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)

The variations in phosphatidate phosphohydrolase activity were investigated in the post-mitochondrial fraction of isolated rat hepatocytes incubated for short periods with epinephrine, dibutyryl cyclic AMP or oleate. Epinephrine decreased the enzyme activity by 42% at 1 microM concentration. The inhibitory effect was abolished in the presence of a beta-adrenoceptor antagonist, propranolol, but was not affected by the alpha-adrenoceptor agonist, phenylephrine, or the agonist, phentolamine. Dibutyryl-cAMP inhibited the enzyme activity by 49%. The presence of the cyclic-AMP phosphodiesterase inhibitor, aminophyline, together with epinephrine slightly increased the enzyme inhibition. Oleate stimulated the enzyme activity (100%) and its effect was antagonized by dibutyryl-cyclic AMP (24%) and by epinephrine (15%). The results indicate that epinephrine acts on rat hepatocytes via beta-adrenoceptor activation and cAMP may be involved in the mechanism by which phosphatidate phosphohydrolase is regulated.
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PMID:Inhibitory effect of epinephrine on phosphatidate activity in isolated rat hepatocytes. 196 35

Adrenal glomerulosa was examined for the presence of an adrenergic influence on aldosterone production. Cultured rat adrenal capsular explants were transferred to a perifusion system where the effect of exposure to catecholamines on aldosterone production was assessed. At 10(-6) M, isoproterenol greater than epinephrine greater than norepinephrine significantly stimulated aldosterone production, whereas at 10(-8) M only isoproterenol showed significant stimulation. Propranolol, a beta-adrenoreceptor antagonist, inhibited stimulation by epinephrine, and the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine, enhanced stimulation by a submaximal dose of epinephrine. Epinephrine and norepinephrine were found by radioenzymatic assay to be present in fresh as well as cultured capsular tissue, although levels were considerably lower in tissue that had been in culture (about one tenth that of fresh tissue). The epinephrine-norepinephrine ratio was similar in capsule and medulla, suggesting a medullary source of capsular catecholamines. Whether catecholamines in the capsule arose from the in vitro manipulation of adrenal tissue or existed in vivo is unclear. In summary, beta-agonists stimulate aldosterone production in cultured rat capsular explants.
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PMID:Beta-adrenergic stimulation of aldosterone production by rat adrenal capsular explants. 241 Feb 37

The hormonal control of proline transport in pyloric ceca was studied in regard to the effects of cortisol, growth hormone (GH), epinephrine, and 3-isobutyl-1-methylxanthine (IBMX). Cortisol pellets implanted in yearling freshwater (FW) salmon for 2 weeks elevated plasma cortisol levels six times above that of control fish. The maximal influx (Jmax) and the half-saturation constant (Kt) of proline influx were twofold greater in cortisol-treated fish than the values in controls; the apparent passive permeability coefficient (Pa) was significantly reduced in the former group. FW salmon implanted with GH for 2 weeks showed increased body weight gain and a higher Jmax of proline influx compared with that of control fish. GH treatment resulted in a higher Pa of proline influx as well as in a 30% increase in area-specific intestinal dry weight. Thus, GH and cortisol may play a regulatory role in intestinal amino acid absorption during salmon development. The in vitro effects of epinephrine and the phosphodiesterase inhibitor, IBMX, on short-circuit current (Isc) and proline influx in salmon intestine were examined. Epinephrine (10(-6) M) caused a rapid increase in negative Isc (mucosa, ground). Pyloric ceca preincubated with epinephrine for 30 min showed reduced total proline influx compared with influx in paired control tissues. Epinephrine increased and IBMX decreased the Kt of proline influx; IBMX also reduced Jmax. The possible interaction between the effects of epinephrine and IBMX on ion transport and Na+-coupled proline influx are discussed.
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PMID:Hormonal effects on L-proline transport in coho salmon (Oncorhynchus kisutch) intestine. 241 38

Using a recently developed canine primary enteric endocrine cell culture system, we have investigated the role of adenosine 3',5'-cyclic monophosphate (cAMP) in mediating the release of neurotensin and enteroglucagon. Epinephrine-stimulated peptide release was concomitant with an increase in cAMP accumulation. Carbachol and somatostatin (SRIF) markedly inhibited the epinephrine effect on both peptide release and cAMP content. The addition of 3-isobutyl-1-methylxanthine potentiated epinephrine-stimulated peptide release without altering the relative inhibition by carbachol and SRIF, suggesting that these agents did not inhibit endocrine cell function by increasing phosphodiesterase activity. To determine the role of cAMP production in mediating inhibition of peptide release, cells were incubated with the bacterial toxin, pertussis toxin (PT). In cultures pretreated with PT, carbachol inhibition of both peptide release and cAMP accumulation was completely reversed. In contrast, SRIF inhibition of cAMP content was completely reversed after PT treatment, but inhibition of peptide release was only partially reversed. Additionally, toxin treatment only partially reversed SRIF inhibition of forskolin- and calcium ionophore-stimulated peptide release. These data suggest that muscarinic cholinergic inhibition of neurotensin and enteroglucagon release is mediated entirely through the guanine nucleotide-binding protein (Ni) or a similar toxin-sensitive, GTP-binding protein. SRIF-inhibited peptide release is mediated partially through a toxin-sensitive substrate, as evidenced by PT reversal of reduced cAMP levels. SRIF may also inhibit neurotensin and enteroglucagon release by a cAMP-independent pathway that is not coupled to Ni or a similar PT-sensitive, GTP-binding protein.
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PMID:Somatostatin and muscarinic inhibition of canine enteric endocrine cells: cellular mechanisms. 244 8

