The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function. 2002

Andrew H Miller, and Gerald J Vogt, and Bradley D Pearce
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr., Suite 4000, Atlanta, GA 30322, USA. amill02@emory.edu

Previous studies have demonstrated that antidepressants can enhance glucocorticoid receptor (GR) translocation and function, possibly through activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we examined GR function in cells treated with rolipram, a phosphodiesterase (PDE) type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated cells, rolipram alone and in combination with dexamethasone significantly enhanced GR function as measured in both mouse L929 cells and rat C6 glioma cells stably transfected with reporter genes driven by upstream glucocorticoid response elements. Rolipram's facilitation of GR function was reversible by the GR antagonist, RU486, and was associated with reduced cytosloic GR binding, indicating rolipram enhancement of GR nuclear translocation. Finally, rolipram potently augmented GR enhancement by the antidepressant, desipramine. These findings broaden the potential pathways by which PDE type 4 inhibitors can influence cellular function and indicate that these agents may have special utility in disorders associated with impaired GR-mediated feedback inhibition.

UI MeSH Term Description Entries
D010726 Phosphodiesterase Inhibitors Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. Phosphodiesterase Antagonists,Phosphodiesterase Inhibitor,Phosphoric Diester Hydrolase Inhibitors,Antiphosphodiesterases,Inhibitor, Phosphodiesterase
D011965 Receptors, Glucocorticoid Cytoplasmic proteins that specifically bind glucocorticoids and mediate their cellular effects. The glucocorticoid receptor-glucocorticoid complex acts in the nucleus to induce transcription of DNA. Glucocorticoids were named for their actions on blood glucose concentration, but they have equally important effects on protein and fat metabolism. Cortisol is the most important example. Corticoid Type II Receptor,Glucocorticoid Receptors,Glucocorticoids Receptor,Corticoid II Receptor,Corticoid Type II Receptors,Glucocorticoid Receptor,Receptors, Corticoid II,Receptors, Corticoid Type II,Receptors, Glucocorticoids,Corticoid II Receptors,Glucocorticoids Receptors,Receptor, Corticoid II,Receptor, Glucocorticoid,Receptor, Glucocorticoids
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015105 3',5'-Cyclic-AMP Phosphodiesterases Enzymes that catalyze the hydrolysis of CYCLIC AMP to form adenosine 5'-phosphate. The enzymes are widely distributed in animal tissue and control the level of intracellular cyclic AMP. Many specific enzymes classified under this heading demonstrate additional spcificity for 3',5'-cyclic IMP and CYCLIC GMP. 3',5'-Cyclic AMP 5'-Nucleotidohydrolase,3',5'-Cyclic-Nucleotide Phosphodiesterase,CAMP Phosphodiesterase,3',5' Cyclic AMP Phosphodiesterase,3',5'-Cyclic AMP Phosphodiesterase,3',5'-Cyclic Nucleotide Phosphodiesterase,3',5'-Cyclic-AMP Phosphodiesterase,3',5'-Nucleotide Phosphodiesterase,3,5-Cyclic AMP 5-Nucleotidohydrolase,3,5-Cyclic AMP Phosphodiesterase,3',5' Cyclic AMP 5' Nucleotidohydrolase,3',5' Cyclic AMP Phosphodiesterases,3',5' Cyclic Nucleotide Phosphodiesterase,3',5' Nucleotide Phosphodiesterase,3,5 Cyclic AMP 5 Nucleotidohydrolase,3,5 Cyclic AMP Phosphodiesterase,5'-Nucleotidohydrolase, 3',5'-Cyclic AMP,5-Nucleotidohydrolase, 3,5-Cyclic AMP,AMP 5'-Nucleotidohydrolase, 3',5'-Cyclic,AMP 5-Nucleotidohydrolase, 3,5-Cyclic,AMP Phosphodiesterase, 3',5'-Cyclic,AMP Phosphodiesterase, 3,5-Cyclic,Nucleotide Phosphodiesterase, 3',5'-Cyclic,Phosphodiesterase, 3',5'-Cyclic AMP,Phosphodiesterase, 3',5'-Cyclic Nucleotide,Phosphodiesterase, 3',5'-Cyclic-AMP,Phosphodiesterase, 3',5'-Cyclic-Nucleotide,Phosphodiesterase, 3',5'-Nucleotide,Phosphodiesterase, 3,5-Cyclic AMP,Phosphodiesterase, CAMP,Phosphodiesterases, 3',5'-Cyclic-AMP
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D054703 Cyclic Nucleotide Phosphodiesterases, Type 4 A cyclic nucleotide phosphodiesterase subfamily that is found predominantly in inflammatory cells and may play a role in the regulation of CELL-MEDIATED IMMUNITY. The enzyme family includes over twenty different variants that occur due to multiple ALTERNATIVE SPLICING of the mRNA of at least four different genes. Cyclic Nucleotide Phosphodiesterase PDE4 Family,Cyclic Nucleotide Phosphodiesterases, Type 4A,Cyclic Nucleotide Phosphodiesterases, Type 4A5,Cyclic Nucleotide Phosphodiesterases, Type 4B,Cyclic Nucleotide Phosphodiesterases, Type 4C,Cyclic Nucleotide Phosphodiesterases, Type 4D,Cyclic Nucleotide Phosphodiesterases, Type 4D3,PDE4 Phosphodiesterases,PDE4D3 Phosphodiesterase,Phosphodiesterase 4,Phosphodiesterase 4A,Phosphodiesterase 4B,Phosphodiesterase 4C,Phosphodiesterase 4D,Phosphodiesterase IV,Phosphodiesterase-4,Type 4 Cyclic Nucleotide Phosphodiesterase,cAMP-Specific Phosphodiesterase 4A5,Phosphodiesterase 4A5, cAMP-Specific,Phosphodiesterase, PDE4D3,Phosphodiesterases, PDE4,cAMP Specific Phosphodiesterase 4A5
D020889 Rolipram A phosphodiesterase 4 inhibitor with antidepressant properties. ZK-62711,ZK 62711,ZK62711

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