Cyclic nucleotide phosphodiesterase: high activity in a mammalian photoreceptor

Purified outer segments of bovine rods exhibit phosphodiesterase activity against adenosine and guanosine cyclic 3',5'-monophosphates (cyclic AMP and cyclic GMP). The enzyme hydrolyzed cyclic GMP more rapidly than cyclic AMP at low substrate concentrations. The presence of high phosphodiesterase activity in this highly specialized organelle suggests that this enzyme may function in control of cyclic nucleotide concentration during visual excitation or adaptation.     

Reversal of catecholamine refractoriness by inhibitors of RNA and protein synthesis

The generation of adenosine 3',5'-monophosphate (cyclic AMP) in response to catecholamines in the 2B subclone of RGC6 rat glioma cells previously exposed to norepinephrine and refractory to further norepinephrine addition is substantially increased by addition of inhibitors of RNA and protein synthesis. The time course of the effect of these inhibitors on cyclic AMP concentration suggests that rapid protein synthesis and turnover are involved in catecholamine refractoriness. Norepinephrine induction of cyclic nucleotide phosphodiesterase is demonstrable in RGC6 cells but not in the 2B subclone. Thus, catecholamine refractoriness cannot be attributed to induction of phosphodiesterase. This implies that induction of a protein or proteins, important in catecholamine refractoriness, affects the synthesis rather than the degradation of cyclic AMP.     

Gonadotropin-releasing hormone: regulation of adenosine 3',5'-monophosphate in ovarian granulosa cells

The antigonadal effects of gonadotropin-releasing hormone in ovarian granulosa cells are due to attenuation of the adenosine 3',5'-monophosphate (cyclic AMP) response to follicle-stimulating hormone. Agonists of gonadotropin-releasing hormone progressively inhibit adenylate cyclase and stimulate phosphodiesterase activities in cultured granulosa cells, indicating that blockade of gonadotropin action is attributable to the combined effects of decreased production and increased degradation of cyclic AMP.     

Luteolin prevents f MLP-induced neutrophils adhesion via suppression of LFA-1 and phosphodiesterase 4 activity

Luteolin is an active ingredient found early from Folium perillae and Flos lonicerae, and has a specific inhibition on phosphodiesterase 4(PDE4) activity in vitro. Researches show luteolin has pharmacological effects of anti-inflammation, anti-anaphylaxis, antitumor, antioxidant, protection of nervous system and so on, and has mainly been used for the treatment of respiratory inflammatory diseases, cancer and cardiovascular disease in clinic. PDE4, specific to hydrolyze cyclic AMP(c AMP), is considered to be a new anti-inflammatory target due to the decisive role on c AMP signal in inflammatory cells such as neutrophils. In order to explore the anti-inflammatory mechanism, we further studied the effects of luteolin on the activity and expression of PDE4, the expression of lymphocyte function-associated antigen-1(LFA-1) and macrophage-1(MAC-1) in neutrophils, and the adhesion of neutrophils and endothelial cells. The results showed that luteolin had a dose-dependent inhibition on both bare PDE4 activity and PDE4 in cultured neutrophils, and had an obviously promotive effect on gene expressions of PDE4 A, 4B and 4D in later period. Luteolin had a significant inhibitory effect on neutrophils adhesion and LFA-1 expression in early stage, and had no obvious effect on MAC-1 expression. Therefore, luteolin can inhibit LFA-1 expression of neutrophils, then inhibit the adhesion of neutrophils and endothelial cells, and the mechanism is at least related with the inhibition of PDE4 activity.     

Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina

As a result of an early deficiency in cyclic nucleotide phosphodiesterase activity, guanosine 3',5'-monophosphate accumulates in retinal photoreceptor cells before they begin to degenerate. It is suggested that degeneration of the photoreceptor cells is related to an imbalance in their metabolism or function which is caused by the elevated levels of cyclic guanosine monophosphate.     

Catecholamine and dibutyryl cyclic AMP effects on myosin adenosine triphosphatase in cultured rat heart cells

Catecholamines and dibutyryl adenosine 3', 5'-monophosphate (dibutyryl cyclic AMP) increase the activity of myosin adenosine triphosphatase in cultured rat heart cells. Dichloroisoproterenol, an inhibitor of the beta receptor of the catecholamines, inhibits the action of the catecholamines but not of cyclic AMP.     

Adenosine 3'5'-monophosphate: inhibition of complement-mediated cell lysis

An increase in adenosine 3',5'-monophosphate (cyclic AMP) in rat mast cells, achieved by stimulating the cells with prostaglandin E(1), by preventing cyclic AMP breakdown with aminophylline, or by adding exogenous dibutyryl cyclic AMP, prevented complement-mediated cytolysis as assessed by both histamine release and vital dye exclusion. Dibutyryl cyclic AMP also suppressed water-induced osmotic lysis.     

