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)

The putative protein kinase C (PKC) inhibitors polymyxin B and staurosporine were used to test the influence of PKC activity on the viability of lymphocytes. The cytotoxic effect of polymyxin B was characterized and it was found to be both time and dose dependent, with an LD50 in micromolar range, and counteracted by phorbol myristate acetate (PMA). To explore further the possible mechanism of action involved in polymyxin B-induced cell death, PKC activity and intracellular calcium were measured in polymyxin B-challenged lymphocytes. Polymyxin B inhibited PKC activity in both resting (25% inhibition) and PMA-stimulated (50% inhibition) cells, and increased intracellular calcium without disruption of the plasma membrane, a signal which is known to trigger apopotosis. Additionally, a number of experiments were conducted to assess the effect of staurosporine on PKC activity, cell growth, cell death and survival of mature lymphocytes. Staurosporine inhibited PKC activity in a dose-dependent manner (Ki close to 1 microM) and this effect correlated to some extent with the inhibition of [3H]thymidine incorporation and the breakdown of DNA into oligonucleosome-sized fragments. These results support the hypothesis that PKC is involved in the survival of mature lymphocytes undergoing apoptosis.
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PMID:Protein kinase C activation promotes cell survival in mature lymphocytes prone to apoptosis. 812 43

Myocardial protection in the rabbit induced by ischemic preconditioning is thought to be adenosine receptor linked, but the signaling pathway responsible for the protection has yet to be identified. This study tests whether protein kinase C could be involved. Either of two inhibitors of protein kinase C, staurosporine (50 micrograms/kg) or polymyxin B (24 mg/kg), were administered to rabbits subjected to 30 min regional myocardial ischemia followed by 180 min reperfusion. Half of the rabbits were preconditioned while the other half served as nonpreconditioned controls. Nonpreconditioned hearts without drug or treated with staurosporine or polymyxin B resulted in 37.8 +/- 3.1, 40.5 +/- 2.8, and 42.0 +/- 7.0% infarction of the risk zone, respectively. Preconditioning limited infarct size to 7.3 +/- 2.7%. Both inhibitors blocked protection in preconditioned hearts with 36.2 +/- 2.7 and 40.9 +/- 2.5% of the risk zone infarcted, respectively. Activation of protein kinase C with 4 beta-phorbol 12-myristate 13-acetate (PMA) or with 1-oleyl-2-acetyl glycerol (OAG) mimicked preconditioning in buffer-perfused hearts. PMA (0.01 nmol/min) or OAG (10 nmol/min) for 5 min was followed by 10 min of washout. Infarct size after 30 min regional ischemia was limited in the PMA and OAG groups (6.4 +/- 1.4 and 11.7 +/- 3.3 vs. 28.0 +/- 4.5% in untreated controls) and was equipotent with ischemic preconditioning (11.8 +/- 2.2%). Polymyxin B also blocked protection from ischemic preconditioning in the isolated heart (33.0 +/- 5.0%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preconditioning protects ischemic rabbit heart by protein kinase C activation. 816 Aug 17

Previous work has shown that PMA and diacylglycerols, activators of protein kinase C (PKC) can suppress cell polarity and locomotor activity of Walker carcinosarcoma cells in vitro, suggesting that PKC activation may result in a stop signal for tumor cell locomotion. This hypothesis was further analysed. The present results show that the DAG kinase inhibitor, R 59022, suppressed tumor cell polarity and strongly inhibited cell locomotion at a concentration of 10(-4), thus supporting the earlier finding that an increased availability of DAGs can suppress the locomotor activity of Walker carcinosarcoma cells. The results support the stop-signal hypothesis of PKC activation insofar as DAG kinase inhibition mimics the effects of DAGs and PMA. In order to clarify further the effects of protein kinase modulation on locomotion, we now extended our studies on structurally different inhibitors of protein kinases. In contrast to H-7, HA-1004 had no effect on cell polarity and did not reduce cell locomotion in the presence of colchicine, but reduced the proportion of spontaneously locomoting cells by 70% at 3 x 10(-4) M. Polymyxin B suppressed cell polarity and locomotion only at concentrations that proved to be toxic. Tamoxifen had no significant effect on cell polarity and locomotor activity. Sangivamycin did not suppress cell polarity and spontaneous locomotion at a concentration range of 10(-9) M to 10(-4) M. However, at 10(-4) M it decreased the proportion of migrating, colchicine-stimulated cells by 50%. The diverse responses to structurally different PKC inhibitors may be explained by their limited and variable specificity for PKC and different mechanisms of action on PKC.
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PMID:Shape changes and chemokinesis of Walker carcinosarcoma cells: effects of protein kinase inhibitors (HA-1004, polymyxin B, sangivamycin and tamoxifen) and an inhibitor of diacylglycerol kinase (R 59022). 839 Aug 1

