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 effects of prostaglandin E1 (PGE1) and histamine on activation of superoxide (O2-) formation, exocytosis of beta-glucuronidase and aggregation in human neutrophils and HL-60 leukemic cells were studied. PGE1, histamine and impromidine, a potent H2-agonist, inhibited O2- formation in neutrophils induced by the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe) with IC50 values of 0.5 microM, 8 microM and 2 microM, respectively. The full H1-agonist and weak partial H2-agonist, betahistine, was much less potent and effective than histamine. Dibutyryl cyclic AMP and forskolin mimicked the effects of histamine and PGE1 on O2- formation. The H2-antagonist, famotidine, competitively reversed histamine-induced inhibition of O2- formation with a pA2 value of 7.5. Histamine inhibited O2- formation when added prior to or after fMet-Leu-Phe. fMet-Leu-Phe-induced aggregation and release of beta-glucuronidase in neutrophils were less sensitive to inhibition by PGE1, histamine, dibutyryl cyclic AMP and forskolin than O2- formation. The inhibitor of cyclic AMP-specific phosphodiesterase, rac-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), additively enhanced the inhibitory effects of histamine and PGE1 on the above cell functions. In HL-60 cells differentiated by dimethyl sulfoxide or dibutyryl cyclic AMP, histamine, impromidine and PGE1 but not betahistine inhibited fMet-Leu-Phe-induced O2- formation as well. Our data suggest that histamine inhibits activation of neutrophils and HL-60 cells via H2-receptors through activation of adenylyl cyclase and increased formation of cyclic AMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histamine inhibits activation of human neutrophils and HL-60 leukemic cells via H2-receptors. 255 36

The CD3(T3)/antigen receptor complex appears to function by transducing an antigen signal presented by macrophages into the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. In order to find out how the CD3/antigen receptor complex regulates the hydrolysis of PtdIns(4,5)P2 to diacylglycerol and inositol trisphosphate, we investigated the possible role played by a guanine nucleotide-binding regulatory protein in PtdIns(4,5)P2 hydrolysis in a human T cell leukemia line, JURKAT. JURKAT cells were made permeable to Al3+, F-, GTP, and a nonhydrolyzable GTP analogue, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), by treatment with pseudomonal cytotoxin. In the presence of AlCl3 NaF stimulated the release of inositol phosphates in the cytotoxin-treated JURKAT cells. NaF plus AlCl3 induced increases in inositol tris-, bis-, and mono-phosphates and decreases in PtdIns(4,5)P2, phosphatidylinositol 4-phosphate, and phosphatidylinositol within 5 min after addition to the cytotoxin-treated cells at 37 C. GTP gamma S stimulated, to some extent, polyphosphoinositide hydrolysis in the cytotoxin-treated JURKAT. The cytotoxin-treated JURKAT cells retained the ability to respond to anti-Leu-4 with polyphosphoinositide hydrolysis. It has been shown that Al3+ in the presence of F- modulates the activity of various guanine nucleotide-binding regulatory proteins. Therefore, the results obtained in this study indicate that a guanine nucleotide-binding regulatory protein regulates the polyphosphoinositide breakdown in JURKAT cells by influencing phosphodiesterase activity.
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PMID:Role of a guanine nucleotide-binding regulatory protein in the hydrolysis of phosphatidylinositol 4,5-bisphosphate in a human T cell line. 283 52

