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)

Two plant lectins, wheat germ agglutinin (WGA) and concanavalin A (Con A), which are known to bind to endothelial cells (ECs), were found to increase the leakage of colloidal carbon (CC) into the walls of microvessels in the villi of rat small intestine, when added to a gelatin-containing perfusate (GPSS) at a concentration of 10 micrograms/ml. Pretreatment of the microvessels with the protein kinase C (PKC) inhibitor Ro 31-8220 (1 x 10(-6) M) significantly reduced this effect. In contrast, the leakage of CC in response to A23187 (1 x 10(-4) M) was not affected by Ro 31-8220. Peanut agglutinin (PNA) and succinyl concanavalin A (SuccCon A), which do not bind to ECs, had no effect at a concentration of 10 micrograms/ml. A lower concentration of WGA (1 microgram/ml) had no significant effect of its own, but significantly reduced the leakage of CC in response to both platelet-activating factor (PAF, 5 x 10(-6) M) and 5-hydroxytryptamine (5-HT, 1 x 10(-4) M), but not to beta-phorbol 12,13-dibutyrate (PDB, 1 x 10(-6) M). These results suggest that all these effects of WGA and Con A involve cell surface receptors, albeit in a non-specific way. A possible mode of action is discussed.
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PMID:Lectin-induced increase in microvascular permeability to colloidal carbon in vitro may involve protein kinase C activation. 794 20

Staurosporine (STAR) is one of the most potent inhibitors of protein kinase C (PKC). It is known that in human polymorphonuclear leukocytes (PMNs), the phorbol ester-induced generation of superoxide anion (respiratory burst) is effectively inhibited by STAR in a dose-dependent manner, whereas superoxide generation induced by chemoattractants, e.g. n-formyl-methionyl-leucyl-phenylalanine (FMLP) or PAF, is regulated biphasically by STAR. We compared the effects of STAR and K252a on FMLP-induced superoxide production from PMNs and examined the effects of propranolol, a inhibitor of phosphatidic acid (PA) phosphohydrolase, on the potentiation of the production by STAR. We also examined the effects of some derivatives of STAR and K252a on the production and the alteration of the effects induced by propranolol pretreatment. When PMNs were stimulated with FMLP, STAR potentiated superoxide production by 240.5 +/- 30.9% at a low concentration (100 nmol/l). Propranolol pretreatment specifically inhibited the potentiation. When phorbol-12-myristate-13-acetate (PMA) was used as a stimulant, STAR inhibited superoxide production dose-dependently and did not enhance the production. K252a inhibited PMA or FMLP-induced superoxide production dose-dependently and did not enhance FMLP-induced superoxide production. STAR derivatives showed potentiation of FMLP-induced superoxide production similar to that of STAR at concentrations ranging from 10-100 nmol/l, and propranolol (200 mumol/l) effectively inhibited it. K252a derivative NA332 did not show any potentiative effect on the production. PMA-induced superoxide production was inhibited by all compounds dose-dependently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Staurosporine and its derivatives enhance f-Met-Leu-Phe-induced superoxide production via phospholipase D activation in human polymorphonuclear leukocytes. 798 27

High concentrations of PGF2 alpha and PGE2 are produced by the uterus during the early postpartum period in cows and may play an important role in both placental separation and uterine involution. In the present study, we have examined the hormonal and intracellular control mechanisms involved in PGF2 alpha and PGE2 secretion by caruncular and allantochorionic tissue in vitro. Tissue explants, obtained about 6 hr postpartum from cows that delivered normally (NFM, n = 10) or cows with retained fetal membranes (RFM, n = 4), were incubated for 6 hr and PGF2 alpha and PGE2 concentrations in the medium were determined by radioimmunoassay. Addition of oxytocin (100 microU/ml), platelet activating factor (PAF, 100 ng/ml) and epidermal growth factor (EGF, 100 ng/ml) had no effect on secretion of PGF2 alpha from the caruncle, but oxytocin and PAF did stimulate PGE2. There was no difference between groups of cows. All three substances stimulated PGF2 alpha from the allantochorion of NFM, but not RFM, cows and stimulated PGE2 secretion from the allantochorion of both groups of cows. Incubation of the tissues with cholera toxin (100 ng/ml), dibutyryl cyclic adenosine 3',5'-monophosphate (dibutyryl cAMP, 1 mM), calcium ionophore A23187 (5 microM) or phorbol ester 12-myristate-13 acetate (PMA, 100 nM) showed that PGF2 alpha secretion is essentially via the calcium-protein kinase C effector pathway. However, calcium-protein kinase C and cAMP second messenger systems appear to be involved in the secretion of PGE2. Prostaglandin secretion was sensitive to cycloheximide in both caruncular and allantochorionic tissues, suggesting that protein synthesis may be involved. In conclusion, these data show that in vitro PGF2 alpha secretion can be modulated by the agonists used only in allantochorion and is essentially via the calcium-protein kinase C effector pathway. PGE2 secretion can be modified in both caruncular and allantochorion tissues and involves both inositol triphosphate-diacylglycerol and cAMP second messenger systems.
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PMID:Control of in vitro prostaglandin F2 alpha and E2 synthesis by caruncular and allantochorionic tissues from cows that calved normally and those with retained fetal membranes. 804 99