1. ACh release from motor nerve endings in diaphragms of rats treated chronically with alpha-bungarotoxin (alpha-BuTX) is upregulated at the level of the individual endplate. Involvement of protein kinases in this mechanism of synaptic adaptation was investigated. 2. Miniature endplate potentials (MEPPs) and endplate potentials (EPPs) were recorded after mu-conotoxin treatment, which prevents muscle action potentials. The quantal content at endplates was calculated 'directly', i.e. by dividing the EPP amplitude by the MEPP amplitude. 3. Incubation of muscles from control and alpha-BuTX-treated rats with H-7, a protein kinase C (PKC) inhibitor, reduced MEPP amplitudes but had no clear effect on quantal contents. Polymyxin B, another PKC inhibitor, had a similar effect on muscles from alpha-BuTX-treated rats. 4. Incubation of muscles from alpha-BuTX-treated rats with K252a, a broad-spectrum protein kinase inhibitor of, amongst others, PKC, Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and neurotrophin receptor tyrosine kinases, resulted in a 30% decrease of the quantal content. However, K252a did not change the quantal content of controls. Incubations with the closely related compound K252b, which has an exclusively extracellular action, had a similar effect. 5. KN62, a specific inhibitor of CaMKII, decreased the mean quantal content of muscles from alpha-BuTX-treated rats by 18%. 6. Tyrphostin 51, a selective tyrosine kinase inhibitor, had no effect on quantal contents of muscles from alpha-BuTX-treated and control rats. However, it increased the frequency and amplitude of MEPPs in muscles from alpha-BuTX-treated rats, leaving those of controls unchanged. 7. The extent of reduction of quantal content, caused by K252a, K252b and KN62, varied between endplates of individual muscles from alpha-BuTX-treated rats; quantal contents at endplates with small MEPPs were more sensitive than those at endplates with large MEPPs. 8. It is concluded that PKC does not play a role in the mechanism of upregulation of ACh release at endplates of alpha-BuTX-treated rats. Instead, CaMKII and some tyrosine kinases in the presynaptic membrane, as well as in the cytoplasm, might be involved.
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PMID:Involvement of protein kinases in the upregulation of acetylcholine release at endplates of alpha-bungarotoxin-treated rats. 873 3

The aims of this study were (1) to determine the characteristics of preconditioning against contractile dysfunction in a blood perfused isolated heart model in the presence of a physiologic combination of substrates, and (2) to determine if protein kinase C (PKC) is involved in preconditioning in this model. In order to investigate these aims, isolated isovolumic, blood perfused rat hearts (balloon-in-LV, n = 6/group) were perfused normoxically for 30 min and then divided into three groups and subjected to: (1) a further 30 min of perfusion (control group) (2) a further 20 min of perfusion + 5 min of ischaemia and 5 min of reperfusion (1 x preconditioned group) and (3) 3 x (5 min of ischaemia+5 min of reperfusion) (3 x preconditioned group). All hearts were then subjected to 30 min of ischaemia and 30 min of reperfusion. Contractile function, myocardial oxygen consumption (MVO2), lactate release and creatine kinase release were all assessed. To determine if PKC is involved in the mechanism of preconditioning in this model, the control and 3 x preconditioned group experiments were repeated in the presence of polymyxin B (50 microM), a relatively specific PKC inhibitor. Final recovery of LVDP was 31 +/- 12, 67 +/- 6 and 60 +/- 5% in the control, 1 x and 3 x preconditioned groups, respectively. Protection of contractile function was accompanied by both a preservation of diastolic function and the ratio of MVO2 to contractile function (ratio of metabolic:mechanical efficiency). However, lactate release was decreased only in the 3 x preconditioned group. Polymyxin B abolished preconditioning-induced protection against contractile and diastolic dysfunction and the protection of the ratio of MVO2 to contractile function. Lactate release was still however reduced in the polymyxin B-preconditioned group. Thus, preconditioning-induced protection against contractile dysfunction appears to be accompanied by a preservation of both diastolic function and the metabolic: mechanical efficiency and is effective in the presence of a physiologic combination of substrates. However, limitation of glycolysis during ischaemia, as assessed by lactate release, appears to be an epiphenomenon of the preconditioning protocol and is not consistently related to protection. PKC activation appears to be pivotal to the mechanism of protection against contractile dysfunction, since administration of polymyxin B abolished any protection.
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PMID:Polymyxin B, a protein kinase C inhibitor, abolishes preconditioning-induced protection against contractile dysfunction in the isolated blood perfused rat heart. 876 36

