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)

Phorbol 12-myristate 13-acetate (PMA), a potent protein kinase C activator, caused down-regulation of receptors for platelet-activating factor (AGEPC) on the plasma membrane of rat Kupffer cells (40-50% reduction) but had a relatively minor effect on the binding affinity of the receptors for AGEPC (Kd = 0.30 nM vs 0.56 nM) when incubated with the cells for a short period of time (30-60 min). As a consequence, the AGEPC receptor-mediated arachidonic acid release was attenuated. The PMA-induced down-regulation of AGEPC receptors was concentration-dependent, specific, and transient (the maximal effect was observed at about 1 h and the level of specific [3H]AGEPC binding gradually returned to the control level within 8.5 h and even higher than the control level at 24 h after addition of PMA). Upon removing PMA from the culture medium, more than half of the lost receptors were replaced within 1 h at 37 degrees C and the recovery process appeared to be independent of protein synthesis. The ability of PMA to down-regulate the AGEPC receptors was lost in cells "down-regulated" for protein kinase C, suggesting that the receptor-regulatory effect of PMA is protein kinase C-dependent. Protein kinase C appeared to be involved in the AGEPC-induced arachidonic acid release since 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride, a protein kinase C inhibitor, attenuated the stimulatory effect of AGEPC in this system. In addition, AGEPC-induced [3H]arachidonic acid release was inhibited significantly in cells down-regulated for protein kinase C. The present study thus demonstrates that protein kinase C has dual actions in the regulation of AGEPC-mediated events, i.e., a positive forward action, regulating AGEPC-stimulated arachidonic acid release, and a negative action, which inactivates or down-regulates AGEPC receptors.
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PMID:Regulation of platelet-activating factor receptor and PAF receptor-mediated arachidonic acid release by protein kinase C activation in rat Kupffer cells. 217 29

Substance K (SK) contracted the guinea pig gallbladder in vitro by predominantly acting on the neurokinin (NK2) receptors localized on the smooth muscle. A comparison of the 50% effective dose among the tachykinins showed that SK is 20 and 176 times more active than neurokinin B (NKB) and substance P (SP), respectively. Senktide, a synthetic NKB agonist with presumably a specificity for only NK3 receptor subtype, was completely inactive even when tested at 6 x 10(-6) M. Studies on both atropine-treated tissues and [3H]acetylcholine release from myenteric plexus have revealed a minor action of SK by way of a stimulation on the intramural cholinergic neurons. There was still a residual 77.4% SK-evoked contraction that was not blocked by atropine. However, the SK-induced contraction was completely abolished in the presence of 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, a direct protein kinase C (PKC) inhibitor. This latter observation suggests a link in the PKC-specific pathway of intracellular signal transduction initiated by NK2 receptor activation on the gallbladder musculature. The preponderance of NK2 receptor subtype further implies a unique functional role it may play in gallbladder contractility.
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PMID:Mode of stimulation of gallbladder contraction by substance K. 217 17

Activated macrophages kill several types of tumor cells in vitro, whereas non-activated macrophages lack this capacity. We, however, observed that non-activated macrophages efficiently kill F9 teratocarcinoma as well as other teratocarcinoma cell lines. Dexamethasone, a glucocorticoid known to prevent macrophage activation, did not perturb the killing of F9 teratocarcinoma cells. Neither tumor necrosis factor alpha, nor the reactive oxygen intermediates, i.e. hydrogen peroxide, superoxide anion, and hydroxyl radical, nor serine proteases participated in this killing, shown by employing various agents which interfere with their production, secretion, or function. Using acridine orange/ethidium bromide vitality staining, the F9 teratocarcinoma cells were shown to be phagocytized alive by macrophages and subsequently killed intracellularly. Intact lysosomal function is required for the killing of F9 cells, as the lysosomotropic drugs chloroquine and ammonium chloride markedly inhibited this killing without perturbing their engulfment. The signal transduction pathway induced in the macrophages upon interaction with F9 teratocarcinoma cells seems to differ from that induced by macrophage activation. Neither the protein kinase C inhibitors polymyxin B and H-7 [1-(5-isoquinolinylsulfonyl)-2-methyl piperazine] nor the protein kinase C activator phorbol 12-myristate-13-acetate affected the killing of F9 cells. However, chlorpromazine (a powerful inhibitor of calmodulin), dibutyryl cAMP (a cAMP analog), and prostaglandin E2 inhibited the macrophage-mediated killing of F9 cells. In vivo studies indicate that an increased number of macrophages at the F9 tumor inoculation site (the peritoneal cavity) as a result of elicitation by thioglycollate prevents F9 tumor development. Our findings indicate that non-activated macrophages kill teratocarcinoma cells using a mechanism which differs from that employed by activated macrophages in the killing of other tumor cells.
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PMID:Engulfment and intracellular killing of F9 teratocarcinoma cells by non-activated murine macrophages. 227 89

