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)

To assess the role of protein kinase C (PKC) in the respiratory burst of adherent human polymorphonuclear leukocytes (PMNL), reduction of ferricytochrome C by cells triggered with a phorbol ester (PMA), ionophore A23187, serum-treated zymosan (STZ) or three lipid derivatives, 3-decanoyl-sn-glycerol (G-3-OCOC9), (R,R)-1,4-diethyl-2-O-decyl-L-tartrate (Tt-2-OC10) and 3-decyloxy-5-hydroxymethylphenol (DHP) was examined in a microtiter plate procedure in the presence of inhibitors of PKC and, for comparison, inhibitors of calmodulin, diacylglycerol and myosin light chain kinases and the peptidyl-prolyl cis-trans isomerase activity of fujiphilin. 1) Of the protein kinase inhibitors examined, Ro 31-7549 and staurosporine reduced responses to all stimuli except possibly STZ; in contrast, K252a and the myosin light chain kinase inhibitors ML-7 and ML-9 blocked responses to A23187 and STZ better than those triggered by PMA. H-7 reduced responses to A23187, DHP and G-3-OCOC9, and calphostin, palmitoyl carnitine, sphingosine and the multifunctional drugs TMB-8 and W-7 reduced A23187; they also, when examined, reduced decane derivative-induced O2- production more effectively than PMA- and STZ-triggered responses. Polymyxin B, 4 alpha-PMA and retinal displayed no inhibitory capacity. 2) Of the selective calmodulin antagonists, CGS 9343B, Ro 22-4839 and calmidazolium did not inhibit the oxidative response irrespective of the stimulus used, whereas metofenazate reduced those evoked by A23187, DHP, G-3-OCOC9 and STZ.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of neutrophil superoxide generation by inhibitors of protein kinase C, calmodulin, diacylglycerol and myosin light chain kinases, and peptidyl prolyl cis-trans isomerase. 128 79

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

This study was designed to investigate the mechanism of endothelin-1 (ET-1) contractions in Staphylococcus alpha-toxin-permeabilized vascular smooth muscle. Rabbit small mesenteric arteries permeabilized with alpha-toxin were mounted for isometric or isotonic force recording or were processed for determination of myosin light chain (MLC) phosphorylation levels. Addition of 100 nM ET-1 plus 10 microM GTP significantly enhanced myofilament Ca2+ sensitivity as compared with the addition of Ca2+ alone (EC50, 0.47 microM Ca2+ for Ca2+ alone and 0.13 microM Ca2+ for ET-1 plus (GTP). This enhanced sensitivity was reversed by GDP beta S. ET-1-induced contractions were relaxed at a constant [Ca2+] by the addition of 30 microM cAMP or cGMP, demonstrating a direct effect of the cyclic nucleotides on contractile regulation. Inhibition of protein kinase C activity by 100 nM staurosporine relaxed ET-1 plus GTP-induced contractions, and pretreatment with 40 microM chelerythrine inhibited the ET-1 plus GTP increase in force. At 0.32 microM Ca2+, steady-state levels of shortening velocity were not increased by ET-1 plus GTP, although steady-state levels of MLC phosphorylation were significantly enhanced. The ET-1-induced increase in MLC phosphorylation was not altered by changes in [Ca2+], whereas the shortening velocity was Ca2+ dependent, suggesting that the increase MLC phosphorylation level may be the result of protein kinase C, rather than MLC kinase, activation. These results are consistent with the hypothesis that ET-1 increases myofilament Ca2+ sensitivity by a G protein-dependent pathway and subsequent activation of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelin increases myofilament Ca2+ sensitivity in alpha-toxin-permeabilized rabbit mesenteric artery. 132 99

