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

Treatment of vascular tissue with lipopolysaccharide (LPS) in vitro induces hyporesponsiveness to contractile agonists. We investigated whether protein kinase C (PKC) transduces the LPS signal into contractile dysfunction. Rat aortic tissue was incubated .5-18 h with LPS (10 or 30 ng/mL) or alpha- and beta-phorbol 12,13-dibutyrate (PDB, .1 or 1 microM), either alone or combined with cycloheximide (50 microM) or the kinase inhibitors sphingosine (20 microM), H7 (1-(5-isoquinolinylsulfonyl)-2-methyl piperazine, 25 microM), and HA1004 (N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, 25 microM). LPS and beta-PDB induced a sustained translocation of PKC activity from the cytosol to the membrane, an increased protein synthesis-dependent expression of nitric oxide synthase (NOS) activity, and an impaired contractility that could be partially reversed by treatment with the NOS inhibitor N omega-nitro-L-arginine methyl ester. Incubation with alpha-PDB, an inactive isomer of beta-PDB, did not alter any of the tissue functions. Sphingosine blocked LPS- and beta-PDB-induced NOS activity and LPS-induced impairments in tissue contractility and PKC translocation. Incubation with H7 also protected against LPS-induced vasoplegia, while HA1004, used as a negative control for H7, provided little protection against LPS. These data indicate that PKC plays a role as an intracellular mediator of LPS-induced NOS activity and vascular suppression.
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PMID:Protein kinase C is a mediator of lipopolysaccharide-induced vascular suppression in the rat aorta. 753 68

In human bronchi, contractions to endothelin-1 were unaltered by atropine (10(-5) M), indomethacin (10(-6) M), nifedipine (10(-5) M), or phosphoramidon (3.67 x 10(-5) M). Endothelin-3-evoked contractions were markedly enhanced by phosphoramidon (3.67 x 10(-5) M), unaffected by atropine (10(-5) M), and attenuated by indomethacin (10(-6) M) or nifedipine (10(-5) M). Phorbol 12,13-dibutyrate (PDB, 10(-8) M) enhanced both endothelin-1- and endothelin-3 (plus phosphoramidon)-evoked responses, an effect abolished by Ro 31-8220 (3 x 10(-8) M). Contractions to endothelin-1 or endothelin-3 alone were unaltered by staurosporine 10(-8)-3 x 10(-7) M) or Ro 31-8220 (3 x 10(-9)-3 x 10(-8) M). Endothelin-1 (3 x 10(-7) M), but not endothelin-3 (10(-10)-3 x 10(-7) M), evoked a rise in levels of inositol (1,4,5) trisphosphate (Ins(1,4,5)P3). These results suggest that endothelin-1 does not act via cyclo-oxygenase metabolites nor require Ca2+ influx via dihydropyridine-sensitive channels. It evokes Ins(1,4,5)P3 production, but does not rely upon protein kinase C activation for contraction. Endothelin-3-evoked contractions are partly mediated by cyclo-oxygenase metabolites. Endothelin-3 does not stimulate phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, nor utilise protein kinase C to produce contraction, but its actions may rely upon extracellular Ca2+.
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PMID:Mechanical and biochemical responses to endothelin-1 and endothelin-3 in human bronchi. 770 68

Daphnoretin, a dicoumarin isolated from Wikstroemia indica C.A. Mey. (Thymelaceae), induced superoxide anion (O2-) formation in rat neutrophils in a concentration-dependent manner. Addition of staurosporine reduced daphnoretin-induced respiratory burst. Removal of extracellular free Ca2+ by EGTA did not affect the respiratory burst of neutrophils in response to daphnoretin. Prior exposure of neutrophils to phorbol 12-myristate 13-acetate (PMA) or daphnoretin reduced the O2- formation caused by a subsequent challenge with PMA and daphnoretin, but potentiated the response caused by a subsequent addition of formyl-Met-Leu-Phe (fMLP). Like PMA, daphnoretin did not increase the [Ca2+]i during cell activation. In neutrophil suspension, daphnoretin increased the membrane associated protein kinase C activity. In the presence of Ca2+ and phosphatidyl-serine, daphnoretin also activated protein kinase C isolated from cytosolic fraction of resting neutrophils. Staurosporine inhibited the direct activation of protein kinase C caused by daphnoretin as well as by PMA. Daphnoretin reduced the [3H]Phorbol-12,13-dibutyrate ([3H]PDB) binding to the neutrophil cytosolic protein kinase C in a concentration-dependent manner with an IC50 value of 1.77 +/- 0.37 microM. These results indicate that daphnoretin, like PMA, may direct activation of protein kinase C which in turn activated NADPH oxidase and elicited respiratory burst.
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PMID:Daphnoretin-induced respiratory burst in rat neutrophils is, probably, mainly through protein kinase C activation. 777 78

