Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
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PMID:Effect of recombinant human granulocyte/macrophage colony-stimulating factor on neutrophil superoxide production. 166 43

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76

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

In several cell types, the expression of the proenkephalin (PEnk) gene is enhanced after activation of protein kinase A. In the present study, astroglial cells cultured from rat cortex were used to investigate whether protein kinases A and C can act in a synergistic manner on the endogenous proenkephalin gene. The activator of protein kinase C tetradecanoylphorbolacetate (0.001-1 microM) increased the level of proenkephalin-mRNA in a concentration dependent manner. When used together with the phosphodiesterase inhibitor Rolipram (1 microM), the effect of tetradecanoylphorbolacetate (0.01 microM) was potentiated. 8-Bromoadenosine 3',5'-cyclic monophosphate (0.01-1 mM) also enhanced the expression of the proenkephalin gene. When used together with tetradecanoylphorbolacetate (0.01 and 0.1 microM), respectively, both agents had additive effects. Inhibition of protein synthesis with cycloheximide (35 microM) significantly changed the effects of both agents. While the effect of 8Br.cAMP (1 mM) on PEnk-mRNA was enhanced, that of tetradecanoylphorbolacetate (0.1 microM) was abolished. The results provide evidence for a synergistic effect of protein kinase A and C on the expression of the proenkephalin gene in astroglial cells. However, the protein kinases seem to act via different transcription factors on the expression of the proenkephalin gene.
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PMID:Interaction of protein kinases A and C in their effects on the proenkephalin gene in astroglial cells. 782 71

In an attempt to determine if PACAP synergistically interacts with vasopressin (VP) and protein kinase C (PKC) to enhance cyclic AMP formation and adrenocorticotrophic hormone (ACTH) secretion, the effects of PACAP, either alone or together with VP and the phorbol ester phorbol 12-myristate 13-acetate (PMA) were examined in primary cultures of rat anterior pituitary cells. VP failed to potentiate the stimulatory effect of PACAP on cyclic AMP formation, while it dramatically enhanced the effect of corticotropin-releasing factor (CRF). However, activation of PKC upon exposure of cells to PMA amplified cyclic AMP production induced by both peptides, though in the case of PACAP, contrary to that of CRF, potentiation was markedly dependent on the blockade of phosphodiesterase (PDE) activity, for it was undetectable in the absence of the inhibitor Rolipram. Depletion of PKC by long-term treatment of pituitary cells with PMA abolished the synergistic influence of PMA. There was no significant effect of PACAP, either alone or together with PMA, on ACTH secretion, while PMA enhanced peptide secretion elicited by CRF. The data show that in anterior pituitary cells cyclic AMP accumulation induced by PACAP and CRF was differentially modulated by PKC and PDE activities and that the potentiation of PACAP-stimulated cyclic AMP accumulation by PMA was not reflected by parallel increment of ACTH secretion.
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PMID:Vasopressin, unlike phorbol ester, fails to synergistically interact with pituitary adenylate cyclase activating polypeptide (PACAP) in stimulating cyclic AMP formation and ACTH secretion in cultured anterior pituitary cells. 839 88

We investigated the effects of age and nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on protein kinase C (PKC), adenylyl cyclase, calcium/calmodulin-independent cyclic-AMP phosphodiesterase (cyclic-AMP PDE) and voltage-dependent L-type calcium channels in Fischer rat brain using autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]forskolin, [3H]rolipram and [3H]PN200-110 were used to label PKC, adenylyl cyclase, cyclic-AMP PDE and calcium channels, respectively. [3H]Forskolin binding significantly decreased in the striatum, hippocampal CA3 sector, dentate gyrus, hilus, thalamus, substantia nigra and cerebellum of 24-month-old (aged) rats, as compared with 6-month-old (adult) animals. [3H]Rolipram binding also showed an age-related reduction in the thalamus and cerebellum in rats. In contrast, no age-related changes were observed in [3H]PDBu and [3H]PN200-110 binding in the rat brain. Chronic treatment with L-NAME (5 mg/kg, once a day for 4 weeks) showed no significant changes in [3H]PDBu, [3H]rolipram and [3H]PN200-110 binding in aged rat brains. However, this treatment significantly increased age-related decreases in [3H]forskolin binding in the frontal cortex; striatum and hippocampal CA1 sector in rats. The results demonstrate that [3H]forskolin binding in the rat brain is more susceptible to aging processes than [3H]PDBu, [3H]rolipram and [3H]PN200-110 binding. Furthermore, our study shows that chronic treatment with NO inhibitor increases the age associated changes in [3H]forskolin binding in most brain areas of aged rats. These findings suggest that NO may play a key role in the regulation of adenylyl cyclase system during aging processes.
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PMID:Effect of nitric oxide synthase inhibitor on age-related changes in second messenger systems and calcium channels in rats. 910 40

