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 46 kD isoform of the 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPI) was expressed in HeLa cells by transfection of its cDNA clone. The distribution of this polypeptide as mapped by indirect immunofluorescence and conventional epifluorescence microscopy appeared diffuse and generally uniform throughout the cytoplasm. Confocal microscopic imaging and analysis of pseudocolored images confirmed this distribution but also revealed that there was a high concentration of CNPI near the plasma membrane of the cell. This pattern is very similar to that observed by immunoelectronmicroscopy of myelinating oligodendrocytes (Trapp et al.: J Neurochem 51:859-868, 1988; Braun et al.: J Neurosci 8: 3057-3066, 1988). These results suggest that CNP may interact with a membrane-associated molecule that is not unique to oligodendrocytes.
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PMID:Expression of the oligodendrocyte marker 2'3'-cyclic nucleotide 3'-phosphodiesterase in non-glial cells. 216 33

2',3'-Cyclic nucleotide-3'-phosphodiesterase (CNP1 and CNP2 with Mr of 46,000 and 48,000, respectively) is the major enzyme of central nervous system myelin. It is associated with oligodendroglial plasma membrane and uncompacted myelin (myelin-like fraction), which are in contact with glial cytoplasm. Proteins of the myelin-like fraction were labeled with [3H]palmitic acid in brain slices from 17-day-old rats and immunoprecipitated with anti-CNP antiserum. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography of immunoprecipitated material revealed intense acylation of CNP1 and CNP2, and radioactivity was released by hydroxylamine. Palmitic acid was covalently bound to CNP because radioactivity was not removed by extraction of immunoprecipitated CNP with organic solvent or by boiling in sodium dodecyl sulfate and dithiothreitol. However, treatment of immunoprecipitated CNP with (a) hydroxylamine-released palmitohydroxamate and palmitic acid, (b) sodium borohydride-released hexadecanol, and (c) methanolic-KOH-released methyl palmitate. Synthesis, acylation, or transport of CNP was not affected by monensin or colchicine. However, acylation of CNP was inhibited 24-32% by cycloheximide. These results provide conclusive evidence that CNP1 and CNP2 are fatty acid acylated with palmitate through a thioester linkage and is posttranslationally modified sometime after synthesis.
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PMID:2',3'-cyclic nucleotide-3'-phosphodiesterase in the central nervous system is fatty-acylated by thioester linkage. 216 18

"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

Myelination was studied between 15 and 135 days postnatally in peripheral nerves of myelin deficient (mld) mice and in unaffected littermates. The nerve weights were not affected by the mutation and showed a 4-fold increase during the developmental period studied. The amounts of myelin present in peripheral nerves, as shown by biochemical and morphological techniques, were slightly reduced in mld in comparison to control mice. In controls, the concentration of myelin doubled during the investigation period. The increase of myelin basic protein (MBP) in total nerve homogenate paralleled the deposition of myelin, but the MBP concentration remained constant in normal myelin. In contrast, in mld myelin MBP concentrations were extremely low until 60 days of age and increased thereafter to reach almost normal values at 135 days. Similarly, the amounts of myelin isolated at 85 and 135 days were normal. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP; EC 3.1.4.37), the myelin-specific enzyme, showed normal specific activities in mld nerves. In mld and control myelin, CNP-specific activities decreased during development suggesting a preferential localization of CNP in Schwann cell plasma membranes. In contrast to the central nervous system, other myelin proteins were not altered in mld peripheral nervous system (PNS) and the very low MBP content had no severe repercussions on the composition and structure of the myelin sheath. Furthermore, Schwann cells appeared normal in mld PNS. Nevertheless, more subtle alterations could be detected. Slightly decreased amounts of myelin were observed in young mld mice and preliminary results indicate discrete alterations of the myelin periodicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myelin basic protein deficit in the PNS of mld mutant mice recovers during development. 620 45

