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)

1. During osmotic swelling, cultured human small intestinal epithelial cells (Intestine 407) exhibited activation of large Cl- currents under the patch-clamp whole-cell configuration. The volume-sensitive Cl- conductance was independent of intracellular Ca2+ and cyclic AMP. 2. The anion permeability sequence of the current was SCN- > I- > Br- > Cl- > F- > gluconate-, corresponding to Eisenman's sequence I. 3. Cl- currents were instantaneously activated by command pulses in a range of -120 to +45 mV. At potentials more positive than +50 mV the current showed a time-dependent inactivation. This inactivation was accelerated by increased depolarization. The instantaneous current-voltage relationship rectified in the outward direction. 4. A stilbene-derivative Cl- channel blocker, 4-acetamido-4'-isothiocyanostilbene (SITS), inhibited the Cl- current at micromolar concentrations. SITS facilitated inactivation at positive potentials. Outward currents were more prominently suppressed by SITS than inward currents. The concentrations required for 50% inhibition (IC50) of outward and inward currents were 1.5 and 6 microM, respectively. The outward and inward currents were equally inhibited by a carboxylate analogue Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) or diphenylamine-2-carboxylate (DPC) at higher doses (IC50 = 25 for NPPB or 350 microM for DPC). Inactivation kinetics at large depolarizations was not affected by NPPB or DPC. 5. The Cl- current was blocked by an unsaturated fatty acid, arachidonic acid (IC50 = 8 microM). Arachidonic acid was still effective in the presence of inhibitors of lipoxygenase (nordihydroguaiaretic acid, 10 microM), cyclo-oxygenase (indomethacin, 10 microM) and protein kinase C (polymyxin B, 30 microM). The Cl- current was also sensitive to another cis unsaturated fatty acid, oleic acid, which is not a substrate for oxygenases. A trans isomer of oleate, elaidic acid, and a saturated fatty acid, palmitic acid, were ineffective. 6. Single Intestine 407 cells exposed to a hypotonic solution showed a regulatory volume decrease after initial osmotic swelling. The volume regulation was abolished by SITS, NPPB, arachidonate and oleate, but not by elaidate and palmitate. 7. It is concluded that outwardly rectifying Cl- channels, which are sensitive to arachidonic acid, are activated upon osmotic swelling and involved in the subsequent cell volume regulation.
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PMID:Volume-regulatory Cl- channel currents in cultured human epithelial cells. 128 79

In myocardial infarction, adrenergic stimulation of the heart is thought to cause cell damage and malignant arrhythmias. In rat hearts as well as in human cardiac tissue, ischemia induces norepinephrine (NE) release, which results in micromolar catecholamine concentrations in the interstitial space of the ischemic myocardium. It has been found that local metabolic, rather than centrally evoked NE release, plays the crucial role in excess adrenergic activation of the ischemic myocardium. NE release in ischemia is nonexocytotic and has been characterized as a two-step process. (a) Induced by energy deficiency, NE escapes from its storage vesicles and accumulates in the axoplasm. (b) NE is transported across the plasma membrane into the extracellular space via the neuronal NE carrier (uptake1), which has reversed its normal transport direction because of increased intracellular sodium concentration. NE release induced by ischemia is independent of the presence of calcium in the extracellular space and is not altered by blockade of N-type (neuronal) calcium channels. Furthermore, modulation of protein kinase C does not interfere with NE liberation in the ischemic myocardium. This independence of extracellular calcium, calcium entry into the neuron, and protein kinase C activity is in contrast to the strong calcium dependence of exocytotic transmitter release, which is found under physiological conditions. On the basis of these findings, it was unexpected that calcium antagonists such as gallopamil, verapamil, diltiazem, felodipine, and nifedipine suppress ischemia-induced NE release. The most potent effect was found for gallopamil with a concentration of 50% inhibition (IC50) of 300 nmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium antagonism and norepinephrine release in myocardial ischemia. 128 51

[Met5]-Enkephalin (ME) secretion and the expression of proenkephalin A (proENK) mRNA were studied following long-term exposure of bovine adrenal medullary chromaffin (BAMC) cells to pertussis toxin. Treatment with pertussis toxin for 24 h increased the secretion of ME in a concentration- and time-dependent manner. The magnitude of ME secretion continued to increase with time in the presence of pertussis toxin. The intracellular concentration of ME in the pertussis toxin-treated group was not significantly different from controls, suggesting that elevated levels of ME secretion result from increased biosynthesis of ME rather than from release of stored ME. Prolonged (24 h) stimulation of BAMC cells with pertussis toxin also increased proENK gene expression. Pretreatment with nimodipine (a calcium channel blocker) and calmidazolium (a calmodulin antagonist) inhibited both the secretion of ME and the increase in proENK mRNA levels induced by pertussis toxin, while the intracellular calcium antagonist dantrolene and the protein kinase C inhibitors sphingosine and H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] were ineffective in blocking pertussis toxin-induced responses. Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA. Our results suggest that a pertussis toxin-sensitive G protein may tonically regulate the secretion of ME as well as the level of proENK mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin stimulates the secretion of [Met5]-enkephalin and the expression of proenkephalin A mRNA in bovine adrenal medullary chromaffin cells. 128 24

