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 calmodulin in human basophil histamine release, we triggered leukocytes with different secretagogues in the presence of putative inhibitors of calmodulin. Calcium ionophore-induced histamine release was reduced or blocked by calmidazolium, CGS 9343B, felodipine, metofenazate, and Ro 22-4839. H 186/86, a felodipine-related dihydropyridine derivative, blocked A23187-but not ionomycin-triggered histamine release, suggesting a difference in the mode of action of these ionophores. In contrast, leukocyte histamine release triggered by the purported protein kinase C (PKC) activator, 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9), was enhanced by calmidazolium, CGS 9349B and metofenazate but not affected by felodipine or Ro 22-4839, whereas the response triggered by 4 beta-phorbol 12-myristate 13-acetate (PMA) was reduced by metofenazate and Ro 22-4839 but not consistently affected by calmidazolium, CGS 9343B or felodipine. The PMA-induced histamine release was enhanced by H 186/86. Anti-IgE- and FMLP-induced responses were either unaffected or slightly enhanced by the examined calmodulin antagonists. In comparison with the calmodulin antagonists, R 59022, an inhibitor of diacylglycerol kinase, failed to reduce calcium ionophore-triggered histamine release, whereas FK506, an inhibitor of peptidyl prolyl cis-trans isomerase (PPI), reduced both anti-IgE- and ionophore-triggered responses. These results indicate that calmodulin constitutes an obligate link in signal transduction pathways leading to human leukocyte histamine release if the trigger is a calcium ionophore but not when responses are induced by anti-IgE, FMLP or PMA; a calmodulin-dependent component may rather balance responses induced by IpOCOC9.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis-trans isomerase in a secretagogue specific manner. 128 Sep 15

The incubation of primary cultures of rat hepatocytes with lipopolysaccharide (LPS) or biologically active phorbol esters promotes the release of nitric oxide to the incubation medium. This process is the result of the induction of the Ca(2+)-and calmodulin-independent form of nitric oxide synthase. Both the release of nitric oxide to the incubation medium and the expression of nitric oxide synthase activity exhibited a lag period of about 45-60 min after cell stimulation. Exposure of hepatocytes to both stimuli produced an antagonistic effect on nitric oxide release, with a half-maximal inhibition obtained with 14 nM phorbol 12,13-dibutyrate at saturating concentration of LPS. Incubation of cells with alpha-phorbol 12,13-didecanoate failed to counteract the effect of LPS or to induce nitric oxide synthase, suggesting that activation of protein kinase C was involved in this process.
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PMID:Phorbol esters induce nitric oxide synthase activity in rat hepatocytes. Antagonism with the induction elicited by lipopolysaccharide. 128 Nov 51

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

[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

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

An in vitro model to study the molecular control of binding of highly purified synaptic vesicles to presynaptic plasma membranes has been developed. Presynaptic plasma membranes were immobilized by dotting onto nitrocellulose, and binding of iodinated synaptic vesicle membranes was studied under varying experimental conditions. Synaptic vesicles bind to presynaptic plasma membranes in the presence of Ca2+ and ATP. Binding is reduced in the presence of EGTA and abolished by the calmodulin antagonist trifluoperazine. Vesicle binding is stimulated 5-fold after incubation--prior to dotting--of presynaptic plasma membranes with ATP in the presence of the phorbol-ester 12-O-tetradecanoylphorbol-13-acetate (1 microM) and 2.5-fold after preincubation with Ca2+ (50 microM). Pretreatment of plasma membranes with alkaline phosphatase strongly reduces vesicle binding. Microsomes prepared from bovine liver did not bind to presynaptic plasma membranes. Our results suggest that activation of protein kinase C and Ca2+ stimulate binding of synaptic vesicles to the presynaptic membrane. In the intact nerve terminal this interaction may represent an initial step in synaptic vesicle exocytosis.
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PMID:In vitro binding of isolated synaptic vesicles to presynaptic plasma membranes: activation by Ca2+ and protein kinase C. 130 19

Forebrain ischemia in gerbils, produced by brief bilateral carotid occlusion, induced the dramatic loss of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) as determined by both kinase activity assays and western blot analysis. In cortex and hippocampus, cytosolic CaM-kinase II was completely lost within 2-5 min of ischemia. Particulate CaM-kinase II was more stable and decreased in level approximately 40% after 10 min of ischemia followed by 2 h of reperfusion. CaM-kinase II in cerebellum, which does not become ischemic, was not affected. The rapid loss of CaM-kinase II within 2-5 min was quite specific because cytosolic cyclic AMP kinase and protein kinase C in hippocampus were not affected. These data indicate that cytosolic CaM-kinase II is one of the most rapidly degraded proteins after brief ischemia. Because the multifunctional CaM-kinase II has been implicated in the regulation of numerous neuronal functions, its loss may destine the neuronal cell for death.
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PMID:Ischemia-induced loss of brain calcium/calmodulin-dependent protein kinase II. 131 Jul 19

