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)

Endothelium-derived relaxing factor (EDRF) inhibits platelet function, but the mechanism underlying this inhibitory effect is not known. To examine this, cultured acetylsalicylic acid (ASA)-treated endothelial cells (EC) from bovine aorta (BAEC) or from human umbilical vein (HUVEC) were incubated with washed, ASA-treated human platelets. Incubation of platelets with either BAEC or HUVEC resulted in inhibition of thrombin-induced platelet aggregation that was dependent on the number of EC added. This effect was potentiated by superoxide dismutase and reversed by treating EC with NG-nitro-L-arginine or by treating platelets with methylene blue, indicating that the inhibition of platelet aggregation was due to the release of EDRF by EC. EC significantly blocked the thrombin stimulated breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) and the production of phosphatidic acid in [32P]orthophosphate-labeled platelets and of inositol trisphosphate in [3H]myoinositol-labeled platelets. In addition, the thrombin-mediated activation of protein kinase C (PKC) and phosphorylation of myosin light chain were inhibited in the presence of EC. Finally, thrombin stimulated an increase in cytosolic ionized calcium concentration ([Ca2+]i) in fura2-loaded platelets that was abolished by concentrations of EC which also blocked thrombin-induced aggregation. These data indicate that EDRF blocks thrombin-induced platelet aggregation by inhibiting the activation of PIP2-specific phospholipase C and thereby suppressing the consequent activation of PKC and the mobilization of [Ca2+]i.
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PMID:Endothelium-derived relaxing factor inhibits thrombin-induced platelet aggregation by inhibiting platelet phospholipase C. 130 23

Interleukin-1 (IL-1), which plays an important role in the inflammatory response, was found to induce colony-stimulating factor-1 (CSF-1) expression in the MIA PaCa-2 cells. IL-1-induced CSF-1 production was markedly suppressed (70%) by pertussis toxin. This inhibition by pertussis toxin was reversed by benzamide, an inhibitor of ADP-ribosylation reactions. Similarly, IL-1-induced CSF-1 production was inhibited by cholera toxin and this inhibition was reversed by an arginine analog, p-methoxy-benzylaminodecamethylene guanidine sulfate. Dibutyryl-cAMP as well as other cAMP elevating agents such as theophylline and forskolin also suppressed IL-1-induced CSF-1 production, suggesting that cAMP concentrations inversely regulate the biosynthesis of CSF-1. Measurement of cAMP concentration indicated that IL-1 treatment of MIA PaCa-2 cells did not change the cAMP level. IL-1-induced CSF-1 production was not suppressed by the protein kinase C (PKC) inhibitor, H7, under conditions in which 12-O-tetradecanoylphorbol-13-acetate-induced CSF-1 production was completely abolished. These data suggest that IL-1-induced CSF-1 production is not mediated via the activation of PKC. Analysis of oncogene c-fos and c-jun expression has shown the enhancement of expression of both protooncogenes prior to CSF-1, suggesting that the expression of these two oncogenes may be the mechanism which triggers CSF-1 gene expression.
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PMID:Stimulation of macrophage colony-stimulating factor synthesis by interleukin-1. 131 5

Bovine lung cGMP-binding cGMP-specific phosphodiesterase (cG-BPDE) is a potent and relatively specific substrate for cGMP-dependent protein kinase (cGK) as compared to cAMP-dependent protein kinase (cAK) (Thomas, M. K., Francis, S. H., and Corbin, J. D. (1990) J. Biol. Chem. 265, 14971-14978). A synthetic peptide, RKISASEFDRPLR (BPDEtide), was synthesized corresponding to the sequence surrounding the phosphorylation site in cG-BPDE. BPDEtide retained the cGK/cAK kinase specificity demonstrated by native cG-BPDE: the apparent Km of BPDEtide for cGK was 5-fold lower than that for cAK (Km = 68 and 320 microM, respectively). Vmax values were 11 mumol/min/mg for cGK and 3.2 mumol/min/mg for cAK. The peptide was not phosphorylated to a measurable extent by protein kinase C or by calcium/calmodulin-dependent protein kinase II. Thus, the primary amino acid sequence of the peptide substrate was sufficient to confer kinase specificity. Studies in crude tissue extracts indicated that BPDEtide was the most selective peptide substrate documented for measuring cGK activity. Peptide analogs of BPDEtide were synthesized to determine the contribution of specific residues to cGK or cAK substrate specificity. Substitution of a Lys for the amino-terminal Arg did not reduce cGK/cAK specificity; neither did the exchange of an Ala for the non-phosphorylated Ser nor the removal of the 3 carboxyl-terminal residues. A truncated BPDEtide (RKISASE) served equally well as substrate (Km approximately 90 microM) for both kinases. However, restoration of the Phe, to yield RKISASEF, reproduced the original cGK/cAK specificity for BPDEtide (Km = 120 and 480 microM, respectively), primarily by decreasing the affinity of cAK. Addition of a carboxyl-terminal Phe to the peptide RKRSRAE (derived from the sequence of the cGK phosphorylation site in histone H2B) or to the peptide LRRASLG (derived from the sequence of the cAK phosphorylation site in pyruvate kinase) also improved the cGK/cAK specificity by decreasing the affinity of cAK. These data suggested that the Phe in each substrate tested is a negative determinant for cAK.
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PMID:A phenylalanine in peptide substrates provides for selectivity between cGMP- and cAMP-dependent protein kinases. 131 60

