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)

Unstimulated bullfrog sympathetic ganglia were studied in vitro by intracellular and extracellular recording methods. In 80% of the cells impaled with K citrate microelectrodes, caffeine caused initial hyperpolarization (ICH) followed by rhythmic membrane hyperpolarization (RMH). Four different patterns of rhythmicity were observed, the most common being a regular beating pattern. RMH frequency depended on both caffeine and Ca2+. Tetraethylammonium reduced RMH amplitude, but did not affect frequency. Caffeine effects on cyclic AMP are not responsible for RMH since neither dibutyryl cyclic AMP nor phosphodiesterase inhibitors elicited RMH. However, the anion in the microelectrode filling solution is critical to both the incidence and amplitude of RMH, the order of effectiveness being: citrate much much greater than glutamate, acetate and chloride. In cells impaled by electrodes filled with K thiocyanate or K iodide, caffeine also caused large amplitude hyperpolarizing oscillations of membrane potential, suggesting that the effectiveness of citrate is not due to Ca2+ chelation. High gain extracellular DC recording revealed no sign of caffeine ICH, RMH or any hyperpolarizing effects. The absence of signs of caffeine hyperpolarization with extracellular recording has several interpretations, and these are discussed.
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PMID:Some new observations on caffeine-induced rhythmic hyperpolarization in frog sympathetic ganglion cells. 180 Jul 97

In studies on the uptake and metabolism of [14C]glutamate by Bradyrhizobium japonicum bacteroids we found that, in the presence of unlabeled malate, succinate or alpha-ketoglutarate, substantial label was recovered in alpha-ketoglutarate in the reaction mixtures. As much as 30% of the total 14C supplied could be found in alpha-ketoglutarate in the reaction mixtures after 30 min and this occurred in the absence of detectable labeling of alpha-ketoglutarate in the cells. The labeling of alpha-ketoglutarate was almost completely inhibited by aminooxyacetate (aminotransferase inhibitor). Direct assay of aspartate aminotransferase in intact bacteroids was possible in the presence of very dilute Triton X-100 (less than or equal to 0.02%, w/v). The response of the aminotransferase to detergent was similar to the response of phosphodiesterase, a periplasmic marker, and different from malate dehydrogenase and beta-hydroxybutyrate dehydrogenase, cytoplasmic markers. Comparison of maximum enzyme activity assayable with intact bacteroids and maximum activity in sonicated bacteroids indicated that about half of the total cellular aminotransferase activity was accessible to the external medium. The combined labeling and enzyme assay results indicated that B. japonicum bacteroids have a capability for transamination in the periplasmic space. Although this may not be important in the transfer of reducing equivalents from host cytoplasm to bacteroids in nodules, the transamination capability may facilitate the acquisition of metabolites by free-living bacteria.
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PMID:Periplasmic metabolism of glutamate and aspartate by intact Bradyrhizobium japonicum bacteroids. 197 84

The present work shows the existence of adenosine-dependent cyclic adenosine monophosphate (AMP) accumulation in the chick optic tectum. When tecta from 18-day-old embryos were incubated with the phosphodiesterase inhibitor IBMX and RO 20-1724, the cyclic AMP level increased from 39.2 to 73.3 and 285.5 pmol/mg protein, respectively. The high level obtained with RO 20-1724 could be inhibited by increasing concentrations of IBMX or by adenosine deaminase, but not by dipyridamole. 2-Chloroadenosine promoted a dose-dependent cyclic AMP accumulation in tecta incubated with RO 20-1724 and adenosine deaminase. This effect was blocked by IBMX and varied substantially during the development of the tissue. The degree of stimulation increased after day 11 of incubation, attaining maximal levels on day 14. The effect of 2-chloroadenosine remained constant until day 18, a period when both the protein content and the basal cyclic AMP levels are increasing in the developing tectum. The cyclic AMP increase elicited by 2-chloroadenosine was greatly reduced in tecta from 20-day-old embryos and 2-day-old chicks. The putative transmitters glutamate and glycine and the neurotransmitter analogs isoproterenol and carbachol had no stimulatory effect on the cyclic AMP accumulation of tecta from 10- and 17-day-old embryos.
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PMID:Development of adenosine-dependent cyclic AMP accumulation in the avian optic tectum. 244 20

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.
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PMID:Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. 255 65

Syntheses of some metabolites of ubiquinone and of related compounds are described. Idebenone (QSA-10), a methyl-dimethoxy-benzoquinone bearing an omega-hydroxydecyl side chain in 3-position, restored the oxidation of succinate and of NADH in ubiquinone-depleted mitochondrial preparations and showed a stabilizing effect on lysosomal membranes and an inhibitory effect on cAMP-phosphodiesterase. It inhibited lipid peroxidation in canine brain mitochondria and in microsomes from canine brain and rat liver. Administered orally to rats, it increased the respiratory control index for glutamate and succinate oxidation but had no effect on the ADP/O2 ratio. Pharmacological effects of idebenon are also briefly discussed.
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PMID:[Synthesis and biochemical actions of idebenone and related compounds. Ubiquinone and related compounds, XL]. 266 30