The Na+/H+ exchanger is a pH-regulatory protein that extrudes one H+ ion in exchange for one Na+ ion when intracellular pH declines. A number of studies have shown phorbol ester stimulation of activity in intact cells, leading to the idea that the exchanger is regulated by protein kinase C-mediated phosphorylation in vivo. cDNA encoding the protein has been cloned, and a recent model suggests a large internal cytoplasmic C-terminal domain that may be a site of regulation of the exchanger [Sardet, Franchi & Pouyssegur (1989) Cell 56, 271-280]. We examined this region of the protein using a rabbit cardiac Na+/H+ exchanger cDNA clone. cDNA of the Na+/H+ exchanger, coding for the C-terminal 178 amino acid residues, was cloned into the expression vector pEX-1 and expressed as a fusion protein with beta-galactosidase. The fusion protein reacted with an antibody produced against a synthetic peptide of the C-terminal 13 amino acid residues of the Na+/H+ exchanger, confirming the identity of the expressed protein. Control and experimental pEX-1-Na+/H+ exchanger protein was purified on a p-aminophenyl beta-D-thiogalactopyranoside-agarose column. Purified Ca2+/calmodulin-dependent protein kinase II readily phosphorylated the Na+/H+ exchanger protein in a Ca(2+)- and calmodulin-dependent manner in vitro, but this region of the protein was not a substrate for purified protein kinase C or for the catalytic subunit of cyclic AMP-dependent protein kinase. Control-expressed beta-galactosidase was phosphorylated to a maximal level of 0.77 +/- 0.17 mol of Pi/mol (mean +/- S.E.M., n = 6) whereas the fusion protein was phosphorylated to a maximal level of 4.09 +/- 0.39 mol of Pi/mol (n = 6), suggesting one site of phosphorylation in beta-galactosidase and three in the C-terminal domain of the Na+/H+ exchanger. Examination of the deduced amino acid sequence of this part of the exchanger reveals three consensus sequences for Ca2+/calmodulin-dependent protein kinase II. These results suggest that the exchanger may be directly regulated in vivo by calmodulin-dependent protein kinase II but not by protein kinase C or cyclic AMP-dependent protein kinase.
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PMID:Phosphorylation of the C-terminal domain of the Na+/H+ exchanger by Ca2+/calmodulin-dependent protein kinase II. 131 52

The 93 kDa protein gephyrin is a tubulin binding peripheral membrane protein that is associated with the inhibitory glycine receptor and has been implicated in its anchoring at central synapses. Here, we demonstrate that gephyrin as well as co-purifying tubulin are phosphorylated by a kinase activity which is endogenous to highly purified glycine receptor preparations. This kinase phosphorylates serine and threonine residues and utilizes ATP, but not GTP, as phosphate donor. Its activity is not affected by various activators and/or inhibitors of cyclic nucleotide-dependent kinases, calcium/calmodulin-dependent kinases, or protein kinase C. A five-fold stimulation of kinase activity was, however, observed in the presence of poly-lysine. Phosphorylation of gephyrin and/or tubulin might regulate receptor/cytoskeleton interactions at postsynaptic membrane specializations.
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PMID:The 93 kDa protein gephyrin and tubulin associated with the inhibitory glycine receptor are phosphorylated by an endogenous protein kinase. 131 18

Stimulation of the human promonocytic cell line U937 with antibody-coated chicken red blood cells (Ab-CRBC), leads to inositol phosphate (IP) release in the effector cells. Neomycin (5 x 10(-4) M) completely inhibits activation of phosphoinositide breakdown, while ADCC is suppressed in a dose-dependent manner. Bordetella pertussis toxin (PT) (0.5 micrograms/ml), entirely inhibits IP release, while ADCC activity is markedly suppressed. The PKC inhibitors H-7 and propranolol also suppress ADCC. HA-1004, which has far lower PKC inhibitory activity than H-7, has a minimal effect on ADCC. The calmodulin antagonists W-7 and TFP are strongly inhibitory. These results indicate that stimulation of U937 cells for ADCC is associated to an increase in IP levels, which may provide positive transduction signals for the activation of this lytic mechanism.
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PMID:Signal transduction during antibody-dependent cellular cytotoxicity mediated by U937 cells. 131 11


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