Epinephrine at concentrations approximating circulating levels in resting subjects produced significant desensitization in wild type S49 lymphoma cells after long term treatment. Desensitization by such low levels of catecholamines was measured by examining subsequent responses of the cells to higher agonist concentrations and was quantified by comparing the integral cAMP accumulations with time in naive and epinephrine-treated cells challenged with the higher epinephrine concentrations. The cells were significantly desensitized after 8 hr of treatment with 3 nM epinephrine or 3 nM terbutaline and were essentially maximally refractory after 24 hr. The 3 nM epinephrine treatment resulted in a small right shift of the EC50. Responses to epinephrine were partially restored by incubating desensitized cells for 8 hr or longer in growth medium that was free of epinephrine. The attenuation of cAMP responses was largely specific, in that the decrease in the response to prostaglandin was small and the response to forskolin was unchanged. This, together with small increases in cAMP destruction in cell-free preparations from treated cells, suggested that higher phosphodiesterase activity contributed in a minor way to the desensitization. However, the response of the adenylate cyclase system to epinephrine was dramatically attenuated, and very significant changes in the properties of the beta-adrenergic receptors were also obvious. That is, the number of binding sites for epinephrine was reduced by about 65% while the number of sites for [125I]iodocyanopindolol was unchanged. The affinity for the radioactive ligand was significantly reduced. Wild type S49 cells remained viable after several days of continuous treatment with 3 nM epinephrine or terbutaline but responded to subsequent increases in cellular cAMP levels with the expected growth arrest and cytolysis. Involvement of cAMP-dependent protein kinase in this type of desensitization was suggested by the observation that S49 kincells were not desensitized by long term incubation with 3 nM epinephrine. Further, low concentrations of dibutyryl cAMP mimicked the effect of low level epinephrine treatment. We conclude that circulating levels of epinephrine in intact animals are sufficiently high to cause desensitization in cells with sensitivities to the catecholamines in the same range as that of the S49 lymphoma cell in vitro. We would predict that cells with those characteristics would always be at least partially desensitized in vivo.
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PMID:Growth of S49 cells in low concentrations of beta-adrenergic agonists causes desensitization. 255 Jul 79

We have been investigating the mechanisms of diurnal and circadian regulation of teleost retinomotor movements. In the retinas of lower vertebrates, photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) undergo movements at dawn and dusk. These movements continue to occur at subjective dawn and dusk in animals maintained in constant darkness. Cone myoids contract at dawn and elongate at dusk; RPE pigment disperses into the epithelial cells' long apical processes at dawn and aggregates into the cell bodies at dusk. We report here that forskolin, an adenylate cyclase activator, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, each induces dark-adaptive cone and RPE retinomotor movements in isolated light-adapted green sunfish retinas cultured in constant light. Forskolin induces a 22-fold elevation in retinal cyclic AMP content. Forskolin- and IBMX-induced movements are inhibited approximately 65% and 95%, respectively, by 3,4-dihydroxyphenylethylamine (dopamine). However, dopamine does not inhibit dark-adaptive movements induced by dibutyryl cyclic AMP. Epinephrine is much less effective than dopamine in inhibiting forskolin-induced movements, while phenylephrine and clonidine are totally ineffective. These results are consistent with our previous findings that treatments that increase intracellular cyclic AMP content promote dark-adaptive retinomotor movement. They further suggest that dopamine inhibits adenylate cyclase activity in photoreceptors and RPE cells and thereby favors light-adaptive retinomotor movements.
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PMID:Dopamine inhibits forskolin- and 3-isobutyl-1-methylxanthine-induced dark-adaptive retinomotor movements in isolated teleost retinas. 258 Sep 51