HeLa cells attach to a variety of substrata but spread only on collagen or gelatin. Spreading is dependent on collagen-receptor upregulation, clustering, and binding to the cytoskeleton. This study examines whether second messengers are involved in initiating the spreading process on gelatin. The levels of cytosolic free calcium ([Ca++]i), cAMP, and cytoplasmic pH (pHi) do not change during cell attachment and spreading. However, a basal level of [Ca++]i and an alkaline pH(i) are required for spreading. There is an activation of protein kinase C (PKC) and a release of arachidonic acid (AA) on attachment and before cell spreading. Inhibition of PKC does not block cell spreading, indicating that PKC activation is not essential for spreading. Inhibition of phospholipase A2 blocks cell spreading, whereas addition of exogeneous AA overcomes this inhibitory effect. Among AA metabolic pathways, inhibitors of lipoxygenase (LOX) block cell spreading, suggesting that a LOX product(s) formed from AA initiates spreading. Clustering receptors for collagen with polyclonal antibodies, or with anti-collagen-receptor antigen-binding fragments (Fab) in combination with a secondary antibody, induce AA release. Also, AA is released when cells attach to either immobilized gelatin or immobilized Arg-Gly-Asp (RGD) peptide. Thus, AA is released whenever receptor clustering is observed. Receptor occupancy is not sufficient to release AA; when cells are treated with gelatin or RGD peptide in solution or anti-collagen-receptor Fab fragments without secondary antibody, conditions where receptor clustering is not observed, AA is not released. Thus, a LOX metabolite(s) of AA formed by collagen-receptor clustering is a second messenger(s) that initiates HeLa cell spreading. LOX inhibitors also block the spreading of bovine aortic endothelial cells, chicken embryo fibroblasts, and CV-1 fibroblasts on gelatin or fibronectin, indicating that other cells might use the same second messenger system in initiating cell-substratum adhesion.
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PMID:Spreading of HeLa cells on a collagen substratum requires a second messenger formed by the lipoxygenase metabolism of arachidonic acid released by collagen receptor clustering. 131 41

Cyclic GMP accumulation induced by noradrenaline in astrocyte-enriched primary cultures from rat cerebrum involves synthesis of NO, as evidenced by the competitive inhibition exerted by the NO synthase inhibitor NG-monomethyl-L-arginine (IC50 = 3 microM). Furthermore, the noradrenaline effect was potently inhibited by haemoglobin (IC50 = 25 nM) and potentiated by superoxide dismutase, indicating that NO synthesis and cyclic GMP formation may occur in different subsets of astrocytes. Investigation of the receptors implicated by using selective adrenoceptor agonists and antagonists indicates that about 75% of the NO-dependent noradrenaline response is mediated by alpha 1-adrenoceptors and the rest by beta-adrenoceptors, with no evidence for potentiating effects between the two receptor types. This noradrenaline effect appears to require Ca2+ entry, since it is strongly dependent on extracellular Ca2+ but is not affected by conditions that will abolish intracellular Ca2+ mobilization (incubation with neomycin or pretreatment with carbachol). Inhibition by pretreatment with pertussis toxin is in agreement with involvement of the alpha 1A-adrenoceptor subtype in this Ca(2+)-dependent effect. However, implication of an unknown alpha 1-adrenoceptor subtype cannot be disregarded, because a similar inhibition is exerted by the presumably selective alpha 1B- and alpha 1C-adrenoceptor blocking agent chloroethylclonidine. Treatment of the cultures with the protein kinase C activator phorbol 12-myristate 13-acetate inhibits to a great extent the noradrenaline-induced cyclic GMP formation.
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PMID:Characterization of noradrenaline-stimulated cyclic GMP formation in brain astrocytes in culture. 133 10