To investigate the role of insulin on Ca2+ regulation of vascular smooth muscle cells (VSMC) in hypertension, the effect of insulin on Ca2+ transport and intracellular free calcium concentration ([Ca2+]i) was measured in cultured VSMC from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Insulin produced a substantial increase in 45Ca uptake as well as [Ca2+]i in quiescent cultured VSMC. The stimulatory effects of insulin were completely inhibited by diltiazem, and partially by H-7, TMB-8, and 5-N,N(hexamethylene)amiloride (HMA), but not by W-7 or trifluoroperazine. Insulin-sensitive 45Ca uptake of SHR VSMC was significantly smaller than that of WKY VSMC. Insulin-sensitive increase in [Ca2+]i of SHR VSMC was also smaller than that of WKY VSMC. It is concluded that insulin increases 45Ca uptake, leading to an increase in [Ca2+]i, presumably through the voltage-dependent Ca2+ channel, intracellular Ca2+ release, or protein kinase C mediated mechanisms in cultured VSMC. A blunted response of insulin-sensitive Ca2+ uptake and [Ca2+]i in SHR VSMC suggests the differential regulation of Ca2+ transport in response to insulin in primary hypertension.
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PMID:Decreased insulin-sensitive Ca2+ transport in cultured vascular smooth muscle cells from spontaneously hypertensive rats. 128 39

Increased knowledge of growth factor and oncogene intracellular signalling presents us with unique opportunities to develop new classes of antiproliferative drugs. The degeneracy of intracellular signalling may allow normal cells to be relatively unaffected by drugs that inhibit just one signalling pathway. Oncoproteins themselves have proved difficult to target and the drugs lack selectivity. More success has come with drugs targeted against other components of signalling pathways. Two examples of such classes of drugs are given. The ether lipid anticancer drugs inhibit intracellular signalling at multiple points; phosphatidylinositol phospholipase C, protein kinase C, intracellular Ca2+ release and phosphatidylinositol-3'-kinase. D-3-deoxy-3-substituted myo-inositols and phosphatidylinositols are a new class of growth inhibitory compounds that appear to act as antagonists of myo-inositol signalling.
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PMID:Drugs active against growth factor and oncogene phosphatidylinositol signalling pathways. 128 55

Many anticancer agents induce an active cell death process, apoptosis, in sensitive tumour cells. Elucidation of molecular mechanisms underlying apoptosis may shed light on why some tumour cells survive chemotherapy, and may identify new targets for anticancer agents whose effects are not tightly linked to proliferative status. The signal transduction events which initiate apoptosis are unclear. A change in cytosolic calcium is generally assumed to be a key signal for apoptosis although the evidence for this is not conclusive. Other putative signal transducers which may modulate apoptosis are protein kinase C and cAMP. Genes which induce apoptosis in response to such signals are largely unidentified, but certain oncogenes, notably bcl-2, act to delay or suppress apoptosis in several cell types.
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PMID:Induction of apoptosis--new targets for cancer chemotherapy. 128 62

Crosslinking HLA-DR molecules by monoclonal antibodies (moAbs) induces protein tyrosine phosphorylation and results in a secondary elevation of free cytoplasmic calcium concentrations in activated human T cells. Binding of bacterial superantigens or moAbs to DR molecules on activated T cells was recently reported to induce homotypic aggregation through activation of protein kinase C (PKC) and mediated by CD11a/CD54 (LFA-1/CAM-1) adhesion molecules. Here, we report that moAbs directed against framework DR, but neither DR1, 2- and DRw52- nor DQ- and DP-specific moABs induced homotypic aggregation of antigen- and alloantigen-activated T cells, antigen-specific CD4+ T-cell lines, a CD8+ T-cytotoxic cell line, and T-leukemia cells (HUT78). Protein tyrosine kinase (PTK) inhibitor herbimycin A partly blocked class-II-induced aggregation responses. In contrast, phorbol ester (PMA)-induced aggregation was essentially unaffected. A potent inhibitor of PKC, staurosporin, inhibited both moAb- and PMA-induced aggregation responses. The aggregation responses were completely inhibited by low temperatures, cytochalasins B and E, and partly inhibited by EDTA and CD18 moAbs, but unaffected by aphidicolin, mitomycin C, an adenylate cyclase inhibitor (2'5'-dideoxyadenosine), and moAbs against other adhesion molecules (CD2/CD58 [LFA-3], CD28/CD28 ligand B7, CD4, and CD44). In conclusion, HLA class-II-induced aggregation responses in activated T cells appear to involve PTK and PKC activation and to be mediated through CD11a-dependent and independent adhesion pathways.
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PMID:Signal transduction by HLA class II molecules in human T cells: induction of LFA-1-dependent and independent adhesion. 128 78

