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)

1. Cyclic nucleotide levels and compound action potential magnitudes were measured in frog sciatic nerves following exposure to carbachol, isoprenaline and cyclic nucleotide related substances. 2. The resting cyclic AMP level was 2-4 p-mole/mg protein and the cyclic GMP level was 0-27 p-mole/mg protein in desheathed nerves. 3. Isoprenaline (100 micrometer) caused a twofold increase in cyclic AMP without affecting cyclic GMP levels. Carbachol (100 micrometer) caused a twofold increase in cyclic GMP without affecting cyclic AMP levels. 4. The phosphodiesterase inhibitor theophylline (5 mM) augmented both cyclic AMP and cyclic GMP. 5. The magnitude of the resting or compound action potential was not affected by isoprenaline, carbachol, or phosphodiesterase inhibitors. 6. The cyclic nucleotides and their butyryl derivatives did not affect the magnitude of the resting or compound action potential, either when applied alone or in the presence of a phosphodiesterase inhibitor. 7. In contrast to sympatic tissue we conclude that hormone mediated cyclic nucleotide metabolism in peripheral nerve is unrelated to control of axonal excitability.
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PMID:Modulation of cyclic nucleotide levels in peripheral nerve without effect on resting or compound action potentials. 19 34

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase) is an enzyme associated with central nervous system myelination. Although present in the mammalian peripheral nerve, it is not clear what its role is during myelination nor how the expression of this gene is regulated in the PNS. In this study, CNPase gene expression was studied in the crushed and permanently transected rat sciatic nerve, two models of peripheral nerve neuropathy. The Schwann cells of the crushed nerve initially demyelinate, remain in a non-myelinating condition until active regeneration induces remyelination (10-21 days after injury), whereas those of the permanently transected nerve remain in a quiescent, non-myelinating state after the initial demyelination. An increase of CNPase mRNA levels is observed during degeneration and remains high whether the peripheral nerve is regenerating or not, suggesting transcriptional activation of CNPase mRNA and/or increased CNPase mRNA stability as a response to nerve injury. In contrast, the steady state level of CNPase protein did not increase during degeneration or regeneration suggesting either negative translational regulation of CNPase gene expression or a higher turnover of this protein in the injured peripheral nerve. Furthermore, CNPase activity dropped sharply during early degeneration and remained low in the quiescent cells of the permanently transected nerve while it increased in the regenerating nerve. The results suggest that although transcriptional or post-transcriptional regulation of CNPase gene expression is not dependent on Schwann cell-axonal contact, the activity of CNPase appears to be dependent on myelination and indirectly dependent on the presence of axons in the peripheral nerve.
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PMID:Regulation of 2',3'-cyclic nucleotide phosphodiesterase gene expression in experimental peripheral neuropathies. 127 49

Expression of myelin protein genes by myelinating Schwann cells in vivo is dependent on axonal influences. This report investigated the effect of axons on myelin protein mRNA levels in the central nervous system (CNS). In situ hybridization studies of rat spinal cord sections localized mRNAs encoding proteolipid protein (PLP) and myelin basic protein (MBP) 20 and 40 days after unilateral rhizotomy. Compared with control tissue, hybridization intensity was reduced in transected tissue, but there was little change in the number of oligodendrocytes labeled. Cellular RNA was extracted from transected and age-matched control optic nerves 5, 10, 20, and 40 days after surgery, and levels of the following mRNAs were determined by slot blot procedures: PLP, MBP, myelin-associated glycoprotein (MAG), and 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP). In transected nerves, PLP and MBP mRNA levels were approximately 85%, 45%, and 25% of control values at 5, 20 and 40 days posttransection, respectively. Axonal transection had a lesser effect on CNP and MAG mRNA levels, which declined to approximately 60% of control levels at 40 days. Immunocytochemical studies indicated that the number of oligodendrocytes was not decreased 40 days after optic nerve transection. These data demonstrate that axons modulate myelin protein mRNA levels in oligodendrocytes. In contrast to Schwann cells, however, oligodendrocytes continue to express significant levels of myelin protein mRNA in vivo following loss of axonal contact.
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PMID:Axons modulate myelin protein messenger RNA levels during central nervous system myelination in vivo. 170 Jan 37

Experiments were carried out in the opener muscle of the claw of small crayfish. After pretreatment of the preparation with serotonin (5-HT), application of the membrane permeant analogue of adenosine 3',5'-cyclic monophosphate (cAMP), 8-bromoadenosine 3',5'-monophosphate was capable of evoking reversibly repetitive discharges in the inhibitory and excitatory axon. Reducing phosphodiesterase activity with application of either 3-isobutyl-1-methylxanthine or theophylline also elicited repetitive axonal discharges after 5-HT treatment. Moreover, application of forskolin dissolved in ethanol caused repetitive axonal discharges. The chemically induced presynaptic action potentials were detected mainly by their postsynaptic effects, i.e. by recording inhibitory and excitatory postsynaptic currents in voltage-clamped muscle fibres. In addition, nerve spikes were recorded extracellularly. It is concluded that 5-HT and intraaxonal cAMP alter membrane properties of the efferent axons innervating crayfish muscle.
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PMID:Repetitive axonal discharges elicited by serotonin and intracellular adenosine 3',5'-cyclic monophosphate in the crayfish neuromuscular junction. 243 86