Arachidonic acid (AA) increased, at constant Ca2+, the levels of force and 20-kDa myosin light chain (MLC20) phosphorylation in permeabilized smooth muscle, and slowed relaxation and MLC20 dephosphorylation. The Ca(2+)-sensitizing effect of AA was not inhibited by inhibitors of AA metabolism (indomethacin, nordihydroguaiaretic acid, or propyl gallate), of protein kinase C (pseudopeptide) or by guanosine-5'-O-(beta-thiodiphosphate) and was abolished by oxidation of AA in air. A non-metabolizable AA analog, 5,8,11,14-eicosatetraynoic acid) also had Ca(2+)-sensitizing effects. Extensive treatment with saponin abolished the Ca(2+)-sensitizing effects of phorbol 12,13-dibutyrate and guanosine-5'-O-(gamma-thiotriphosphate), but not that of AA. A purified, oligomeric MLC20 phosphatase isolated from gizzard smooth muscle was dissociated into subunits by AA, and its activity was inhibited toward heavy meromyosin but not phosphorylase. We conclude that AA may act as a messenger-promoting protein phosphorylation through direct inhibition of the form of protein phosphatase(s) that dephosphorylate MLC20 in vivo.
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PMID:Arachidonic acid inhibits myosin light chain phosphatase and sensitizes smooth muscle to calcium. 132 35

Sodium azide completely inhibits the serotonin release induced by ADP, arachidonic acid and the thromboxane A2 mimetic U46619, but does not have any effect on the activation by PMA. Collagen and thrombin are inhibited when used at low concentrations, but not at high concentration. This pattern of activation suggests that the inhibition by azide is not a metabolic inhibition. The antagonism of U46619-induced secretion was further studied and was shown to be non-competitive. It is selective for certain components of the U46619 stimulus-response coupling: aggregation, serotonin secretion and the activation of protein kinase C are completely or almost completely inhibited by 300 microM sodium azide. Shape change, calcium elevation, cytoplasmic alkalinization and phosphorylation of myosin light chain are only partially modified. This suggests that azide may specifically inhibit one of the different forms of thromboxane A2 receptors present in platelets.
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PMID:Low concentrations of sodium azide specifically inhibit a thromboxane A2 pathway in human platelets. 141 87

Vanadate, 30 microM, contracts uterine smooth muscle of estrogen-dominated non-pregnant rats in Ca(2+)-free medium after preincubation with 3 mM EGTA. In spite of the phosphorylation of the myosin light chain during this contraction, studies with fura-2 suggested that this contraction was not accompanied by an increase in the cytosolic Ca2+ level. Inhibitors of the myosin light chain kinase and protein kinase C partly inhibited this contraction. Vanadate seems to enter the cell through anion channels to inhibit phosphatases, resulting in phosphorylation via basal activities of the myosin light chain kinase and protein kinase C. An increase in the cytosolic free Ca2+ level resulted in relaxation of the contracting muscle in the same manner as in the oxytocin-induced Ca(2+)-free contraction.
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PMID:Ca(2+)-independent contraction of uterine smooth muscle induced by vanadate and its inhibition by Ca2+. 142 86

We investigated the intracellular processes of the shape change in human megakaryoblastic leukemic cells, MEG-01, by platelet agonists. Thrombin induced the formation of many pseudopods. This shape change was also induced by phorbol 12-myristate 13 acetate (TPA) and weakly by Ca2+ ionophore, A23187, but not by ADP, collagen, or epinephrine. Electron microscopy and FITC-labeled phalloidin staining revealed thick submembranous microfilament bundles in the pseudopods of the shape-changed cells by thrombin. Shape change was inhibited by cytochalasin B. Since Ca(2+)-dependent phosphorylation reactions play central role on the initiation of shape change of platelet, we examined the effects of protein kinase C (PKC) inhibitor, H-7, and myosin light chain (MLC) kinase inhibitor, ML-9, on the shape change of MEG-01 cells induced by thrombin, and observed that H-7 potently inhibited thrombin-induced shape change, while ML-9 did not. These results suggest that thrombin-induced reorganization of microfilaments and shape change of MEG-01 cells are mediated by PKC, but not by MLC kinase.
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PMID:Thrombin-induced shape change in human megakaryoblastic leukemic cells, MEG-01, is mediated by protein kinase C. 144