1. The involvement of cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKC) in the effects of cyclic AMP-elevating agents on vascular smooth muscle relaxation, cyclic nucleotide dependent-protein kinase activities and ATP-induced calcium signalling ([Ca2+]i was studied in rat aorta. Cyclic AMP-elevating agents used were a beta-adrenoceptor agonist (isoprenaline), a phosphodiesterase 3 (PDE3) inhibitor (SK&F 94120) and a PDE4 inhibitor (rolipram). 2. In rat intact aorta, the relaxant effect induced by isoprenaline (0.01-0.03 microM) was decreased by a specific inhibitor of PKA, H-89, whereas a specific inhibitor of PKG, Rp-8-Br-cyclic GMPs, was without effect. NO significant difference in PKA and PKG activity ratios was detected in aortic rings when isoprenaline 10 microM was used. At the same concentration, isoprenaline did not modify ATP-induced changes in [Ca2+]i in smooth muscle cells. Neither H-89 nor Rp-8-Br-cyclic GMPs modified this response. These findings suggest that PKA is only involved in the relaxant effect induced by low concentrations of isoprenaline (0.01-0.3 microM), whereas for higher concentrations, other mechanisms independent of PKA and PKG were involved. 3. The relaxant effects induced by SK&F 94120 and rolipram were inhibited by Rp-8-Br-cyclic GMPS with no significant effect of H-89. Neither SK&F 94120, nor rolipram at 30 microM significantly modified the activity ratios of PKA and PKG. Rolipram inhibited the ATP-induced transient increase in [Ca2+]i. This decrease was abolished by Rp-8-Br-cyclic GMPS whereas H-89 had no significant effect. These results suggests that PKG is involved in the vascular effects induced by the inhibitors of PDE3 and PDE4. Moreover, since it was previously shown that PDE3 and PDE4 inhibitors only increased cyclic AMP levels with no change in cyclic GMP level, these data also suggest a cross-activation of PKG by cyclic AMP in rat aorta. 4. The combinations of 5 microM SK&F 94120 with rolipram markedly potentiated the relaxant effect of rolipram. This relaxation was decreased by H-89 and not significantly modified by Rp-8-Br-cyclic GMPS. Moreover, the association of the two PDE inhibitors significantly increased the activity ratio of PKA without changing the PKG ratio. The present findings show that PKA rather than PKG is involved in this type of vasorelaxation. The differences in the participation of PKA vs PKG observed when inhibitors of PDE3 and PDE4 were used alone or together could be due to differences in the degree of accumulation of cyclic AMP, resulting in the activation of PKA or PKG which are differently localized in the cell. 5. These findings support for both PKA and PKG in cyclic AMP-mediated relaxation in raT aorta. Their involvement depends on the cellular pathway used to increase the cyclic AMP level.
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PMID:Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation. 929 42

Cholinergic neurotransmission and protein kinase C (PKC) in the brain play important roles in the processes of cognitive function. In this study, we examined the effect of chronic treatment with rolipram, a 3',5'-cyclic adenosine monophosphate (cyclic AMP)-selective phosphodiesterase inhibitor, on age-related changes in [3H]quinuclidinyl benzilate (QNB) and [3H]phorbol 12,13-dibutyrate (PDBu) binding, which labeled brain muscarinic cholinergic receptors and PKC, respectively. Rolipram was administered per os to young (15 weeks old) and old (80 weeks old) Wistar rats at dosage of 0.01 mg/kg and 0.1 mg/kg once a day over 4 weeks. Then, quantitative in vitro autoradiography was performed. Control old rats showed elevations in [3H]PDBu binding in the hippocampus and the cerebellum compared to young rats, but [3H]QNB binding was largely unchanged. Chronic treatment of the old rats with the higher dose of rolipram led to reductions in [3H]QNB and [3H]PDBu binding in many brain regions. However, the same treatment of the young rats induced no or minimal effect. Thus, the response of the brain to rolipram was different between young and old rats. These results suggest that the cyclic AMP-selective phosphodiesterase system in the brain is modified during aging, modulating subsequently cholinergic neurotransmission and PKC activity exclusively in old rat brains.
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PMID:Age-related effects of rolipram on [3H]quinuclidinyl benzilate and [3H]phorbol 12,13-dibutyrate binding in the rat brain. 974 50

The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms. The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 alpha-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K(+)) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca(2+)). In addition, levonorgestrel depressed contractions evoked by Ca(2+) and reduced (45)Ca(2+) influx in depolarized veins. Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca(2+). Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins. These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca(2+) entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca(2+) entry.
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PMID:The progestin levonorgestrel induces endothelium-independent relaxation of rabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP. 1095 82