"Paralytic tremor" (pt) rabbit mutant is characterized by a severe hypomyelination of the CNS, however, it is not defined if the defect in myelinogenesis is an "assembly" or "synthesis" type. In this study, we have compared the general metabolic and biosynthetic properties of the myelinating mutant brain with unaffected controls of the same age. In the brain slices of 4 wk old "pt" rabbits the incorporation of U-[14C]glucose, 6-[3H] galactose, and U-[14C] leucine into macromolecules (total lipids and proteins, galactolipids, and myelin basic protein) was substantially elevated. In isolated myelin fraction, the total reduction of the radioactivity was followed by the increased specific activity of all examined macromolecules. The myelin to homogenate specific activity ratio was similar in control and "pt" rabbits. Distribution of the label and myelin marker, cyclic nucleotide 3'-phosphodiesterase (CNP-ase) among the membranous fractions suggests the partial inhibition of myelin formation in "pt" rabbits on the step of premyelin, unilamellar membranes. 14CO2 yields derived from differently labeled glucose were used for the evaluation of the basal oxidative metabolism in "pt" brain slices. 14CO2 production from U-[14C] glucose was normal. The depolarization of the slices by 50 mM K+ stimulated glucose oxidation to a higher extent in "pt" than in control. Hexose monophosphate pathway (HMP), the route providing much of NADPH required for lipid biosynthesis, did not change significantly by mutation. The activity of glucose 6-phosphate dehydrogenase (Glc-6-P DH), an oligodendroglia enriched, HMP connected enzyme, was slightly lower in "pt" homogenates by 13-17%, whereas CNP-ase was lowered more than 30% in the same samples. All this data suggest that the capacity for the synthesis of myelin constituents is well preserved in the mutant brain and the impairment of myelogenesis is probably caused by increased elimination of already synthesized, myelin-related components.
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PMID:Metabolic studies on dysmyelinating mutant "pt" rabbit brain in vitro. 284 Jun 12

1. Multiple-barreled microelectrodes were used to record from neurons in the area postrema of anesthetized dogs and to test the responses of the neurons to a variety of substances in this structure, which is known to function as the chemoceptive trigger zone for emesis. 2. The neurons in area postrema were silent at rest but could be "found" by virtue of their response to ionophoretic glutamate. The glutamic response was brief and of short latency with high frequency of discharge. 3. Dog area postrema neurons were also excited by over 20 other substances, including acetylcholine, the biogenic amines, several peptides, and at least two hormones. Not all agents were excitatory, however. 4. The responses to all excitatory agents except glutamate were similar and unusual. All responses showed a relatively long latency (3-20 s), a long duration of excitation (30 s to many minutes), and a low discharge frequency (1-3 Hz). 5. There was a good correlation between substances that were excitatory on area postrema neurons and substances known to cause emesis. Because emesis due to intravenous application of these substances is known to be abolished in animals with ablation of the area postrema, it is very likely that recordings were from the neurons which trigger the response. 6. Because so many substances elicit the same type of response there is a possibility that all utilize a common second messenger. Neurons were not excited by ionophoresis of guanosine 3',5'-cyclic monophosphate (cGMP) but were excited by 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) and by forskolin, an activator of adenylate cyclase. 7. Behavioral studies were performed looking for emetic responses in awake dogs following intravenous injection of apomorphine, insulin, angiotensin II, and leucine enkephalin. For each a threshold concentration could be determined, which would consistently evoke emesis. 8. Dogs pretreated with phosphodiesterase inhibitors (theophylline, 3-isobutyl-1-methylxanthine, or RO 1724) showed a shift in the threshold concentration of the above substances that triggered emesis, such that emesis was evoked by lower concentrations than in the control. 9. These results suggest that neurons of the dog area postrema trigger the emetic reflex in response to specific receptors for a great variety of transmitters, peptides, and hormones, and that these receptors act through a common second messenger, cAMP.
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PMID:Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. 289 67