In this study we have examined the subcellar pathways along which angiotensin II (ANG II) causes renal vasoconstriction. Using the isolated perfused rat kidney model, we found that renal vasoconstriction produced by ANG II (100 pM) was not altered by the calmodulin antagonists calmidazolium (1 microM) and N-(6-aminohexyl)-5-chloro-1-naphthalensulfonamide (W-7, 10 microM) but was blunted by staurosporine (100 nM) and 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7, 50 microM), two structurally distinct putative protein kinase C inhibitors. The phorbol ester 4 alpha-phorbol 12,13-didecanoate (1-100 nM) did not alter renal vascular resistance, whereas phorbol 12-myristate 13-acetate (PMA, 1-100 nM) caused potent and dose-dependent vasoconstriction that was prevented by staurosporine (100 nM) and H-7 (50 microM). The vasoconstrictory effects of ANG II and PMA were attenuated by the calcium channel blockers verapamil (5 microM) and nifedipine (5 microM) and were reversibly inhibited when cobaltous chloride (2 mM) was added to the perfusate. Taken together, our findings support the concept that the renal vasoconstrictory effect of ANG II is essentially mediated by protein kinase C activation, which either requires or enhances the entrance of extracellular calcium.
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PMID:Role of protein kinase C in renal vasoconstriction caused by angiotensin II. 239 65

Potent inhibitors of protein kinases C and A, including 1-(5 isoquinolinyl sulfonyl) 2-methyl piperazine (H7), staurosporine, and 2-aminopurine, depressed phorbol ester-induced HIV-1 virion production and HIV-specific transcripts by greater than 90% in chronically infected promonocytic cells. Suppression was dose-dependent and occurred at concentration that had little effect on cell growth. These effects appeared to be specific to activation of the PKC-diacylglycerol system. They did not alter IUdr-mediated induction of HIV. In addition, PMA enhancement of an HIV-LTR driven reporter gene was not blocked by H7 in the presence or absence of exogenous tat, at concentrations capable of inhibiting upregulation of virus at the cellular level. Insight into the biochemical mechanisms of these processes is critical to understanding interactions of HIV with the immune system, and may eventually uncover new therapeutic strategies.
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PMID:Phorbol ester-mediated induction of HIV-1 from a chronically infected promonocyte clone: blockade by protein kinase inhibitors and relationship to tat-directed trans-activation. 240 49

Calcium ionophore, A23187, is known to be a comitogen, but it activates a suicide process characterized by DNA fragmentation at linker regions in mouse immature thymocytes. It did not induce DNA fragmentation in T lymphocytes prepared from lymph node and spleen cells. Induction of DNA fragmentation by A23187 depends on protein phosphorylation and synthesis of mRNA and protein, because an inhibitor of protein kinase, 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride (H-7), actinomycin D, and cycloheximide, respectively, inhibits the DNA fragmentation and cell death. Studies adding the inhibitors at various times show that protein phosphorylation and mRNA synthesis occur within a few hours after incubation with A23187 followed by the protein synthesis responsible for inducing DNA fragmentation. Phorbol esters, 12-O-tetradecanoyl 13-acetate (TPA) and phorbol 12,13-dibutyrate (PBD), which are capable of activating protein kinase C, also induced similar DNA fragmentation in immature thymocytes, followed by cell death. PBD committed the suicide process after 6 h of incubation, because the DNA fragmentation above the control level was not induced when PDB was removed from the medium before 6 h of incubation. A23187 or a phorbol ester alone induced DNA fragmentation followed by cell death, whereas the addition of TPA at low concentration inhibited the DNA fragmentation induced by A23187 accompanied with an increase in DNA synthesis. The result suggests that TPA switched a suicide process induced by A23187 to an opposite process: stimulation of DNA synthesis. Physiologic factors and mechanisms which regulate cell proliferation and death in the thymus are not known at present, but the signals by protein kinases and calcium ions may regulate both cell proliferation and death, independently, synergistically or antagonistically.
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PMID:Activation of a suicide process of thymocytes through DNA fragmentation by calcium ionophores and phorbol esters. 250 69