The extension of cellular processes from the oligodendrocyte soma is an early and critical event in myelin formation. Previous reports from this laboratory have implicated a role for protein kinase C (PKC) as an important intracellular mediator of this critical step in myelinogenesis. In the current study, the regrowth of fibers by adult human oligodendrocytes was examined and was found to be significantly enhanced by the PKC stimulator, 4 beta-phorbol-12,13-didecanoate (PDB); this was accompanied by a 400-500% increase in oligodendroglial PKC activity. In contrast to other cell types, the increased PKC activity in oligodendrocytes was not followed by subsequent down-regulation of the enzyme. The role of PKC in oligodendroglial process formation was further demonstrated by the ability of inhibitors of PKC to block the basal- or PDB-enhanced fiber outgrowth. As well, studies employing isoform-specific agonists implicated PKC alpha as the major determinant of fiber outgrowth by oligodendrocytes. The potential significance of PKC in myelin formation was further underscored by the observation that the synthesis of myelin basic protein, a prerequisite component for myelinogenesis, was increased by 2-fold in PDB-treated oligodendrocytes. Collectively, these observations suggest that PKC, in particular the alpha isoform, constitutes an important mediator in the initiation of myelin formation.
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PMID:Protein kinase C in cultured adult human oligodendrocytes: a potential role for isoform alpha as a mediator of process outgrowth. 780 94

1. This study examined the ability of various nitro-vasodilators, 8-bromo cyclic guanosine 3':5' monophosphate (8-BrcGMP) and forskolin to relax rings of rat thoracic aorta pre-contracted with either noradrenaline (0.1 microM) or the protein kinase C activators, phorbol 12,13-dibutyrate (PDB, 0.1 microM) or phorbol 12-myristate 13-acetate (PMA, 0.5 microM). 2. In noradrenaline pre-contracted rings, acetylcholine (10 nM-10 microM), sodium nitroprusside (1 nM-0.5 microM), the calcium ionophore A23187 (10 nM-10 microM) and 8-BrcGMP (10 mM) totally reversed the smooth muscle contraction. In PDB-contracted aortic rings acetylcholine, sodium nitroprusside and 8-BrcGMP-induced relaxation was reduced compared to that in noradrenaline-contracted aortic rings, but A23187 and forskolin-induced relaxations were unaffected. Both acetylcholine and A23187-induced relaxations in PDB-contracted rings were abolished in the presence of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine (NOLA, 100 microM). 3. Acetylcholine and sodium nitroprusside were even less potent in their ability to relax PMA-contracted aortic rings compared with noradrenaline and PDB-contracted rings. A23187-induced relaxation was also inhibited in PMA-contracted rings. 4. These results show that protein kinase C activation reduces the ability of agents which liberate nitric oxide to induce smooth muscle relaxation, and also inhibits the biochemical pathways which are subsequently activated by nitric oxide and lead to vascular smooth muscle relaxation.
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PMID:Phorbol esters impair endothelium-dependent and independent relaxation in rat aortic rings. 792 9

Two plant lectins, wheat germ agglutinin (WGA) and concanavalin A (Con A), which are known to bind to endothelial cells (ECs), were found to increase the leakage of colloidal carbon (CC) into the walls of microvessels in the villi of rat small intestine, when added to a gelatin-containing perfusate (GPSS) at a concentration of 10 micrograms/ml. Pretreatment of the microvessels with the protein kinase C (PKC) inhibitor Ro 31-8220 (1 x 10(-6) M) significantly reduced this effect. In contrast, the leakage of CC in response to A23187 (1 x 10(-4) M) was not affected by Ro 31-8220. Peanut agglutinin (PNA) and succinyl concanavalin A (SuccCon A), which do not bind to ECs, had no effect at a concentration of 10 micrograms/ml. A lower concentration of WGA (1 microgram/ml) had no significant effect of its own, but significantly reduced the leakage of CC in response to both platelet-activating factor (PAF, 5 x 10(-6) M) and 5-hydroxytryptamine (5-HT, 1 x 10(-4) M), but not to beta-phorbol 12,13-dibutyrate (PDB, 1 x 10(-6) M). These results suggest that all these effects of WGA and Con A involve cell surface receptors, albeit in a non-specific way. A possible mode of action is discussed.
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PMID:Lectin-induced increase in microvascular permeability to colloidal carbon in vitro may involve protein kinase C activation. 794 20