Previous studies have proposed that oxygen radicals may play a role in the triggering of ischemic preconditioning. However, studies evaluating the effects of radical scavengers have yielded conflicting results, possibly because of differences in the number of preconditioning episodes used. The present study tested whether N-2-mercaptopropionylglycine (MPG) could block protection of both single and multiple episodes of preconditioning in in situ and in vitro rabbit hearts. All hearts were subjected to 30 min of regional ischemia followed by reperfusion for 2 (in vitro) or 3 (in situ) h. Infarct size was measured by tetrazolium. Infarction in control in situ hearts was 37.5+/-3.5% of the risk zone. A single cycle of preconditioning (PC1), with 5 min ischemia/10 min reperfusion, reduced infarct size to 12.3+/-2.0% (P<0.05). Four cycles of preconditioning (PC4) were equally protective. MPG (1 mg/kg/min i.v.) alone had no effect on infarction but abolished protection afforded by PC1 (35.4+/-3.9%). However, MPG failed to block protection in the PC4 group. In isolated control hearts, infarct size was 31.1+/-1.8% and was reduced to 10.2+/-2.2% (P<0.05) by preconditioning. MPG (300 microM) aborted protection. Infusion of hypoxanthine or xanthine oxidase separately in lieu of preconditioning had no effect on infarct size, but induced protection when combined (14.1+/-2.2%; P<0.05). Polymyxin B, an inhibitor of protein kinase C (PKC), abolished this protection (53.1+/-4.1%). In conclusion, oxygen radicals contribute to ischemic preconditioning in the rabbit and appear to do so via activation of PKC. The fact that MPG could not block protection by PC4 suggests that oxygen radicals act in concert with other triggers of preconditioning such as adenosine and bradykinin.
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PMID:Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. 904 35

1. The substrate of nitric oxide synthase (NOS), L-arginine (L-Arg, 0.01 microM - 1 mM), induced endothelium-independent relaxations in segments of middle cerebral arteries (MCAs) from normotensive Wistar-Kyoto (WKY) and hypertensive rats (SHR) precontracted with prostaglandin F2alpha (PGF2alpha). These relaxations were higher in SHR than WKY arteries. 2. L-N(G)-nitroarginine methyl ester (L-NAME) and 2-amine-5,6-dihydro-6-methyl-4H-1,3-tiazine (AMT), unspecific and inducible NOS (iNOS) inhibitors, respectively, reduced those relaxations, specially in SHR. 3. Four- and seven-hours incubation with dexamethasone reduced the relaxations in MCAs from WKY and SHR, respectively. 4. Polymyxin B and calphostin C, protein kinase C (PKC) inhibitors, reduced the L-Arg-induced relaxation. 5. Lipopolysaccharide (LPS, 7 h incubation) unaltered and inhibited these relaxations in WKY and SHR segments, respectively. LPS antagonized the effect polymyxin B in WKY and potentiated L-Arg-induced relaxations in SHR in the presence of polymyxin B. 6. The contraction induced by PGF2alpha was greater in SHR than WKY arteries. This contraction was potentiated by dexamethasone and polymyxin B although the effect of polymyxin B was higher in SHR segments. LPS reduced that contraction and antagonized dexamethasone- and polymyxin B-induced potentiation, these effects being greater in arteries from SHR. 7. These results suggest that in MCAs: (1) the induction of iNOS participates in the L-Arg relaxation and modulates the contraction to PGF2alpha; (2) that induction is partially mediated by a PKC-dependent mechanism; and (3) the involvement of iNOS in such responses is greater in the hypertensive strain.
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PMID:Role of iNOS in the vasodilator responses induced by L-arginine in the middle cerebral artery from normotensive and hypertensive rats. 1005 Nov 27