The involvement of a GTP-binding protein (G-protein) in the process of neurotransmitter release was examined using pertussis toxin and cholera toxin. Cholinergic agonists are shown to mediate [3H]noradrenaline release in rat brain slices via a pertussis toxin (1.2 micrograms/ml) sensitive, and cholera toxin (0.5 microgram/ml) insensitive G-protein. An indication for the involvement of a G-protein and phospholipase C activation in the release process was implied from the inhibitory effect of neomycin on K+-, veratridine- and carbachol-induced-norepinephrine release. Depolarizing agents mediate a neomycin-sensitive release, which is not which is not affected either by pertussis toxin or cholera toxin, suggesting a different mode of phospholipase C activation, unlike carbachol-induced release, which is both neomycin and pertussis toxin sensitive. Similarly, a hormone-sensitive carrier activated by phenylephrine not via alpha 1-adrenergic receptors, mediates a non-exocytosis efflux which is not affected by neomycin and is shown to be pertussis toxin-insensitive. The inhibitory action of protein kinase C inhibitors polymyxin B, K252a and H-7 [(1-(5-isoquinolinesulphonyl)-2-methyl-piperazine] on release, strongly suggests its participation in the process. Polymyxin B, a relatively selective protein kinase C inhibitor, inhibited carbachol-induced release (IC50 = 0.53 microM) as well as the K+ and the veratridine induced [3H] noradrenaline release, K252a, an inhibitor of various protein kinases at the ATP site, and H-7, another protein kinase C inhibitor, inhibited carbachol-induced noradrenaline released with IC50 = 35 nM and 3 microM respectively. Consistent with its inability to activate phospholipase C, phenylephrine-induced noradrenaline efflux was unaffected by polymyxin B (greater than 70 microM). These results offer more supportive evidence for a major role played by the dual messengers inositol trisphosphate and diacylglycerol (IP3/DG) in the mechanisms of neuronal release.
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PMID:Cholinergic-induced [3H] noradrenaline release in rat brain cortical slices is mediated via a pertussis toxin sensitive GTP binding protein and involves activation of protein kinase C. 251 86

A specific stimulation of tubulin tyrosinolation in human neutrophils (PMNs) is induced by the synthetic peptide chemoattractant N-formylmethionylleucylphenylalanine (fMet-Leu-Phe), and this stimulation is closely associated with activation of the NADPH oxidase-mediated respiratory burst (Nath, J., and Gallin, J. I. (1983) J. Clin. Invest. 71, 1273-1281). In contrast, along with tubulin tyrosinolation, a distinctly different respiratory burst-associated random posttranslational incorporation of tyrosine into multiple PMN proteins is observed in PMNs stimulated with the phorbol ester phorbol 12-myristate 13-acetate (PMA) or sn-1,2-dioctanoylglycerol (DAG). In studies exploring the mechanism(s) of signal transduction for these distinct neutrophil responses, we found that the fMet-Leu-Phe-induced stimulation of tubulin tyrosinolation in PMNs and in differentiated HL-60 cells is completely blocked by pertussis toxin, while the PMA-induced random incorporation of tyrosine is not inhibited. We also found that expression of the fMet-Leu-Phe-mediated stimulation of tubulin tyrosinolation in HL-60 cells is correlated with increases in the specific activity of protein kinase C and with the acquisition of respiratory burst activity which occur during induced myeloid maturation of these cells. Furthermore, both the fMet-Leu-Phe-induced stimulation of tubulin tyrosinolation and the PMA or DAG-induced random posttranslational incorporation of tyrosine into multiple proteins in activated neutrophils, were found to be reversibly inhibited (greater than 70%) by the protein kinase inhibitors 1-(5-isoquinolinesulfonyl)piperazine (C-I) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), in parallel with inhibition of superoxide (O2-) generation. In related studies, we also found that fMet-Leu-Phe-stimulated O2- production is comparably inhibited by C-I and H-7, but in a highly temperature-dependent manner. Inhibition was observed only when C-I or H-7 is added to PMNs at physiologic temperature, i.e. 37 degrees C. Interestingly, inhibition of the PMA-induced O2- generation by C-I or H-7 was not found to be similarly temperature-dependent. Considered together, these findings argue against the suggestion that there is a protein kinase C-independent pathway for activation of the respiratory burst in neutrophils stimulated with N-formyl peptides.
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PMID:Studies of signal transduction in the respiratory burst-associated stimulation of fMet-Leu-Phe-induced tubulin tyrosinolation and phorbol 12-myristate 13-acetate-induced posttranslational incorporation of tyrosine into multiple proteins in activated neutrophils and HL-60 cells. 253 26