In urethane anesthetized rats, the intracerebroventricular (icv.) microinjection of sodium glutamate or KCl induced cardiac arrhythmias. These cardiac rhythm disorders could be prevented by the icv. administration of imidazole. The i.v. injection of the same doses of imidazole elicited cardiac arrhythmias. The antiarrhythmic activity of imidazole is probably due to its ability to stimulate phosphodiesterase activity, which leads to a decrease in cGMP and/or cAMP cerebral levels.
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PMID:Central antiarrhythmic effects of imidazole in anesthetized rats. 286 55

In the present experiments we have examined the effect of N-ethylmaleimide (NEM) on the release of [3H]glutamate from rat hippocampal slices. Pretreatment of slices with NEM in a concentration between 50 microM and 200 microM, can inhibit the GTP-binding protein (Ni) that transmits receptor signals into inhibitions of adenylate cyclase, without affecting the Ns-protein, that transmits signals into stimulation of the cyclase, or the cyclase. The adenosine receptor agonist R-phenylisopropyladenosine (R-PIA, 1 microM) caused an approximately 50% inhibition of the evoked [3H]glutamate release. This effect was completely prevented by NEM treatment, which did not affect basal or stimulated release of the amino acid. By contrast, the effect of R-PIA was unaffected by adding an adenylate cyclase stimulator (forskolin 1 microM) and a phosphodiesterase inhibitor (rolipram, ZK 62.711, 30 microM) which raised the cyclic AMP content of the slices approximately 10-fold. In conclusion, these results suggest that the adenosine receptor that mediates prejunctional inhibition of glutamate release is coupled to a protein similar to the Ni-protein, but that another effector than adenylate cyclase is involved.
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PMID:Effects of N-ethylmaleimide and forskolin on glutamate release from rat hippocampal slices. Evidence that prejunctional adenosine receptors are linked to N-proteins, but not to adenylate cyclase. 287

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

Normal human erythrocytes were fractionated in a density gradient. Capacity to metabolize polyphosphoinositides was compared in young (least dense) and old (most dense) cells. Polyphosphoinositide synthesis was assessed by following the incorporation of radioactivity from [gamma-32P]ATP into the 1-(3-sn-phosphatidyl)-D-myo-inositol 4-phosphate (PtdIns4P) and 1-(3-sn-phosphatidyl)-D-myo-inositol 4,5-bisphosphate (PtdIns(4,5)P2) of isolated membranes. There was no significant age-dependent change in the ability to synthesize PtdIns4P and PtdIns(4,5)P2 or in the response of the PtdIns and PtdIns4P kinases to Mg2+. The cytosolic Mg2+-dependent PtdIns(4,5)P2 phosphatase was also unaffected by age. The membrane cation-independent PtdIns4P phosphatase activity declined slightly (12%). Therefore, the capacity to catalyse the interconversion among the three phosphoinositides in the membrane is retained throughout the life of the erythrocyte. The Ca2+-dependent polyphosphoinositide phosphodiesterase activity in the membranes was reduced in old cells (57%) to the same extent as the glutamate-oxaloacetate transaminase activity used as an index of cell age. Thus, irreversible loss of polyphosphoinositide from the membrane by the action of this diesterase (prevented in healthy cells by the active maintenance of a very low intracellular Ca2+ concentration) is not very likely even in senescent cells when Ca2+ homeostasis begins to fail.
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PMID:Polyphosphoinositide metabolism in aging human erythrocytes. 300 May 48

Alteration of residues 82-84 in the alpha-helix that links the two halves of calmodulin results in a differential effect on activator activity. Previous studies (Lukas, T. J., Burgess, W. H., Prendergast, F. G., Lau, W., and Watterson, D. M. (1986) Biochemistry 25, 1458-1464) indicated the importance of positive charge clusters in the calmodulin-binding protein, myosin light chain kinase. This suggested the possible importance of complementary negative charge clusters in calmodulin. By using an efficient cassette mutagenesis approach and a synthetic calmodulin gene (Roberts, D. M., Crea, R., Malecha, M., Alvarado-Urbina, G., Chiarello, R. H., and Watterson, D. M. (1985) Biochemistry 24, 5090-5098), this possibility was directly addressed by engineering a new calmodulin, VU-8 calmodulin, in which the glutamate cluster at residues 82-84 in the synthetic gene product (VU-1 calmodulin) was replaced by three lysines. VU-8 calmodulin activated phosphodiesterase to the same maximal extent as VU-1 calmodulin, although there was an alteration in the concentration of calmodulin required for half-maximal stimulation. In contrast, myosin light chain kinase was activated to only 30% of maximal activity and NAD kinase was not activated. These results provide insight into the functional role of the unusual central helix structure found in the calmodulin family of proteins and indicate that different, although possibly overlapping, chemical complementarities are employed in the interaction between calmodulin and its various physiological targets.
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PMID:Site-specific mutagenesis of the alpha-helices of calmodulin. Effects of altering a charge cluster in the helix that links the two halves of calmodulin. 302 8


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