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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forskolin increased cyclic AMP accumulation in isolated adipocytes and markedly potentiated the elevation of cyclic AMP due to isoproterenol. In adipocyte membranes, forskolin stimulated adenylate cyclase activity at concentrations of 0.1 microM or greater. Forskolin did not affect the EC50 for activation of adenylate cyclase but did increase the maximal effect of isoproterenol. Neither the soluble nor particulate low-Km cyclic AMP phosphodiesterase activity was affected by forskolin. Low concentrations of forskolin (0.1-1.0 microM), which significantly elevated cyclic AMP levels, did not increase lipolysis, whereas similar increases in cyclic AMP levels due to isoproterenol elevated lipolysis. Forskolin did not inhibit the activation of triacylglycerol lipase by cyclic AMP-dependent protein kinase or the subsequent hydrolysis of triacylglycerol. Higher concentrations of forskolin (10-100 microM) did increase lipolysis. Both the increased cyclic AMP production and lipolysis due to forskolin were inhibited by the antilipolytic agents insulin and N6-(phenylisopropyl)adenosine. Hypothyroidism reduced the ability of forskolin to stimulate cyclic AMP production and lipolysis. These results indicate that forskolin increases cyclic AMP production in adipocytes through an activation of adenylate cyclase. Lipolysis is activated by forskolin but at higher concentrations of total cyclic AMP than for catecholamines.
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PMID:Forskolin as an activator of cyclic AMP accumulation and lipolysis in rat adipocytes. 628 66

Forskolin (40 microM) stimulated adenylate cyclase activities of bovine thyroid plasma membranes without the addition of guanine nucleotides. GDP had little effect on the forskolin-stimulated adenylate cyclase activity while Gpp[NH]p (0.1-1.0 microM) decreased it. In the presence of TSH (10 mU/0.11), Gpp[NH]p no longer caused inhibition. Forskolin did not affect phosphodiesterase activities of thyroid homogenates. Forskolin (10 microM) rapidly increased cAMP levels in bovine thyroid slices both in the absence and presence of a phosphodiesterase inhibitor. The effect of TSH (50 mU/ml) on cAMP levels was additive or greater than additive to that of forskolin. An initial 2-h incubation of slices with forskolin did not decrease their subsequent cAMP responses to either forskolin and/or TSH while similar treatment of slices with TSH induced desensitization of the cAMP response to TSH, but not to forskolin. Forskolin (10 microM) as well as TSH (50 mU/ml) activated cAMP-dependent protein kinase of slices in the absence of a phosphodiesterase inhibitor. Although forskolin activated the adenylate cyclase cAMP system, it did not stimulate iodide organification or glucose oxidation, effects which have been attributed to cAMP. In fact, forskolin inhibited these parameters and 32P incorporation into phospholipids as well as their stimulation by TSH. These results indicate that an increase in cAMP levels and cAMP-dependent protein kinase activity in thyroid slices may not necessarily reproduce the effects of TSH on the thyroid.
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PMID:Effects of forskolin on adenylate cyclase, cyclic AMP, protein kinase and intermediary metabolism of the thyroid gland. 629 78

Forskolin, a specific diterpene activator of adenylate cyclase in intact cells and cellular homogenates, was used to examine the relationship among adenosine 3',5'-cyclic monophosphate (cAMP) metabolism, gastric acid, and pepsinogen secretion in isolated gastric glands. This agent was found to stimulate [14C]aminopyrine (AP) accumulation and respiration, both measurements of which are indexes of parietal cell acid secretory responsiveness and pepsinogen secretion, which is a measure of chief cell activity. Forskolin also increased cAMP content and activated cAMP-dependent protein kinase in the glands. The histamine H2-receptor antagonist, cimetidine, inhibited forskolin-stimulated increases in AP accumulation and respiration when submaximal concentrations of forskolin were used but had not effect on the other response parameters. Forskolin also potentiated the action of the muscarinic agonist, carbachol, in both the presence and absence of cimetidine. Since there was a close kinetic and temporal correlation between the secretory response parameters and cAMP-dependent protein kinase activation, it appears that cAMP plays an important role in the mediation of gastric acid and pepsinogen secretion. The inhibitory action of cimetidine on forskolin-stimulated AP accumulation and respiration suggest that forskolin potentiates the action of endogenous histamine present in the glands. Forskolin potentiation of carbachol in the presence of maximum inhibitory concentrations of cimetidine indicates that previously observed potentiating interactions between carbachol and histamine, secretagogues which appear to act via cAMP-independent and cAMP-dependent mechanisms, respectively, involve intracellular events that occur subsequent to the binding of these agents to their respective receptors and subsequent to an increase in intracellular cAMP content.
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PMID:Forskolin stimulation of acid and pepsinogen secretion in isolated gastric glands. 631 18