Normal oocyte maturation depends on signal transmission between granulosa cells and the oocyte. We have analysed the effects of inhibiting (I) cyclic AMP-dependent protein kinase (protein kinase A, PK-A), (II) Ca2+/phospholipid-dependent protein kinase (protein kinase C, PK-C) and (III) calmodulin (CaM) on pig oocyte maturation in vitro, protein synthesis and phosphorylation. The inhibition of PK-A using a specific inhibitor H8, decreased the maturation rate (rate of germinal vesicle breakdown, GVBD) of cumulus-enclosed pig oocytes in a dose-dependent manner by approximately 12%, reaching a plateau at 100 microM. The inhibition of PK-C with H7, an inhibitor with some side-effects on PK-A, decreased the maturation rate of cumulus-enclosed oocytes in a dose-dependent manner to a maximum of 20% at a concentration of 100 microM. The calmodulin antagonist W7 up to a concentration of 200 microM had no effects on maturation of cumulus-enclosed pig oocytes. None of the inhibitors (H7, H8 and W7) altered the patterns of protein synthesis of either pig oocytes and cumulus cells after maturation in vitro. Oocyte phosphoprotein patterns were, however, clearly changed by W7. Cumulus cell protein phosphorylation patterns were changed by all 3 agents. Since inhibition of cyclic AMP and Ca2+ phospholipid pathways by PK-A and PK-C blocking chemicals affected only a limited proportion of oocytes (12 and 20%, respectively) and inhibition of Ca2+ binding to CaM was without effect on oocyte maturation, we conclude that these pathways modulate rather than regulate oocyte maturation in the pig.
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PMID:Effects of protein kinase inhibitors on pig oocyte maturation in vitro. 129 83

To examine the role of protein kinase C (PKC) in induction of human colon adenocarcinoma cell line, DETA/W, by polypeptide growth-promoting factors, ornithine decarboxylase activity (ODC) and DNA synthesis were determined in cells depleted of PKC. PKC depletion was achieved by prolonged cultivation (more than 30 passages) with 10(-6) M phorbol 12-myristate 13-acelate. Lack of PKC in studied cells was proved by measurements of PKC activity and immunoreactivity. Although ODC activities and DNA syntheses in PKC-depleted cells were decreased by about 40-50% compared to normal DETA/W cells, the percentage increase of these mitogen-responsive reactions was quantitatively similar in both cell sublines. These results raise the possibility that not all of the biological responses to growth factors are connected with the activation of calcium-dependent PKC.
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PMID:Induction of ornithine decarboxylase in normal and protein kinase C--depleted human colon carcinoma cells. 129 68

The delta-subspecies of protein kinase C (PKC) was purified to near homogeneity from the Triton X-100 extract of the rat brain particulate fraction by successive chromatographies on S-Sepharose Fast Flow, Phenyl 5PW, Heparin 5PW, hydroxyapatite, and Mono Q columns. The purified enzyme was doublet with molecular weight of 78 kDa and 76 kDa on SDS-PAGE. This doublet proteins were separated partially by Mono Q column chromatography, both of which were recognized by the antibodies raised against synthetic oligopeptides, parts of the deduced amino acid sequence of the rat delta PKC. Protein phosphatase 2A treatment suggested that the 78 kDa protein was a phosphorylated form of the 76 kDa protein. To confirm the structural and genetic identity of the doublet proteins, delta PKC was expressed in COS 7 cells by transfecting its cDNA-constructed plasmid, and was purified for comparison. This recombinant enzyme was also doublet. The enzymes isolated from the brain and COS 7 cells showed identical reactivities with delta PKC-specific antibodies, chromatographic behaviors, and V8 protease peptide mapping. In addition, these the enzyme preparations were indistinguishable from each other in their responses to phosphatidylserine, diacylglycerol, phorbol esters, free fatty acids, and Ca2+. Comparison was also made between the enzymological properties of delta PKC and alpha PKC, such as activation kinetics, sensitivity to protein kinase inhibitors and substrate specificity which were distinctly different from each other.
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PMID:Enzymatic properties of ubiquitously expressed delta-subspecies of protein kinase C differing from other members of protein kinase C family. 129 10


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