The effects of aqueous extract of Spiraea prunifolia var. simpliciflora's root, a traditional medicine for the treatment of malaria in Chinese medicine, on the generation of nitric oxide (NO) are investigated in RAW 264.7 cells. NO generation from IFN-gamma primed RAW 264.7 cells is markedly increased by the addition of aqueous extract in a dose-dependent manner. The enhancement of NO generation by the aqueous extract is accompanied by a significantly increased expression of inducible nitric oxide synthase (iNOS). However, the aqueous extract of Spiraea prunifolia var. simpliciflora's root does not affect the viability of RAW 264.7 cells, as assessed by MTT assay. Polymyxin B does not inhibit NO generation by the aqueous extract in IFN-gamma primed RAW 264.7 cells. However, polymyxin B significantly decreases NO generation by lipopolysaccharide (LPS) in IFN-gamma primed RAW 264.7 cells. These data indicate that the signaling pathway of the aqueous extract-induced NO generation is not dependent on PKC. These results strongly support the mechanism by which the aqueous extract may exert anti-malarial effect via direct cytotoxicity of NO as well as NO-mediated modulation of immune functions.
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PMID:Enhancement of nitric oxide synthesis by the aqueous extract of Spiraea prunifolia var. simpliciflora's root in RAW 264.7 cells. 1031 85

N-Methyl-D-aspartate (NMDA)-receptor stimulation evoked a selective and partly delayed elevated efflux of glutathione, phosphoethanolamine, and taurine from organotypic rat hippocampus slice cultures. The protein kinase inhibitors H9 and staurosporine had no effect on the efflux. The phospholipase A2 inhibitors quinacrine and 4-bromophenacyl bromide, as well as arachidonic acid, a product of phospholipase A2 activity, did not affect the stimulated efflux. Polymyxin B, an antimicrobal agent that inhibits protein kinase C, and quinacrine in high concentration (500 microM), blocked efflux completely. The stimulated efflux after but not during NMDA incubation was attenuated by a calmodulin antagonist (W7) and an anion transport inhibitor (DNDS). Omission of calcium increased the spontaneous efflux with no or small additional effects by NMDA. In conclusion, NMDA receptor stimulation cause an increased selective efflux of glutathione, phosphoethanolamine and taurine in organotypic cultures of rat hippocampus. The efflux may partly be regulated by calmodulin and DNDS sensitive channels.
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PMID:Searching for mechanisms of N-methyl-D-aspartate-induced glutathione efflux in organotypic hippocampal cultures. 1260 1

There is increasing evidence that Chlamydia pneumoniae is linked to atherosclerosis and thrombosis. In this regard, we have recently shown that C. pneumoniae stimulates platelet aggregation and secretion, which may play an important role in the progress of atherosclerosis and in thrombotic vascular occlusion. The aims of the present study were to investigate the effects of C. pneumoniae on platelet-mediated formation of reactive oxygen species (ROS) and oxidation of low-density lipoprotein (LDL) in vitro. ROS production was registered as changes in 2',7'-dichlorofluorescin- fluorescence in platelets with flow cytometry. LDL-oxidation was determined by measuring thiobarbituric acid reactive substances (TBARs). We found that C. pneumoniae stimulated platelet production of ROS. Polymyxin B treatment of C. pneumoniae, but not elevated temperature, abolished the stimulatory effects on platelet ROS-production, which suggests that chlamydial lipopolysaccharide has an important role. Inhibition of nitric oxide synthase with nitro-L-arginine, lipoxygenase with 5,8,11-eicosatriynoic acid and protein kinase C with GF 109203X significantly lowered the production of radicals. In contrast, inhibition of NADPH-oxidase with di-phenyleneiodonium (DPI) did not affect the C. pneumoniae induced ROS-production. These findings suggest that the activities of nitric oxide synthase and lipoxygenase are the sources for ROS and that the generation is dependent of the activity of protein kinase C. The C. pneumoniae-induced ROS-production in platelets was associated with an extensive oxidation of LDL, which was significantly higher compared to the effect obtained by separate exposure of LDL to C. pneumoniae or platelets. In conclusion, C. pneumoniae interaction with platelets leading to aggregation, ROS-production and oxidative damage on LDL, may play a crucial role in the development of atherosclerotic cardiovascular disease.
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PMID:Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets. Effects on oxidation of low density lipoproteins. 1611 22


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