A variety of anthraquinone (anthracene-9,10-dione) derivatives inhibits rat brain Ca(2+)- and phospholipid-activated protein kinase C (PKC) of which the most potent inhibitors are mitoxantrone (1,4-dihydroxy-5,8-bis[2-(hydroxyethylamino)-ethylamino]-9,10- anthracenedione) (IC50 4 microM) and quinalizarin (1,2,5,8-tetrahydroxy-anthraquinone (IC50 4 microM). Anthraquinone derivatives with less polar substitution in positions 1 to 4 and 5 to 8 are less effective as inhibitors of PKC. Wheat germ Ca(2+)-dependent protein kinase (CDPK) assayed with a myosin light chain-based peptide substrate is much less sensitive to inhibition by anthraquinones, the most effective anthraquinone inhibitors being the 1,2,4-trihydroxy (IC50 14 microM), 1,8-dihydroxy-3-methyl (IC50 56 microM) and 1,2,5,8-tetrahydroxy (IC50 65 microM) derivatives. Ca(2+)-calmodulin-dependent myosin light chain kinase (MLCK) is inhibited by a range of di-, tri- and tetrahydroxylated anthraquinones (IC50 values 2 to 53 microM), the most potent inhibitors being the more polar compounds, namely mitoxantrone (IC50 2 microM) and emodin (1,3,8-trihydroxy-6-methylanthraquinone) (IC50 8 microM). Mitoxantrone interacts with calmodulin as determined from abolition of Ca(2+)-dependent fluorescence enhancement of dansyl-calmodulin (IC50 4 microM). A range of anthraquinone derivatives inhibits the catalytic subunit of cAMP-dependent protein kinase (cAK). In a number of cases compounds acting as potent inhibitors of MLCK (such as mitoxantrone and emodin) are very poor inhibitors of cAK and vice versa.
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PMID:Inhibition of myosin light chain kinase, cAMP-dependent protein kinase, protein kinase C and of plant Ca(2+)-dependent protein kinase by anthraquinones. 146 88

Recently, one of the authors (K.I.) and other investigators reported that myosin light chain (MLC) of smooth muscle (gizzard, arterial and tracheal) was diphosphorylated by myosin light chain kinase (MLCK) and that diphosphorylated myosin showed a marked increase in the actin-activated myosin ATPase activity in vitro and ex vivo. In this study, we prepared myosin, actin, tropomyosin (human platelet), MLCK (chicken gizzard) and calmodulin (bovine brain) and demonstrated diphosphorylation of MLC of platelet by MLCK in vitro. Our results are as follows. (1) Platelet MLC was diphosphorylated by a relatively high concentration (greater than 20 micrograms/ml) of MLCK in vitro. As a result of diphosphorylation, the actin-activated myosin ATPase activity was increased 3 to 4-fold as compared to the monophosphorylation. (2) Both di- and monophosphorylation reactions showed similar Ca2+, KCl, MgCl2-dependence. Maximal reaction was seen at [Ca2+] greater than 10(-6) M, 60 mM KCl and 2 mM MgCl2. This condition was physiological in activated platelets. (3) Di- and monophosphorylated myosin showed similar Ca2+, KCl-dependence of ATPase activity but distinct MgCl2-dependence. Diphosphorylated myosin showed maximal ATPase activity at 2 mM MgCl2 and monophosphorylated myosin showed a maximum at 10 mM MgCl2. (4) The addition of tropomyosin stimulated actin-activated ATPase activity in both di- and monophosphorylated myosin to the same degree. (5) ML-9, a relatively specific inhibitor of MLCK, inhibited the aggregation of human platelets induced by thrombin ex vivo in a dose-dependent manner. Moreover, this drug also partially inhibited both di- and monophosphorylation reactions and actin-activated ATPase activity. On the other hand, H-7, a synthetic inhibitor of protein kinase C, had little effect on the aggregation of human platelets induced by thrombin ex vivo. From these results, we conclude that diphosphorylation of platelet myosin by MLCK may play an important role in activated platelets in vivo.
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PMID:Diphosphorylation of platelet myosin by myosin light chain kinase. 153 1

This review covers the recent developments gained in the exploration of V1-vascular vasopressin (AVP) receptors. We examine the different radioligands available for the pharmacological characterization of these receptors. The immediate transmembrane signaling of V1-vascular AVP receptors involves ligand-receptor complex formation, receptor lateral mobility and internalization, coupling to a Gq protein, activation of phospholipases A2, C and D, translocation and activation of protein kinase C, production of inositol 1,4,5-triphosphate and 1,2-diacylglycerol, mobilization of intracellular calcium, alteration of intracellular pH with activation of the Na+/H+ exchanger, calmodulin activation and myosin light chain phosphorylation. The secondary nuclear signal mechanisms triggered by activation of V1-vascular AVP receptors includes tyrosine phosphorylation, induction of gene expression and protein synthesis.
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PMID:Signal transduction of V1-vascular vasopressin receptors. 153 67


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