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

1. The mechanism of stimulation of cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation by adrenaline and ouabain and the effect of Mn(++) substitution for Mg(++) as the metal ion requirement of this system was studied in cell-free preparations of adenyl cyclase from rat brain.2. In the rat cerebral cortex preparation, substitution of Mn(++) for Mg(++) significantly increased cyclic AMP accumulation while significantly inhibiting adenosine triphosphate (ATP) and adenosine diphosphate (ADP) hydrolysis and adenosine 5'-monophosphate (AMP) accumulation. In the synaptic membrane preparation, in the absence of NaF, the highest amount of ATP hydrolysis was obtained in tissue prepared with Mn(++) and incubated with Mg(++); under these conditions cyclic AMP accumulation was equal to that produced under any other condition and significantly higher than that observed in the presence of Mg(++) prepared and Mg(++) incubated tissue.3. Preparation and/or incubation of tissue with Mn(++) significantly reduced phosphodiesterase (PDE) activity compared to that observed in Mg(++) prepared tissue.4. Adrenaline and ouabain both significantly increased cyclic AMP accumulation in the rat cerebral cortex preparation but did not inhibit ATP or ADP hydrolysis. In the synaptic membrane preparation, in the presence of 0.01 mM Ca(++), adrenaline but not ouabain significantly increased cyclic AMP accumulation. Phenoxybenzamine (0.1 mM) and pronethalol (0.1 mM) significantly inhibited adrenaline-induced cyclic AMP accumulation in both these preparations.5. Ouabain and adrenaline both failed to stimulate cyclic AMP accumulation in the presence of Mn(++) prepared and/or incubated tissue.6. Ouabain and adrenaline had no effect on PDE activity in either of these preparations.7. It was concluded that Mn(++) increased cyclic AMP accumulation in part by indirect inhibition of ATP and ADP hydrolysis which provides inhibitors of cyclic AMP destruction, by direct stimulation of adenyl cyclase and by inhibition of cyclic AMP destruction in a way unrelated to nucleotide inhibition of PDE. Adrenaline and ouabain appeared tp stimulate cyclic AMP accumulation in a more direct manner.
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PMID:The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn++. 414 40

In primary cultures of rat hepatocytes, addition of dexamethasone (10 microM) plus glucagon (0.5 microM) caused several-fold increases in the activities of serine dehydratase (EC 4.2.1.13), tryptophan oxygenase (EC 1.13.11.11), and tyrosine aminotransferase (EC 2.6.1.5) in 24 h. These inductions were inhibited by insulin. Addition of epinephrine or phenylephrine at 10 microM blocked these inductions. This suppressive effect of adrenergic compounds was completely abolished by the alpha-adrenergic antagonist phenoxybenzamine at 10 microM. Immunochemical analysis with antiserum to serine dehydratase showed that the changes in enzyme activity were due to changes in the amount of enzyme. Epinephrine was effective even when glucagon was replaced by dibutyryl cAMP (50 microM), indicating that alpha-adrenergic suppression of enzyme inductions was mediated by a cAMP-independent mechanism. Furthermore, the findings that prazosin antagonized this epinephrine effect, but yohimbine did not, indicate that the alpha 1- but not the alpha 2-receptor is involved in this inhibition. However, the alpha-adrenergic effect was different from that of insulin in that, unlike the latter, the inductions of tryptophan oxygenase and tyrosine amino-transferase by dexamethasone alone were not inhibited. The alpha-adrenergic action apparently counteracts the action of glucagon and cAMP. For determination of the beta-adrenergic effect of catecholamines on the inductions of enzymes, beta-adrenergic compounds were tested without glucagon. Isoproterenol or epinephrine plus phenoxybenzamine induced tryptophan oxygenase and tyrosine aminotransferase. Induction of serine dehydratase was shown by isoproterenol only in the presence of 1-methyl-3-isobutylxanthine, an inhibitor of phosphodiesterase. These results indicate that catecholamines play dual roles in regulation of the amount of enzyme through their alpha 1- and beta-adrenergic actions.
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PMID:alpha-Adrenergic regulation of enzymes of amino acid metabolism in primary cultures of adult rat hepatocytes. 613 92

Human blood platelets display alpha2-adrenergic receptors, which promote platelet aggregation and inhibit the adenylate cyclase. We investigated the effects of the antihypertensive agent clonidine and its analogue para-aminoclonidine on this receptor in the intact human platelet to determine their pharmacological effects and their ability to bind to the receptor by radioligand displacement. Both agents potentiated platelet aggregation induced by a submaximal concentration of ADP. Epinephrine-induced aggregation, on the other hand, was antagonized by clonidine and para-aminoclonidine in a dose-dependent fashion. Both agents inhibited the accumulation of cyclic AMP in platelets exposed to prostaglandin E1 and a phosphodiesterase inhibitor, but to a lesser extent than the inhibition caused by epinephrine. Both antagonized this excess inhibitory action of epinephrine. Clonidine and para-aminoclonidine blocked the binding of [3H]yohimbine (a selective alpha 2-adrenergic antagonist) to intact platelets with half-maximal effects at 0.3 and 0.7 microM, respectively. No evidence for the existence of a second class of binding sites with high affinity for clonidine was seen in intact platelets, either by this technique or by direct binding of [3H]clonidine. It is concluded that these two agents are partial agonists for the alpha 2-adrenergic receptors on blood platelets and that this receptor exists predominantly in the low-affinity state in the intact cell.
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PMID:Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets. 613 85


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