The effects of insulin and secretory agonists on amino acid incorporation into submandibular gland proteins were studied using isolated acinar cell aggregates. Insulin stimulated the incorporation of 3H-leucine into TCA-precipitable proteins in a rapid, dose-dependent manner (half-maximal response at 1 nM). Isoproterenol, a beta-adrenergic agonist, also stimulated amino acid incorporation, and this effect was mimicked by both dibutyryl cAMP and IBMX, a phosphodiesterase inhibitor. Although insulin further stimulated incorporation in the presence of isoproterenol and IBMX, no additional increase in the rate of synthesis was observed after stimulation by dibutyryl cAMP. High concentrations of carbamylcholine, a cholinergic agonist, inhibited both basal and insulin-stimulated incorporation. At low concentrations, however, carbamylcholine stimulated synthesis, and the effects of insulin and carbamylcholine were additive. A23187, a calcium ionophore, also inhibited 3H-leucine incorporation and insulin stimulation, but in contrast to carbamylcholine, low concentrations of A23187 neither inhibited nor enhanced the rate of synthesis. Thus, protein synthesis in the rat submandibular gland is regulated by both insulin and neurotransmitters. Whereas beta-adrenergic stimulation appears to be mediated through cAMP, the intracellular signals mediating the actions of insulin and cholinergic agonists remain to be elucidated.
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PMID:Insulin-stimulated protein synthesis in submandibular acinar cells: interactions with adrenergic and cholinergic agonists. 289 24

The secretory response of cytochalasin B-treated human polymorphonuclear neutrophils to the peptide chemoattractant f-Met-Leu-Phe (FMLP), the calcium ionophore A23187 and other secretagogues was measured by assaying neutrophil supernatants for the granular enzymes beta-glucuronidase and lysozyme. The dose-dependent enzyme secretion in response to 10(-8)-10(-4) M FMLP and A23187 was unaffected by pretreatment with 10-75 microM forskolin (an activator of adenylate cyclase), but inhibited by high concentrations of prostaglandins E1 and E2. The phosphodiesterase inhibitors isobutyl-methyl-xanthine (IBMX), papaverine and Ro 20-1724 dose dependently inhibited enzyme secretion from FMLP- or A23187-treated cells, and this effect was augmented in the presence of 50-75 microM forskolin. Similar results for PGE1, forskolin and forskolin/IBMX combinations were also obtained using leukotriene B4, platelet activating factor and C5a des-Arg as secretagogues. We conclude that the adenylate cyclase system of human neutrophils is activatable by forskolin, but that the regulatory effects of adenylate cyclase stimulants in these cells are greatly attenuated unless cyclic AMP-phosphodiesterases are inhibited. Thus the phosphodiesterase activity of neutrophils may be of functional importance and is relevant to the modulation of neutrophil activity in inflammation.
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PMID:Inhibition of human neutrophil degranulation by forskolin in the presence of phosphodiesterase inhibitors. 301 41

The content of cAMP was measured in monocytes treated with fMet-Leu-Phe and adenosine, either singly or in combination. Adenosine caused a small and variable rise in cAMP, which was considerably less than that caused by fMet-Leu-Phe. The rise induced by peptide plus adenosine was twice the sum of the increases caused by each agent alone. An inhibitor of phosphodiesterase also enhanced the adenosine-induced rise in cAMP. The data suggest that the increase in cAMP by adenosine-induced cyclase activation is limited by the activity of phosphodiesterase, and that the latter can be inhibited by fMet-Leu-Phe.
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PMID:Synergistic action of adenosine and fMet-Leu-Phe in raising cAMP content of purified human monocytes. 301 43

Chronic exposure to anesthetic concentrations of halothane during the prenatal and early postnatal periods inhibits the incorporation of the leucine into myelin subcellular fractions in the rat. The enzyme 2',3' - cyclic nucleotide 3' - phosphodiesterase (CNPase) has been widely used as a myelin marker. To determine the effect of halothane on the developmental profile of CNPase, two groups of pregnant Sprague Dawley rats were exposed to 500 p.p.m. or 250 p.p.m. halothane, eight hours per day, five days per week from the third day after conception through postnatal day ten. Control animals were exposed to air alone. CNPase activity was significantly decreased by 500 p.p.m. halothane (34%) and by 250 p.p.m. halothane (29%) at postnatal day 17. Brain and body weights in both halothane treated groups were also less than control animals throughout the measurement period. The data indicates that chronic pre- and postnatal halothane exposure at low levels delays myelination in the rat.
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PMID:Effect of halothane on brain 2',3'-cyclic nucleotide 3'-phosphodiesterase during neurodevelopment in the rat. 302 Jun 53