Forskolin is a positive inotropic-acting and blood pressure lowering agent which was isolated from the Indian plant Coleus forskohlii. In isolated heart tissue, forskolin activates a membrane bound adenylatecyclase and a cytoplasmic cAMP-dependent protein kinase to a much higher degree than does isoprenaline. This activation does not require the hormone receptor. In isolated and electrically stimulated left guinea pig atria, the adenylate-cyclase activation by forskolin is the prerequisite for the positive inotropic effect. We therefore postulate the adenylatecyclase activation to be correlated with the positive inotropic effect via an enhanced calcium uptake by the heart muscle cell.
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PMID:The positive inotropic-acting forskolin, a potent adenylate cyclase activator. 719 29

We have identified and studied a posttranscriptional mechanism of lactate dehydrogenase A (LDH) subunit gene expression at the level of mRNA stability. Using the well differentiated rat C6 glioma cell line as a model system, the effects of activators of the protein kinase A and C pathways on the half-life of LDH A mRNA were measured by two independent methods: 1) by the RNA synthesis inhibitor-chase method using actinomycin D, and 2) by analysis of decay of LDH A [3H]mRNA in [3H]uridine-labeled cells. By each method, the half-life of relatively short-lived LDH A mRNA was increased 5- to 7-fold in 8- (4-chloro-phenylthio) cAMP or forskolin-treated and about 3-fold in 12-0-tetradecanoylphorbol-13- acetate (TPA) or dioctanoylglycerol-treated cells. Forskolin acted synergistically with TPA to prolong LDH A mRNA half-life from 55 min to more than 20 h. The relatively rapid basal decay rate of LDH A mRNA was also considerably slowed in the presence of the protein phosphatase inhibitor okadaic acid, suggesting a functional role for protein phosphorylation in the stabilization process. In glioma cells stably transformed with a protein kinase A catalytic subunit expression vector, overexpression of the catalytic subunit stabilized LDH mRNA to the degree seen in forskolin-treated cells. In cells transfected with a protein kinase A inhibitor-expression vector, cAMP-mediated stabilization of LDH A mRNA half-life was prevented. Furthermore, both staurosporin and 3- [1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol- 3-yl)- maleimide, inhibitors of protein kinase C, prevented the TPA-induced stabilization of LDH A mRNA. We conclude from the experimental data that the protein kinase A and C signal pathways play an active functional role in regulating LDH A mRNA stability and act cooperatively to achieve LDH A mRNA stability regulation.
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PMID:Lactate dehydrogenase A subunit messenger RNA stability is synergistically regulated via the protein kinase A and C signal transduction pathways. 747 96

Insulin secretion has been studied in isolated rat pancreatic islets under stringent Ca(2+)-depleted, Ca(2+)-free conditions. Under these conditions, the effect of 16.7 mM glucose to stimulate insulin release was abolished. Forskolin, which activates adenylyl cyclase, also failed to stimulate release in the presence of either low or high glucose concentrations. A phorbol ester (phorbol 12-myristate 13-acetate; PMA) increased the release rate slightly and this was further increased by 16.7 mM glucose. Remarkably, in the presence of both forskolin and PMA, 16.7 mM glucose strongly augmented insulin release. The augmentation was concentration dependent and monophasic and had a temporal profile similar to the "second phase" of glucose-stimulated insulin release, which is seen under normal conditions when Ca2+ is present. Metabolism is required for the effect because mannoheptulose abolished the glucose response. Other nutrient secretagogues, alpha-ketoisocaproate, and the combination of leucine and glutamine augmented release under the same conditions. Norepinephrine, a physiological inhibitor of insulin secretion, totally blocked the stimulation of release by forskolin and PMA and the augmentation of release by glucose. Thus, under the stringent Ca(2+)-free conditions imposed, the stimulation of insulin release by forskolin and PMA, as well as the augmentation of release by glucose, is under normal physiological control. As no increase in intracellular [Ca2+] was observed, the results demonstrate that glucose can increase the rate of exocytosis and insulin release by pancreatic islets in a Ca(2+)-independent manner. This interesting pathway of stimulus-secretion coupling for glucose appears to exert its effect at a site beyond the usual elevation of intracellular [Ca2+] and is not due to an activation by glucose of protein kinase A or C.
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PMID:Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets. 747 73

1. The tight-seal whole cell recording technique was used to study the effects of the metabotropic glutamate receptor (mGluR) agonist, trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) on spontaneous gamma-aminobutyric acid (GABA)-mediated synaptic currents in neonatal rat CA1 hippocampal neurons in slices obtained from postnatal (P) days P6-P12. 2. Bath application of t-ACPD (3-30 microM), in the presence of kynurenic acid, induced a concentration-dependent increase in frequency but not in amplitude of spontaneous GABAergic currents. The mean frequency ratio (t-ACPD 10 microM over control) was 2.6 +/- 1 (mean +/- SD), whereas the mean amplitude ratio was 1.1 +/- 0.3. 3. The effect of t-ACPD was partially antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM). 4. t-ACPD (10-30 microM) did not modify the frequency of miniature GABAergic synaptic currents recorded in tetrodotoxin (the mean frequency ratio of t-ACPD over control was 0.7 +/- 0.3). 5. Forskolin (30 microM), but not its analogue 1,9 dideoxyforskolin (30 microM), mimicked the effect of t-ACPD. Similar effects were obtained with 3-isobutyl-1-methylxanthine (IBMX, 200 microM). 6. The potentiating effect of t-ACPD on spontaneous GABAergic currents was prevented by Rp-cAMPS (30 microM), a specific antagonist of protein kinase A. This suggests that mGluRs localized at the soma-dendritic level of GABAergic interneurons and positively coupled to cyclic AMP may modulate GABA release during a critical period of postnatal development.
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PMID:Activation of metabotropic glutamate receptors increase the frequency of spontaneous GABAergic currents through protein kinase A in neonatal rat hippocampal neurons. 750 Jan 37