Intracellular signaling pathways regulating vascular smooth muscle (VSM) cell growth and hypertrophy can be initiated by activation of receptor tyrosine kinases and/or protein kinase C (PKC). Mitogen-activated protein kinases (MAP kinases) are cytosolic serine/threonine kinases, proposed to act as a point of convergence for diverse growth factors utilizing these signaling pathways. The goals of this study were (1) to determine whether MAP kinase is expressed in cultured rat aortic VSM, (2) to assess the activation of MAP kinase by known proliferative and hypertrophic stimuli, and (3) to determine if stimulation of a PKC-dependent signaling pathway in these cells results in MAP kinase activation. MAP kinase activity was measured in cytosolic extracts of aortic VSM by quantifying myelin basic protein phosphorylation. Three peaks of activity were resolved chromatographically and identified as MAP kinase isoforms (MW 42, 44, and 46 kDa) by immunoblotting with antipeptide antibodies specific for MAP kinase. MAP kinase activity in quiescent growth-arrested cells (157 +/- 19 pmole 32P/min/mg) was markedly stimulated within 15 min by known mitogens (10% serum, 731 +/- 40 pmole 32P/min/mg; 40 ng/ml PDGF, 670 +/- 105 pmole 32P/min/mg; P < 0.01) and partially sustained for at least 90 min (serum, 606 +/- 34 pmole 32P/min/mg; PDGF, 323 +/- 59 pmole 32P/min/mg P < 0.05). Angiotensin II (AII, 0.1 microM) and a pharmacological PKC activator, phorbol 12,13-dibutyrate (PDB, 0.1 microM), are reported to be nonmitogenic hypertrophic stimuli in these cells. These stimuli transiently increased MAP kinase activity with a peak at 5 min (AII, 328 +/- 15 pmole 32P/min/mg; PDB, 592 +/- 41 pmole 32P/min/mg; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of MAP kinase activity by growth stimuli in vascular smooth muscle. 804 Nov 41

By the use of pharmacological tools, we tested the hypothesis that age-related alterations in the regulatory pathways of chloride channels might contribute to the lowered chloride conductance (GCl) found in skeletal muscle of aged rats. The resting GCl of extensor digitorum longus (EDL) muscles from adult rats either young (3-4 months old) or aged (29 months old) was measured by means of computerized intracellular microelectrode recordings. In EDL muscle from 3 to 4-month-old rats, 4-beta-phorbol 12,13-dibutyrate (4-beta-PDB), a direct activator of protein kinase C (PKC), decreased GCl in a concentration-dependent manner. The same effect was exerted by cholera toxin. The effects of both the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activation of PKC accounts for the decrease of GCl. An increase of cytosolic Ca2+ by the ionophore A23187 also significantly decreased GCl by 25%. In EDL muscles from aged rats, 4-beta-PDB was 20-fold more potent in blocking GCl than in muscles from younger controls, and the ionophore blocked GCl by 40%. On the other hand, cholera toxin was ineffective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of the aging process.
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PMID:Aging and chloride channel regulation in rat fast-twitch muscle fibres. 805 78

Changes in adhesive properties play important regulatory roles in activation and differentiation of B-cells. To better understand the regulation of interactions between B-cells and other cells during the immune response, we have studied surface expression of the adhesion molecules LFA-1 (CD11a/CD18) and ICAM-1 (CD54). Both adhesion molecules were upregulated during B-cell activation. However, upon stimulation with anti-IgM and IL-4, ICAM-1 levels started to increase within 12 hr, while LFA-1 levels did not start to increase until after 36 hr. When B-cells were stimulated with the PKC activator PDB and a calcium ionophore, ICAM-1 levels, but not LFA-1 levels, increased. Only if these activators were removed after around 24 hr of activation and the cells were recultured in fresh medium was there an eightfold induction of LFA-1. Such reculturing in fresh medium led, however, to decreased ICAM-1 levels.
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PMID:Differential regulation of LFA-1 and ICAM-1 on human primary B-lymphocytes. 809 39

There is now convincing evidence that excessive accumulation of the excitatory amino acid glutamate (Glu) in the extracellular space is toxic to neurons. However, the regulation of the release and uptake of Glu in producing this toxic concentration has not been adequately ascertained. The authors report that in hippocampal slices, the output of Glu significantly increased under in vitro ischemic states. Glu in the extracellular space increased fivefold. Since daurisoline, a drug that blocks N-type Ca2+ channels, or Ca(2+)-free solution potently and effectively lowered this stimulated output, it was hypothesized that the Glu output is mediated by Ca2+ influx in nerve terminals. When the slices were incubated for 30 minutes under ischemic state, daurisoline caused only small alterations in the postischemic accumulation of Glu. However, Glu accumulation was markedly attenuated by H-7, but not by calmidazolium, facilitated by PDB whereas 8-bromo-cAMP was without effect. It appears therefore that during a 30-minute ischemic insult, protein kinase C (PKC) was involved in the Glu accumulation of supernatant. A direct demonstration of this concept was obtained by showing significant increases in PKC activation in presynaptic nerve terminals (from 1.34 +/- 0.1 to 9.34 +/- 0.89 U) following 30 minutes of ischemia. DNQX, a non-NMDA receptor antagonist, potently reduced PKC activities and decreased extra Glu accumulation. Also observed was the inhibition of 1-[3H]-Glu uptake into synaptosomes by PDB. These results provide direct evidence that Ca2+ influx enhances Glu release, which in turn leads to inhibition of its reuptake, and is coupled with PKC activities in presynaptic nerve terminals.
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PMID:Accumulation of glutamate is regulated by calcium and protein kinase C in rat hippocampal slices exposed to ischemic states. 810 81


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