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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
1995-11-29
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pubmed:abstractText |
Prostaglandin E2 produces a transient increase in the intracellular concentration of cAMP in a human promonocytic cell line (U937). The temporal pattern consists of a rapid increase followed by a gradual decline to a new steady state. The decline phase coincides with an increase in the activity of a high affinity form of cAMP phosphodiesterase (PDE). Immunoprecipitation with specific antibodies revealed that the activated enzyme is a variant of PDE-4D. To confirm this observation, three isoforms of human PDE-4 (A, B, and D) were cloned and expressed in Sf9 cells with recombinant baculovirus infection. The activity of only one of the isoforms (PDE-4D3) increased after incubation with the catalytic subunit of protein kinase A and Mg-ATP. Hydrolytic activity of human PDE-4D3 was dependent on Mg2+. Before phosphorylation, the concentration-response curve for Mg2+ was biphasic and ranged from 0.1 to 100 mM. Phosphorylation of PDE-4D3 by protein kinase A produced a monophasic Mg2+ response curve (0.5 Vmax = 0.2 mM). Phosphorylation of PDE-4D3 increased the sensitivity of the enzyme to inhibition by RS-25344 (approximately 100-fold) and RS-33793 (approximately 330-fold). Thus, phosphorylation of PDE-4D3 induces an apparent conformation change that increases maximum velocity and sensitivity to inhibition by some analogues of nitraquazone. These observations provide the basis for a novel pharmacological strategy that targets an activated form of PDE in human leukocytes. Selective PDE-4D3 inhibitors may have useful anti-inflammatory properties with fewer adverse side effects than other PDE-4 inhibitors.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3',5'-Cyclic-AMP Phosphodiesterases,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic Nucleotide...,
http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Magnesium,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphodiesterase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Diester Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridazines,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/RS 25344,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0026-895X
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
616-22
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:7476886-3',5'-Cyclic-AMP Phosphodiesterases,
pubmed-meshheading:7476886-Cyclic AMP,
pubmed-meshheading:7476886-Cyclic Nucleotide Phosphodiesterases, Type 4,
pubmed-meshheading:7476886-Dinoprostone,
pubmed-meshheading:7476886-Enzyme Activation,
pubmed-meshheading:7476886-Humans,
pubmed-meshheading:7476886-Intracellular Fluid,
pubmed-meshheading:7476886-Isoenzymes,
pubmed-meshheading:7476886-Kinetics,
pubmed-meshheading:7476886-Magnesium,
pubmed-meshheading:7476886-Monocytes,
pubmed-meshheading:7476886-Phosphodiesterase Inhibitors,
pubmed-meshheading:7476886-Phosphoric Diester Hydrolases,
pubmed-meshheading:7476886-Phosphorylation,
pubmed-meshheading:7476886-Precipitin Tests,
pubmed-meshheading:7476886-Pyridazines,
pubmed-meshheading:7476886-Quinazolines,
pubmed-meshheading:7476886-Recombinant Proteins,
pubmed-meshheading:7476886-Sensitivity and Specificity,
pubmed-meshheading:7476886-Tumor Cells, Cultured
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pubmed:year |
1995
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pubmed:articleTitle |
Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3.
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pubmed:affiliation |
Institute of Pharmacology, Syntex Discovery Research, Palo Alto, California 94304, USA.
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pubmed:publicationType |
Journal Article
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