One component of the nocturnal changes in cellular immediate-early gene expression in the rat pineal gland is a decrease in c-jun expression, mediated through beta-adrenoceptors. An in vitro study of the intracellular mechanisms which control c-jun expression has now shown that a norepinephrine-induced increase in c-jun mRNA levels in organ-cultured pineals is differentially modulated by protein kinase inhibitors; N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004) potentiated the response; however, in the presence of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a significant decrease in c-jun mRNA was found. Treatment with HA-1004 alone elevated the level of c-jun mRNA, H-7 alone was without effect. Forskolin together with 3-isobutyl-1-methylxanthine suppressed c-jun, whereas phorbol 12,13-dibutyrate raised c-jun mRNA levels. The results demonstrate opposing pathways for c-jun regulation in the pineal gland, and indicate that the nocturnal attenuation of c-jun expression involves selective activation of a negative pathway which may be linked to cAMP.
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PMID:Noradrenergic regulation of c-jun expression in the rat pineal gland in culture: positive and negative components. 750 96

The role of the cAMP/A-kinase signaling pathway in G-CSF dependent proliferation of murine myeloblastic NFS-60 cells was investigated. G-CSF treatment resulted in a rapid and transient elevation of cAMP content of NFS-60 cells. G-CSF treatment of NFS-60 cells also resulted in the activation of A-kinase parallel to the increase in cAMP concentration. A low concentration (0.2-10 nM) of forskolin augmented the G-CSF-dependent cell proliferation, although forskolin by itself had no effect on NFS-60 cell growth. Forskolin did not affect the IL-3-induced proliferation of this cell line. Addition of forskolin resulted in further increases in the cAMP level, activation of A-kinase in NFS-60 cells stimulated by G-CSF. Proliferation of NFS-60 cells by G-CSF, but not by IL-3, was blocked by the axial diastereoisomer of adenosine 3',5'-phosphorothioate (Rp-cAMPS), a competitive cAMP antagonist. KT-5720(8R*,9S*,11S*)-(-)-9-hydroxy-9-n-hexyloxy-8-methyl-2, 3, 9, 10-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2,7b, 11a-triazadibenzo(a,g) cycloocta(c,d,e)trinden-1-one), an A-kinase inhibitor, inhibited the G-CSF-dependent proliferation. These findings suggest that activation of the cAMP/A-kinase signaling pathway may be involved in G-CSF-mediated cell proliferation of NFS-60 cells, whereas IL-3-dependent proliferation is not mediated in such a manner.
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PMID:Forskolin potentiates G-CSF-induced proliferation of a murine myeloblastic leukemia cell line. 750 14

Phosphorylation of glutamate receptors (GluRs) is emerging as an important regulatory mechanism. In this study 32P labeling of non-NMDA GluRs was investigated in cultured hippocampal neurons stimulated 2-15 min with agonists that selectively stimulate either Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II), Ca2+/phospholipid-dependent protein kinase C (PKC), or cAMP-dependent protein kinase A (PKA). Treatment of hippocampal neurons with glutamate/glycine (Glu/Gly), ionomycin, or 12-O-tetradecanoylphorbol 13-acetate (TPA) increased 32P labeling of immunoprecipitated alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA)-type GluRs by 145%, 180%, and 227%, respectively, of control values. This increased phosphorylation of GluRs was predominantly 32P-Ser with little 32P-Thr and no detectable 32P-Tyr. Glu/Gly and ionomycin, but not TPA, also increased 32P labeling of CaM-kinase II by 175% and 195%, respectively, of control values. Of these three agonists, only TPA stimulated phosphorylation of MARCKS (225% of control), a specific substrate of PKC. Forskolin treatment gave a three- to fourfold increase in the active catalytic subunit of PKA but did not result in the 32P labeling of AMPA-type GluRs, CaM-kinase II, or MARCKS. Phosphorylation of GluRs in response to Glu/Gly was blocked by a specific NMDA receptor/ion channel antagonist (DL-2-amino-5-phosphonovaleric acid) or by a cell-permeable inhibitor of CaM-kinase II (1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, KN-62). These results are consistent with the hypothesis that Ca2+ influx through the NMDA-type ion channel can activate CaM-kinase II, which in turn can phosphorylate and regulate AMPA-type GluR ion channels (McGlade-McCulloh et al., 1993).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphorylation of AMPA-type glutamate receptors by calcium/calmodulin-dependent protein kinase II and protein kinase C in cultured hippocampal neurons. 750 63


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