1. The effects of bradykinin on nociceptors have been characterized on a preparation of the neonatal rat spinal cord with functionally connected tail maintained in vitro. Administration of bradykinin to the tail activated capsaicin-sensitive peripheral fibres and evoked a concentration-dependent (EC50 = 130 nM) depolarization recorded from a spinal ventral root (L3-L5). 2. The response to bradykinin was unaffected by the peptidase inhibitors, bestatin (0.4 mM), thiorphan (1 microM), phosphoramidon (1 microM) and MERGETPA (10 microM) or by the presence of calcium blocking agents, cadmium (200 microM) and nifedipine (10 microM). 3. Inhibition of cyclo-oxygenase with indomethacin (1-5 microM), aspirin (1-10 microM) and paracetamol (10-50 microM) consistently attenuated responses to bradykinin. 4. The effect of bradykinin was mimicked by the phorbol ester PDBu, an activator of protein kinase C. The response to bradykinin was attenuated following desensitization to PDBu but desensitization to bradykinin did not induce a cross-desensitization to PDBu. The protein kinase C inhibitor staurosporine (10-500 nM) consistently attenuated the effects of PDBu and bradykinin. 5. Bradykinin responses were reversibly enhanced by dibutyryl cyclic AMP (100 microM). However dibutyryl cyclic GMP (0.5 mM) and nitroprusside (10 microM) produced prolonged block of responsiveness to bradykinin. Prolonged superfusion with pertussis toxin did not affect responses to bradykinin. 6. The B1-receptor agonist des Arg9-bradykinin (10-100 microM) was ineffective alone or after prolonged exposure of the tail to lipopolysaccharide (100 ng ml-1) or epidermal growth factor (100 ng ml-1) to induce B1 receptors. The BI-receptor antagonist, des Arg9 Leu8-bradykinin (10 JM) did not attenuate the response to bradykinin. A number of bradykinin B2 antagonists selectively and reversibly attenuated the response to bradykinin. The rank order potency was Hoe 140> LysLys [Hyp3,Thi5 8,D-Phe7]-bradykinin> D-Arg[Hyp3, Thi5'8, D-Phe7]-bradykinin = D-Arg[Hyp2,Thi5'8, D-Phe7]-bradykinin.7. These data show that bradykinin produces concentration-dependent activation of peripheral nociceptors in the neonatal rat tail. The responses were unaffected by calcium channel block and were partially dependent on the production of prostanoids. Bradykinin-evoked responses were consistent with the activation of protein kinase C-dependent mechanisms. Cyclic GMP-dependent mechanisms may be involved in bradykinin-receptor desensitization whereas cyclic-AMP dependent mechanisms increase fibre excitability and facilitate bradykinin-induced responses. The effects of bradykinin were mediated by a B2 receptor.
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PMID:Bradykinin-induced activation of nociceptors: receptor and mechanistic studies on the neonatal rat spinal cord-tail preparation in vitro. 133 51

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary arterial hypoxic contraction: signal transduction. 135 5

A set of peptides derived from myelin basic protein was synthesized and the kinetics of their phosphorylation by protein kinase C was studied. The replacement or the removal of the N-terminal Gln had no effect on the activity of the parent peptide. The removal of the following Lys or Arg led to a systematic decrease in substrate activity. The modifications in the C-terminal part of the peptide had a weaker influence on the parameters Vmax and KM than those in the N-terminal. The rather regular dependence of the activity of substrates upon their structure does not allow the strict definition of a minimum substrate for protein kinase C.
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PMID:Peptide fragments of myelin basic protein as substrates of protein kinase C. 138 95

Modification of basic residues of protein kinase C by phenylglyoxal results in a reversible, dose-dependent inhibition of autophosphorylation and substrate phosphorylation. The inhibition is not due to specific modification of the Ca2+ or ATP binding sites. Modified PKC bound more [3H] phorbol ester than unmodified providing further evidence that the binding of lipids and the catalytic phosphotransferase activity have different regulatory sequences. Additionally, the effects of these modifying reagents were different on enzyme stimulated by phorbol esters or by the endogenous activator, 1,2-diacylglycerol. These studies suggest that there is at least 1 arginine residue that is unique in the binding site of these different activators.
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PMID:Chemical modification of arginine residues of protein kinase C. 141 81

In regenerating rat liver, nuclear protein histone H2A was shown to be phosphorylated on its amino-terminal serine residue [Sung et al. (1971) J. Biol. Chem. 246, 1358-1364], but the protein kinase which phosphorylates this residue has not been identified. To evaluate the possibility that protein kinase C can phosphorylate this residue, calf thymus histone H2A was 32P-labeled by incubation with [gamma-32P]ATP and highly purified protein kinase C from rat brain in the presence of calcium and phospholipid. About 1 mol of 32P was incorporated per mol of histone H2A and the Km and apparent Vmax of the reaction were calculated to be 2.1 microM and 0.35 mumol/min/mg, respectively. So histone H2A seemed to be a good substrate for protein kinase C. Further, the proteolytic phosphopeptides of 32P-labeled histone H2A were isolated by means of a series of column chromatographies and analyzed for their amino acid compositions. Comparison of the data with the known primary structure of histone H2A revealed their amino acid sequence as 1Ser-Gly-Arg. These data suggest that protein kinase C may be a candidate for the protein kinase which phosphorylates the amino-terminal serine residue of histone H2A during the regeneration of rat liver.
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PMID:Phosphorylation of histone H2A by protein kinase C and identification of the phosphorylation site. 150 Apr 20


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