A particulate preparation was obtained by low speed centrifugation of guinea pig cerebral cortical homogenates prepared with a Krebs-Henseleit buffer. Light microscopic examination, using a reflected light differential interference contrast system, reveals the presence of intact neurons, axonal fragments, glial cells, and erythrocytes along with an abundance of small spherical entities (diameter about 1.1 micron) and snowman-shaped entities (diameter of larger sphere about 1.1 micron, diameter of attached smaller sphere about 0.6 micron). Many unattached smaller spherical entities are also present (diameter about 0.6 micron). Pressure filtration through 5- or 10-micron Millipore filters, followed by low speed centrifugation and resuspension, removes most of the larger entities to afford a suspension composed mainly of the small spherical and snowman-shaped entities. Electron microscopic examination reveals the presence of many synaptosomes with attached resealed postsynaptic entities. It is proposed that these correspond to the snowman-shaped entities to be termed synaptoneurosomes. Accumulations of cyclic AMP elicited by 2-chloroadenosine and histamine, and by combinations of 2-chloroadenosine, histamine, norepinephrine, and forskolin, are lower in filtered than in unfiltered preparations, whereas accumulations elicited by forskolin are unchanged. Levels of adenylate cyclase are reduced by filtration, whereas levels of phosphodiesterase are unchanged. Filtration reduces levels of markers for whole cells and endothelial cells, whereas neuronal markers such as acetylcholinesterase activity and norepinephrine uptake are increased. Levels of S-100 protein, a marker for glial cells, are not significantly decreased. There is no apparent change in the density of many receptors or ion channels. Levels of A1-adenosine and H1-histamine receptors are increased, whereas levels of so-called peripheral benzodiazepine-binding sites are decreased.
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PMID:Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems, receptors, and enzymes. 299 84

Our previous investigation indicates that forskolin, a robust activator of adenylate cyclase, promotes sensory nerve regeneration in amphibians. The present study was designed to determine if forskolin had a similar effect in mammals. We also wished to test the hypothesis that cyclic AMP modulates nerve regeneration by comparing the effects of chronically infused forskolin with the effects of infused dibutyryl cyclic AMP, 8-bromo cyclic AMP, and the phosphodiesterase inhibitor, theophylline. Our results indicated that all agents promoted some aspect of regeneration. The two which presumably generated the largest increase in cyclic AMP concentration, forskolin and 8-bromo cyclic AMP, had the most profound effect on axonal elongation. All agents decreased the time to sprout initiation, but theophylline produced the largest decrease and its effect was mimicked by caffeine, a methylxanthine with limited ability to inhibit phosphodiesterase. This suggests that sprout formation may be triggered by an increase in intraaxonal free Ca2+, possibly modulated by cyclic AMP. The role of cyclic AMP in axonal elongation remains to be determined, but may be associated with stimulation of protein synthesis in the nerve cell body.
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PMID:Chronic infusion of agents that increase cyclic AMP concentration enhances the regeneration of mammalian peripheral nerves in vivo. 302 33

Myelinated axons were isolated by flotation from bovine pons, middle cerebellar peduncle, cervical spinal cord and three regions of the subcortical white matter. The myelinated axons were osmotically and mechanically shocked, followed by fractionation on a linear 15% sucrose to 45% sucrose density gradient. Axolemma-enriched fractions (AEF) found in the 28% to 32% sucrose region of the gradient from brainstem and cord white matter had high acetylcholinesterase (AChE) while little or nil AChE activity was found in corresponding AEF derived from the subcortical white matter. Morphologically, the subcortical white matter from all regions contained a heterogeneous population of well-myelinated to thinly myelinated axons, while brainstem and cord regions contained a more homogeneous population of well-myelinated axons. Histochemical analysis of AChE localized this enzyme to axonal elements. The AEF derived from any white matter source had similar polypeptide compositions. AEF derived from subcortical white matter contained two-fold more myelin basic protein and a three-fold greater content of 2' 3' cyclic nucleotide 3' phosphodiesterase (CNP) compared with AEF derived from well myelinated white matter. We conclude that the purity of the AEF is related to the degree of myelination of the white matter from which the AEF is derived. Homogeneously well myelinated white matter (pons, cerebellar peduncle, cervical spinal cord) yields the highest purity AEF, as judged by the low CNP and myelin basic protein content and highest enrichment in AChE specific activity.
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PMID:Isolation and characterization of axolemma-enriched fractions from discrete areas of bovine CNS. 340 70