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP, EC 3.1.4.37) has been isolated from rat brain myelin by chromatography on successive columns of phenyl-Sepharose CL-4B, CM-Sepharose CL-6B, and 8-(6-aminohexyl) amino-2'AMP-Sepharose 4B. From 15 g of rat brain, approximately 400 micrograms of pure CNP was obtained, with a specific activity of 1,200 (2',3'-cyclic AMP) units/mg protein. The Km of the rat enzyme was 3.7 mM, using 2',3'-cAMP as the substrate. Isoelectric focusing of the enzyme indicated a broad isoelectric range of 8.5-9.0. On SDS polyacrylamide gels, rat CNP appears as two protein bands of approximately 48,000 and 50,000 M.W., with an upper band intensity of about 1/10 that of the lower band. The relative intensities of the bands for CNP and the molecular weights correspond to the Wolfgram proteins W1 and W2 described by other investigators. The amino acid analysis of the purified rat enzyme compared favorably with reported determinations for the bovine enzyme and also with reported values for the rat Wolfgram proteins W1 and W2.
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PMID:Purification of rat 2',3'-cyclic nucleotide 3'-phosphodiesterase. 625 58

Preincubation of AtT-20 mouse pituitary tumour cells with the phorbol ester PMA resulted in a concentration-dependent inhibition of CNP-stimulated cyclic GMP production. The phorbol ester analogue 4 alpha phorbol had no inhibitory effect and 24 h preincubations with PMA resulted in a characteristic down-regulation of the response indicating that the inhibitory actions were mediated via the activation of protein kinase C. Forskolin in the presence of the phosphodiesterase inhibitor IBMX stimulated intracellular cyclic AMP concentrations by up to eight fold, but did not alter basal nor CNP-stimulated cyclic GMP production. These results indicate that CNP-stimulated guanylate cyclase activity associated with the GC-B natriuretic peptide receptor expressed in AtT-20 cells is inhibited by protein kinase C.
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PMID:Phorbol ester activation of protein kinase C inhibits CNP-stimulated cyclic GMP production in the mouse AtT-20 pituitary tumour cell line. 752 63

The production of cyclic GMP (cGMP) induced by acetylcholine and other stimuli was studied in bovine chromaffin cells. Acetylcholine increased intracellular cGMP in a transitory (peak at 2 min) and concentration-dependent manner (estimated half maximal increase, EC50 = 61 +/- 5 microM). NG-nitro-L-arginine methyl ester (NAME) inhibited such a rise in cGMP with a half maximal inhibitory concentration (IC50) of 231 +/- 55 microM. The acetylcholine-induced increase in cGMP was also inhibited by a calmodulin antagonist (calmidazolium, 30 microM) and by the absence of extracellular calcium. Other agents that strongly increased cytosolic calcium concentration ([Ca2+]i) as acetylcholine did, such as the nicotinic-agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), high-KCl (50 mM), and ionomycin, also caused a rise in cGMP in cultured bovine chromaffin cells. Veratridine, an activator of sodium channels, produced a slowly developing calcium increase and no significant cGMP production. The muscarinic-agonist, muscarine, failed to increase cytosolic calcium, and was the weakest stimulator of cGMP production. cGMP formation, induced by sodium nitroprusside (SNP, 100 microM) and by C-type natriuretic peptide (CNP, 100 nM), was inhibited by 30-40% by increasing [Ca2+]i with ionomycin. This inhibition was abolished by calmidazolium (30 microM) and by the absence of calcium in the extracellular medium. In conclusion, bovine chromaffin cells synthesize nitric oxide (NO) to activate guanylate cyclase in response to several stimuli, which increase [Ca2+]i. Moreover, the increase in [Ca2+]i also stimulates a Ca2+/calmodulin phosphodiesterase, which could down-regulate the levels of cGMP in these cells.
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PMID:Activation of NO:cGMP pathway by acetylcholine in bovine chromaffin cells. Possible role of Ca2+ in the down-regulation of cGMP signaling. 757 35