Exposure of the bag cell neurons of Aplysia to activators of protein kinase C, such as phorbol esters, enhances electrically evoked action potentials by increasing the voltage-dependent calcium current. We have hypothesized that this effect is mediated by the activation of protein kinase C (PKC). An important prediction of this hypothesis is that inhibitors of PKC should inhibit these phorbol ester-induced changes in bag cell neuronal excitability. We have now found that treatment of bag cell neurons with the protein kinase inhibitor 1-[5-isoquinolinesulfonyl]-2-methyl piperazine (H-7) inhibits the phorbol ester-induced enhancement of bag cell action potentials and prevents the enhancement of calcium current by phorbol esters. The height and width of electrically evoked action potentials in bag cell neurons can also be enhanced by cAMP analogs or agents that elevate cAMP. These agents do not influence the major voltage-dependent calcium current in the bag cell neurons but may act by modulating potassium currents and other voltage-dependent currents. We have found that microinjection of a protein inhibitor of cAMP-PK (PKA-I) into isolated bag cell neurons prevents and reverses the effect of the adenylate cyclase activator forskolin on action potentials of these cells. In contrast, H-7 does not inhibit the effects of forskolin on a variety of responses in these cells, including its effects on action potentials, granule movement, and 32P incorporation into phosphoproteins. This suggests that H-7 is selective for PKC relative to cAMP-PK in intact bag cell neurons.
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PMID:Protein kinase inhibitors selectively block phorbol ester- or forskolin-induced changes in excitability of Aplysia neurons. 253 89

The biochemical mechanisms involved in the activation and killing of tumor targets by large granular lymphocytes (LGL) have not yet been clearly defined. This laboratory has investigated these processes by analyzing the effects of protein kinase C (PKC) inhibitors (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride and retinol) on LGL cytotoxicity and IFN-gamma production. We now report that PKC inhibitors block the LGL functions of 1) NK activity, 2) IFN-gamma production, and 3) LAK activity induced by IL-2. Complete inhibition of cytotoxic activity occurs rapidly because only 2.5 h treatment of the LGL with the inhibitors was required. However, the inhibition of NK activity by the PKC inhibitors could be reversed by IL-2 or the synthetic diacylglycerol, L-gamma-1-oleyl-2-acetol-sn-3-glycerol (OAG), but not by IFN-alpha. The reversal of inhibition observed with OAG indicates that, in these studies, (1-(5-isoquinolinesulfonyl)2-methyl-piperazine-dihydrochloride is inhibiting PKC activity and not the activity of other cellular kinases. Furthermore, inhibition of LGL functional activity with PGE2 could not be reversed with OAG, supporting the contention that PG inhibition of NK activity is mediated by a pathway that does not directly involve PKC. These results indicate, in addition to IL-2-mediated events, that basal NK activity is under PKC regulatory control.
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PMID:Modulation of CD3- large granular lymphocyte functions by agonist and antagonists of protein kinase C: effects on NK and lymphokine-activated killer activity and production of IFN-gamma. 254 2


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