The effects of intravitreous injections of colchicine on the myelination of the optic nerve were studied in rabbits at different times during development using biochemical and morphological techniques. Myelin basic protein concentrations and 2',3-cyclic nucleotide 3'-phosphodiesterase activities were affected in a similar way by colchicine treatment and reflected the degree of myelination of the tissue. During early development, colchicine produced axonal degeneration and secondary demyelination (Wallerian degeneration). Later, axonal and myelin abnormalities were more variable. Some demyelination was observed amd myelin formation also may have been inhibited. Thus, the effect of colchicine was proportional to the degree of optic nerve and retinal maturation (the youngest being the most sensitive) and, to a lesser extent, to the dosage, Under conditions used for this study, no remyelination was observed. In adult animals, no lesions could be detected histologically one to four months after injection of colchicine, Thus, intravitreous administration of colchicine is a useful chemical technique for producing Wallerian degeneration in optic nerves of young developing rabbits.
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PMID:Effects of colchicine on myelination of rabbit optic nerve: a biochemical study. 627 73

The role of prejunctional purinoceptors (P1-subtype) in the control of ATP-release from inhibitory motoneurons was investigated electrophysiologically, by studying fast purinergic inhibitory junction potentials (IJPs) in guinea-pig ileal circular muscle. Pressure ejections of adenosine and ATP (but not of alpha,beta-methylene ATP) onto circular muscle depressed the amplitude of fast IJPs, indicating the presence of prejunctional P1-purinoceptors. An adenosine (A1/2)-receptor antagonist, theophylline (10(-8)-10(-4) M), increased the amplitude of fast IJPs in a dose-related manner (EC50 = 17.5 microM), suggesting the existence of a basal 'adenosine tone' that regulated ATP-release from ileal motoneurons. However, three methylxanthine derivatives, caffeine (10(-8)-10(-4) M), 3-isobutyl-1-methylxanthine (IBMX; 10(-8)-10(-4) M) and the potent A1-receptor antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (DPCPX; 10(-8)-10(-4) M), failed to potentiate fast IJPs and placed in doubt the existence of this inhibitory adenosine tone. Caffeine and IBMX, but not DCPCX, hyperpolarised ileal circular muscle in a dose-related manner and reduced IJP-amplitude; DPCPX did not alter the amplitude of IJPs. The non-specific inhibitor of phosphodiesterases, Ro-20-1724 (5 x 10(-7)-5 x 10(-5) M), increased the amplitude of fast IJPs, mimicking the actions of theophylline. To this extent, facilitation of inhibitory transmission appeared to involve phosphodiesterase inhibition and modification of intra-axonal cAMP levels and phosphorylation of intra-axonal protein kinases. The phenomenon of IJP rundown, presumed to be a manifestation of prejunctional autoinhibition, was studied using theophylline and DPCPX as A1-receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prejunctional autoinhibition of purinergic transmission in circular muscle of guinea-pig ileum; a mechanism distinct from P1-purinoceptor activation. 802 18

The cyclic AMP (cAMP) system plays a critical role in olfactory learning in the fruit fly, Drosophila melanogaster, as evidenced by the following: [1] The dunce gene encodes a form of cAMP phosphodiesterase (PDE). Flies carrying mutations at this gene show reduced PDE activity, high cAMP levels, and deficits in olfactory learning and memory [2]. The rutabaga gene encodes one type of adenylyl cyclase (AC) similar in properties to the Type I AC characterized from vertebrate brain. This enzyme is activated by G-protein and Ca++ and has been postulated to be a molecular coincidence detector, capable of integrating information from two independent sources such as the conditioned stimulus (CS) and the unconditioned stimulus (US) delivered to animals during Pavlovian conditioning. Rutabaga mutant flies are deficient in AC activity and show behavioral defects similar to those exhibited by dunce mutants [3]. Flies carrying mutations in the gene (DC0) that encodes the catalytic subunit of protein kinase A (PKA), the major mediator of cAMP actions, show alterations in learning performance and a loss in PKA activity. All three genes are expressed preferentially in mushroom bodies, neuroanatomical sites that mediate olfactory learning. Interestingly, the PDE and the catalytic subunit of PKA are found primarily in axonal and dendritic compartments of the mushroom body cells, whereas the AC is found primarily in the axonal compartment. The reason for this differential compartmentalization is unclear, although the hypothetical role of AC as coincidence detector would predict that CS and US stimuli are integrated in the axonal compartment. These observations suggest that cAMP is a dominant second messenger utilized by mushroom body cells to modulate their physiology while the animal is learning and consolidating memory. However, many other types of molecules are likely involved in the physiological alterations that occur in these cells during learning, including cell surface proteins, transcription factors, and synaptic proteins.
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PMID:The cyclic AMP system and Drosophila learning. 856 40


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