Calmodulin from the yeast Saccharomyces cerevisiae was purified to complete homogeneity by hydrophobic interaction chromatography and HPLC gel filtration. The biochemical properties of the purified protein as calmodulin were examined under various criteria and its similarity and dissimilarity to other calmodulins have been described. Like other calmodulins, yeast calmodulin activated bovine phosphodiesterase and pea NAD kinase in a Ca2+-dependent manner, but its concentration for half-maximal activation was 8-10 times that of bovine calmodulin. The amino acid composition of yeast calmodulin was different from those of calmodulins from other lower eukaryotes in that it contained no tyrosine, but more leucine and had a high ratio of serine to threonine. Yeast calmodulin did not contain tryptophanyl or tyrosyl residues, so its ultraviolet spectrum reflected the absorbance of phenylalanyl residues, and had a molar absorption coefficient at 259 nm of 1900 M-1 cm-1. Ca2+ ions changed the secondary structure of yeast calmodulin, causing a 3% decrease in the alpha-helical content, unlike its effect on other calmodulins. Antibody against yeast calmodulin did not cross-react with bovine calmodulin, and antibody against bovine calmodulin did not cross-react with yeast calmodulin, presumably due to differences in the amino acid sequences of the antigenic sites. It is concluded that the molecular structure of yeast calmodulin differs from those of calmodulins from other sources, but that its Ca2+-dependent regulatory functions are highly conserved and essentially similar to those of calmodulins of higher eukaryotes.
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PMID:Purification and biochemical properties of calmodulin from Saccharomyces cerevisiae. 331 40

The generation of the two inositol trisphosphate (IP3) isomers, 1,4,5-IP3 and 1,3,4-IP3, and its relation to changes in the cytosolic free calcium concentration, [Ca2+]i, in response to the chemotactic peptide fMet-Leu-Phe was studied in the human promyelocytic cell line HL-60, induced to differentiate with dimethyl sulfoxide. Stimulation by fMet-Leu-Phe within seconds transiently elevates 1,4,5-IP3 to peak values averaging 8-fold basal levels, and leads to a concomitant rise in [Ca2+]i and to degranulation. These responses are followed by a slower and more sustained rise in 1,3,4-IP3. Alterations in [Ca2+]i modulate differentially the generation of the two IP3 isomers. At [Ca2+]i lower than 30 nM, no IP3 is generated upon fMet-Leu-Phe stimulation. Working at normal resting [Ca2+]i, but preventing the fMet-Leu-Phe induced transient rise in [Ca2+]i (by prior depletion of intracellular Ca2+ stores and working in calcium-free medium) the fMet-Leu-Phe stimulation of 1,3,4-IP3 levels is attenuated, whereas the response of 1,4,5-IP3 is not significantly altered. Maintained elevation of [Ca2+]i to micromolar levels with the Ca2+ ionophore ionomycin generates enhanced 1,3,4-IP3 levels in the absence of fMet-Leu-Phe, whereas the fMet-Leu-Phe stimulation of 1,4,5-IP3 generation is markedly inhibited. Pertussis toxin selectively abolishes the fMet-Leu-Phe-induced IP3 production, whereas ionomycin stimulation of 1,3,4-IP3 generation is unaffected. These findings indicate that in intact cells: receptor-triggered phosphatidylinositol bisphosphate phosphodiesterase activation has a minimal Ca2+ requirement, but does not depend on a previous or concomitant rise in [Ca2+]i; Ca2+ elevations above micromolar levels decrease the fMet-Leu-Phe-induced generation of 1,4,5-IP3; and 1,3,4-IP3 generation is not directly linked to receptor activation and appears to result both from increased [Ca2+]i and 1,4,5-IP3 levels.
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PMID:The role of cytosolic free calcium in the generation of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate in HL-60 cells. Differential effects of chemotactic peptide receptor stimulation at distinct Ca2+ levels. 348 12


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