Phosphodiesterase in Dictyostelium discoideum and the chemotactic response to cyclic adenosine monophosphate

A phosphodiesterase with a low Michaelis constant for cyclic adenosine monophosphate was found in the membrane fraction of the cellular slime mold. This activity was highest during the aggregation stage. Enzyme with similar properties was also secreted by the cells. Dithiothreitol inhibited both enzymes and potentiated the cellular response to cyclic adenosine monophosphate.     

Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine

The growth in vitro of human breast cancer cells, line MCF-7, was inhibited by a daily supplement of L-arginine (1 milligram per milliliter). Arginine acted synergistically with dibutyryl adenosine 3',5'-monophosphate (cyclic AMP) (10(-6) molar) to enhance the growth inhibitory effect: the cell replication ceased completely within 2 days after treatment. The growth arrest accompanied a change in cell morphology and was preceded by increases in the cellular concentration of cyclic AMP, adenylate cyclase, and type II cyclic AMP-dependent protein kinase activities as well as a decrease of estrogen binding activity. The results suggest that growth of human breast cancer cells is subject to cyclic AMP-mediated regulation and that arginine may play a specific role in this process.     

Cyclic 3',5'-nucleotide phosphodiesterase: cytochemical localization in cerebral cortex

The distribution of cyclic 3',5'-nucleotide phosphodiesterase activity in rat cerebral cortex was determined by cytochemical methods. The detectable phosphodiesterase activity was localized in postsynaptic (dendritic) nerve endings, most of it immediately adjacent to the synaptic membrane. Most of the postsynaptic nerve endings showed phosphodiesterase activity.     

Adenosine 3',5'-monophosphate waves in Dictyostelium discoideum: a demonstration by isotope dilution--fluorography

The distribution of adenosine 3',5'-monophosphate (cyclic AMP) in fields of aggregating amoebae of Dictyostelium discoideum was examined by a novel isotope dilution-fluorographic technique. Cellular cyclic AMP was visualized by its competition with exogenous 3H-labeled cyclic AMP for high-affinity binding sites on protein kinase immobilized on a Millipore filter used to blot the monolayer. The cyclic AMP was distributed in spiral or concentric circular wave patterns which centered on the foci of the aggregations. These patterns were correlated with those of cell shape change that propagate through the monolayers: cells in regions of high concentrations of cyclic AMP were elongated (presumably moving up a cyclic AMP gradient), whereas those in regions of low cyclic AMP concentrations were randomly directed. The highest cyclic AMP concentrations were about 10(-6)M. The widths of the regions of elevated cyclic AMP were about 0.3 to 1 millimeter which, assuming a wave velocity of 300 micrometers per minute, suggests that a cell signals for about 1 to 3 minutes. These observations support the hypothesis that the aggregation process in Dictyostelium is mediated by the periodic relay of cyclic AMP signals and suggest a simple scheme for the dynamics of the aggregation process.     

Adenosine 3',5'-monophosphate modulates thyrotropin receptor clustering and thyrotropin activity in culture

A biologically active rhodamine conjugate of thyrotropin binds at 4 degrees C to diffusely distributed membrane thyrotropin receptors which patch and become endocytosed into thyroid cells in a temperature-sensitive process. When the cells are first incubated with 8-bromo-cyclic adenosine monophosphate at 37 degrees C, the conjugate also binds to clustered receptors at 4 degrees C. Furthermore, 8-bromo-cyclic adenosine monophosphate reduces the amount of adenosine 3',5'-monophosphate (cyclic AMP) induced by thyrotropin. Hence, increased intracellular cyclic AMP induces receptor patching and reduces the concentration of cyclic AMP normally induced by thyrotropin. This suggests that cyclic AMP acts both as the second messenger of thyrotropin and also as the regulator of the level of thyrotropin receptors.     

Selective reduction of forskolin-stimulated cyclic AMP accumulation by inhibitors of protein synthesis

Inhibiting protein synthesis by incubating C6-2B rat astrocytoma cells with cycloheximide or emetine for periods up to 24 hours caused a progressive decrease in the accumulation of adenosine 3',5'-monophosphate (cyclic AMP) when the cells were challenged for 30 minutes with 100 microM forskolin. In contrast, cholera toxin-stimulated (6 nM, 3 hours) cyclic AMP accumulation was not diminished in cycloheximide-treated cells, and cyclic AMP was only minimally diminished in response to a 30-minute challenge with 10 microM (-)-isoproterenol. These experiments suggest the presence of a previously unrecognized cyclase component, which is essential for forskolin-stimulated cyclic AMP accumulation and has a shorter half-life than the beta-adrenergic receptor, the guanine nucleotide regulatory proteins, or the cyclase catalytic component.     

Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety

Drugs that reduce anxiety may be mediated by cyclic adenosine monophosphate in the brain because (i) potent anxiety-reducing drugs are also potent inhibitors of brain phosphodiesterase activity; (ii) dibutyryl cyclic adenosine monophosphate has the ability to reduce anxiety; (iii) the methylxanthines show significant anxiety-reducing effects; (iv) theophylline and chlordiazepoxide produce additive anxiety-reducing activity; and (v) there is a significant correlation between the anxiety-reducing property of drugs and their ability to inhibit phosphodiesterase activity in the brain.     

A chemoattractant receptor controls development in Dictyostelium discoideum

During the early stages of its developmental program, Dictyostelium discoideum expresses cell surface cyclic adenosine monophosphate (cyclic AMP) receptors. It has been suggested that these receptors coordinate the aggregation of individual cells into a multicellular organism and regulate the expression of a large number of developmentally regulated genes. The complementary DNA (cDNA) for the cyclic AMP receptor has now been cloned from lambda gt-11 libraries by screening with specific antiserum. The 2-kilobase messenger RNA (mRNA) that encodes the receptor is undetectable in growing cells, rises to a maximum at 3 to 4 hours of development, and then declines. In vitro transcribed complementary RNA, when hybridized to cellular mRNA, specifically arrests in vitro translation of the receptor polypeptide. When the cDNA is expressed in Dictyostelium cells, the undifferentiated cells specifically bind cyclic AMP. Cell lines transformed with a vector that expresses complementary mRNA (antisense) do not express the cyclic AMP receptor protein. These cells fail to enter the aggregation stage of development during starvation, whereas control and wild-type cells aggregate and complete the developmental program within 24 hours. The phenotype of the antisense transformants suggests that the cyclic AMP receptor is essential for development. The deduced amino acid sequence of the receptor reveals a high percentage of hydrophobic residues grouped in seven domains, similar to the rhodopsins and other receptors believed to interact with G proteins. It shares amino acid sequence identity and is immunologically cross-reactive with bovine rhodopsin. A model is proposed in which the cyclic AMP receptor crosses the bilayer seven times with a serine-rich cytoplasmic carboxyl terminus, the proposed site of ligand-induced receptor phosphorylation.     

Protein kinase translocation as an early event in the hormonal control of uterine contraction

beta-Adrenergic stimulation with isoproterenol inhibits contractility, increases cyclic adenosine monophosphate (AMP) concentration, decreases the concentration of unsaturated cyclic AMP receptor sites, and increases cyclic AMP-independent kinase in the uterus of ovariectomized rats. The total soluble kinase activity is reduced. The protein kinase activity lost from the cytosol was translocated to the microsomal fraction mostly in a cyclic AMP-independent form, suggesting a particulate substrate for the activated enzyme.     

Cyclic adenosine monophosphate: function in photoreceptors

Inactivation of adenylate cyclase in outer segments of retinal photoreceptor cells is proportional to the bleaching of rhodopsin. Membranes of the outer segments also contain a particulate, light-insensitive phosphodiesterase of high specific activity. In electrophysiological experiments, application of cyclic adenosine monophosphate along with a methylxanthine mimics the effects of illumination on the photoreceptor cell of the compound eye of Limulus.     

Norepinephrine-sensitive adenylate cyclases in rat brain: relation to behavior and tyrosine hydroxylase

Responses of norepiniephrine sensitive adeniosinie 3',5'-monophosphate (cyclic AMP)-generating systems in combined midbrain-striatal slices of four rat strains correlate positively with spontaneous behavioral activity and negatively with levels of midbrain and striatal tyrosine hydroxylase. Responses of cerebral cortical norepinephrine-sensitive cyclic AMP systems correlate negatively with spontaneous behavioral activity antd positively with midbrain and striatal tyrosine hydroxylase. Such correlations were not found with responses of the cyclic AMP- generatinlg systems to isoproterenol, adenosine. veratridine or of an adenosne and norepinephrine combination.     

Cyclic adenosine monophosphate and hypertension in rats

Aortas from spontaneously hypertensive and stress hypertensive rats contained significantly lower intracellular concentrations of cyclic adenosine monophosphate than did their respective controls. Adenylate cyclase activity was normal but was less responsive to stimulation, while phosphodiesterase activity (especially the low Michaelis-Menten constant form) was significantly elevated. Human aortas contained two forms of phosphodiesterase that were similar to those in rat aortas.