylate cyclase activity, and whole-cell cAMP levels. However, incubation of infected endothelial cells with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) resulted in less than a 60% increase in cell cAMP in contrast to the greater than a 100% increase observed in uninfected endothelial cells under otherwise identical reaction conditions. Infected endothelial cells demonstrated a twofold increase in phosphodiesterase activity when measured directly. Moreover, homogenates prepared from infected endothelial cells previously incubated with isoproterenol for 20 min showed little or no change in PDE activity. In contrast, homogenates prepared from uninfected endothelial cells treated under otherwise identical reaction conditions showed a 5.7-fold increase in PDE activity. In the presence of IBMX, isoproterenol-dependent stimulation of cAMP levels in infected endothelial cells reached a maximum level at 5 min of incubation, and thereafter rapidly declined. In contrast, cAMP levels in uninfected endothelial cells reached a maximum at 2 min of incubation, and thereafter remained elevated throughout the duration of the incubation. Infection-associated changes in isoproterenol dependent stimulation of cAMP accumulation appear to relate, in part, to changes in PDE activity.
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PMID:Trypanosoma cruzi: alteration of cAMP metabolism following infection of human endothelial cells. 130 2

Hormonal activation of the cGMP-inhibited low Km cyclic AMP phosphodiesterase isoenzyme (cGI.PDE) by effectors, acting either through the cAMP-independent (insulin) or through cAMP-dependent (isoproterenol, forskolin ACTH and 8Br-cAMP) mechanisms, were compared in parametrial (PM) and femoral subcutaneous (SC) adipocytes from sham-operated (SHAM) and ovariectomized (OVX) rats. In SHAM rats, the basal cGI.PDE activity was 50% higher in PM than in SC adipocytes. In OVX rats, the cGi.PDE activatory responses to all the effectors tested remained unchanged in SC, but were completely suppressed in PM adipocytes. The mechanism underlying these defective cGI.PDE activatory responses to cAMP-dependent effectors observed in PM adipocytes after OVX seems to involve protein kinase A, since a decreased activation of cGI.PDE by protein kinase A was also found in these cells. Treatment of OVX rats with both estradiol and progesterone reversed the defective cAMP-dependent activation of cGI.PDE, but not the refractoriness of this isoenzyme to insulin activation. Taken together with previous observations from this laboratory on the fat cell adenylate cyclase system (Lacasa et al. (1991) Endocrinology 128, 747-753), these results: (a) demonstrate that the influence of the ovarian status on the key enzymes controlling cAMP metabolism in fat cells depends on the anatomical origin of these cells, and; (b) provide a biochemical explanation to the insensitivity of the SC adipocyte lipolytic system to ovarian hormones.
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PMID:Hormonal activation of the cGMP-inhibited low-Km cyclic AMP phosphodiesterase of rat adipocytes from different sites: influence of ovariectomy. 132 10

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.
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PMID:Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog. 138 77

Prostaglandin (PG) E2 potentiates platelet aggregation at low concentrations (10(-8)-10(-6) M). It also inhibits aggregation at a higher concentration (10(-5) M), probably by acting through cyclic adenosine 3',5'-monophosphate (cyclic AMP). The mechanism of this biphasic effect of PGE2 and its implications for thrombosis are not clearly understood. Using a sensitive cyclic AMP assay, in conjunction with platelet aggregation studies, we have examined the interactions between PGE2 and other inhibitors of platelet aggregation which act through cyclic AMP. Low concentrations of PGE2 reversed the inhibition of platelet aggregation and increase in cyclic AMP levels induced by PGI2, PGD2 and adenosine (which stimulate adenylate cyclase (AC) through separate and specific platelet receptors). In contrast, low concentrations of PGE2 added to the inhibition of platelet aggregation and increase in cyclic AMP levels induced by forskolin (which stimulates AC directly) and AH-P 719 and DN-9693 (which inhibit cyclic AMP phosphodiesterase (PDE]. These results suggest that the biphasic effect of PGE2 may be mediated by interaction with two separate platelet receptors. Low concentrations appear to potentiate aggregation by acting at a receptor which is directly coupled to an inhibitory guanine nucleotide-binding protein (Gi), possibly the putative PG endoperoxide receptor. High concentrations of PGE2 appear to inhibit aggregation by acting at an additional receptor, probably the PGI2 receptor. The ease with which PGE2 reverses the effects of PGI2, PGD2 and adenosine, but adds to the effects of AH-P 719 and DN-9693, suggests that PDE inhibitors might offer greater potential than these AC stimulators as an anti-thrombotic strategy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions between prostaglandin E2 and inhibitors of platelet aggregation which act through cyclic AMP. 164 65


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