CNP (2,3'-cyclic nucleotide 3'-phosphodiesterase) is the earliest myelination specific polypeptide to be synthesized by oligodendrocytes (OLs). When non-myelinating "naive" cells are transfected with the rat CNP cDNA, CNP accumulates intracellularly in a punctate manner, as well as at the plasma membrane. Filopodia and processes, like those of OLs become elongated and more numerous, and are filled with this protein. Post-translational isoprenylation of the terminal C-T-I-I sequence with either farnesyl or geranylgeranyl is essential for this phenomenon. In contrast, the non-isoprenylated C397S mutant is homogeneously distributed throughout the cytoplasm and does not markedly affect cellular morphology. We have synthesized CNP and the C397S mutant in vitro and have shown that isoprenylation is essential for the binding of newly synthesized CNP to myelin.
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PMID:Isoprenylation of brain 2',3'-cyclic nucleotide 3'-phosphodiesterase modulates cell morphology. 788 18

We conditionally immortalized jimpy primary oligodendrocytes (ODCs) with the temperature-sensitive SV40 large T antigen. Two cell lines (clones JP1.1 and JP1.2) were generated that expressed a number of ODC markers. Both jimpy cell lines expressed DM20 mRNAs at the proliferative temperature of 34 degrees C, but not at the "differentiation" temperature of 39 degrees C. Interestingly, at 39 degrees C neither cell line appeared to differentiate further, and neither survived longer than 7 days, in contrast to other ODC cell lines from normal animals that survive many weeks at 39 degrees C. These findings are not consistent with the notion that a PLP/DM20 gene product is the cause of oligodendrocyte cell death in jimpy, since neither jimpy cell line survived at 39 degrees C, and neither line expressed PLP or DM20 proteins. Analysis of the expression of the CNP (2'3' cyclic nucleotide-3'-phosphodiesterase) gene indicated that in both cell lines only one of the two CNP isoforms was expressed at 34 degrees C. Raising the temperature to 39 degrees C caused a greater reduction in the levels of CNP protein than CNP mRNA. Taken together, the DM20 and CNP data suggest that at least some of the decline in myelin/oligodendrocyte components observed in jimpy brains may not be due simply to fewer mature oligodendrocytes, but also to a down regulation of expression of these genes at several levels including transcriptional and post-transcriptional events. Our results provide two cell models for in vitro investigations into the nature of the jimpy mutation at several cellular and molecular levels.
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PMID:Temperature-dependent regulation of PLP/DM20 and CNP gene expression in two conditionally-immortalized jimpy oligodendrocyte cell lines. 913 Feb 45

Regeneration after an injury in the Central Nervous System is dependent on intrinsic and extrinsic factors. Among the latter are the reactions of glial cells. Using the model of total section of adult rat spinal cord, we have studied the spatial and temporal responses of astrocytes and oligodendrocytes to the lesion of spinal cord axons. We studied at molecular and cellular levels the specific markers GFAP (glial fibrillary acidic protein) for the astrocytes, CNP (2'-3' cyclic 3' nucleotide phosphodiesterase) which is principally expressed by immature oligodendrocytes, and MBP (myelin basic protein) implicated later in the myelin compaction, and which is more specific of mature oligodendrocytes. After injury, all astrocytes, but more markedly those of the grey matter, reacted by an increase of GFAP messenger and protein. This increase was very rapid for messenger, and peaked at 3 days. This increase was more protracted for the protein and persisted after 3 weeks. Messenger increase is more marked and more protracted below than above the lesion. Oligodendrocytes also reacted quickly by an increase of CNP and MBP messengers. For CNP, both messenger and protein increased rapidly and returned to control level after 1 week. MBP showed the same time course of changes, with lower and slower decrease above the lesion. Counts of oligodendrocytes showed that the percentage of the less mature form (light oligodendrocytes) increased dramatically above and below the lesion. After 1 week, above the lesion, this percentage was well below that of the control, whereas below the lesion, it reverted to control value. These results indicate that, following a lesion, astrocytes react quickly and intensely, but more so below the lesion; oligodendrocytes resume a sequence of maturation which is eventually completed above the lesion where remyelinisation can occur and which is prematurely interrupted below the lesion. However, intact oligodendrocytes persist below the lesion, where they constitute a potential for remyelinisation of regenerated and/or transplanted axons.
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PMID:Astrocytes and oligodendrocytes reactions after a total section of the rat spinal cord. 947 54


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