The formylpeptide (fMLP) and C5a chemoattractants were previously shown to cross-desensitize each other's ability to mobilize Ca2+ in leukocytes but not to affect nonchemoattractant Ca(2+)-mobilizing receptors, and vice versa. Our data show that all receptors studied underwent homologous desensitization. Interestingly, peptide chemoattractants (fMLP, C5a, and IL-8) desensitized each other's Ca(2+)-mobilizing responses, but had no effect on a Ca(2+)-mobilizing purinergic receptor. Lipid chemoattractant receptors (PAF and leukotriene B4) were also desensitized by peptide chemoattractants but not vice versa. In the presence of cytochalasin B, only fMLP and C5a caused the activation of phospholipase D in intact leukocytes and enhanced desensitization of IL-8 and C5a but not fMLP receptors. To measure receptor/G protein interactions, agonist-stimulated GTP gamma S binding to leukocyte membranes was measured. Whereas all peptide receptors underwent homologous desensitization, C5a and IL-8, but not fMLP, receptors were cross-desensitized by other peptide chemoattractants. Furthermore, PMA caused inhibition of C5a- and IL-8- but not fMLP-stimulated GTP gamma S binding. These data suggest that in addition to homologous desensitization, peptide chemoattractant receptors cross-desensitize one another by at least two processes. One can be detected at the level of receptor/G-protein interaction and possibly involves receptor phosphorylation by protein kinase C. The fMLP receptor is resistant to this process. The second process is distal to receptor/G-protein interaction and utilizes an undefined pathway to cross-desensitize the Ca2+ mobilization response to all peptide chemoattractants. We propose that receptor cross-desensitization in leukocytes is orchestrated at several levels by mechanisms with selectivity for types of chemoattractant receptors.
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PMID:Cross-desensitization of receptors for peptide chemoattractants. Characterization of a new form of leukocyte regulation. 808 98

The capacity of human neutrophils to bind PAF was rapidly diminished upon cell stimulation with both physiological agonists (N-formylmethionylleucylphenylalanine (FMLP), leukotriene B4 (LTB4)) and pharmacologic agonists (phorbol 12-myristate 13-acetate (PMA), A23187). As a consequence, PAF responses in neutrophils were blunted, as monitored by an inhibition of intracellular Ca2+ mobilization. Downregulation of the PAF receptor in neutrophils by diverse agonists was temperature-sensitive and required intact cells. Scatchard analysis of binding data revealed that PAF binding sites were lost without an appreciable change in the affinity of the ligand for the receptor. The binding of the PAF receptor antagonist WEB2086 to neutrophils decreased in parallel with PAF binding. PMA-induced PAF receptor downregulation was staurosporine-sensitive while PAF receptor downregulation by A23187, FMLP, or LTB4 was staurosporine-resistant. Both neutrophil aggregation (a form of intercellular adhesion) and PAF receptor downregulation occurred only at high concentrations of agonists while other signaling processes such as the increase in [Ca2+]i, PKC activation, and PAF synthesis were stimulated at low concentrations of agonists. Furthermore, agonist-induced PAF receptor downregulation was observed only under conditions in which the activated neutrophils were stirred (or shaken) and were allowed to aggregate. Additionally, chelation of extracellular Ca2+ with EGTA minimized cell aggregation and also inhibited PAF receptor downregulation. While the nature of the biochemical signal or the physical changes in the plasma membrane associated with aggregation or that follow aggregation remain to be elucidated it is clear that full expression of cell activation (i.e., neutrophil aggregation) is required for PAF receptor downregulation.
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PMID:Impaired surface expression of PAF receptors on human neutrophils is dependent upon cell activation. 810 73

1. Accumulation of [3H]-inositol phosphates (IPs) was slightly enhanced by PAF in a concentration-dependent manner, but the accumulation was very small as compared with that induced by carbachol. 2. The levels of [32P]-phosphatidic acid which is transformed from diacylglycerol (DAG) were increased by treatment with PAF or with carbachol. 3. PAF-induced contraction was significantly reduced by treatment with phorbol 12-myristate 13-acetate (PMA). 4. These results suggest that while PAF slightly stimulates the turnover of phosphatidylinositol (PI) in the rat stomach fundus, this response may not be responsible for the PAF-induced contractile response, and that the desensitization induced by repeated application of PAF may be due to the activation of protein kinase C.
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PMID:Mechanism of the contractile response to platelet-activating factor (PAF) of the rat stomach fundus. II. PAF-induced phosphatidylinositol turnover and desensitization. 811 4

The vasculature of the rat small intestine and attached mesentery was perfused in vitro with a gelatin-containing physiological salt solution (GPSS). The inclusion of colloidal carbon (CC) in the perfusate towards the end of the experimental period enabled the "leakiness" of microvessels in the villi to be determined, since "leaky" vessels trap CC in their walls. Addition to the perfusate of the inflammatory agonists platelet-activating factor (PAF, 5 x 10(-6) M) or 5-hydroxytryptamine (5-HT, 1 x 10(-4) M), or the microtubule-disrupting agents podophyllotoxin (5 x 10(-5) M), or colcemid (5 x 10(-5) M), or the protein kinase C (PKC) activator phorbol 12, 13-dibutyrate (PDB, 1 x 10(-6) M), caused significantly increased microvascular "blackening" as assessed by image analysis. 4 alpha-phorbol 12, 13-didecanoate (PDD, 1 x 10(-6) M) had no effect. Pretreatment with the PKC inhibitor Ro 31-8220 [corrected] (1 x 10(-6) M) significantly reduced the effects of PAF, 5-HT and PDB, but not those of podophyllotoxin or colcemid. These results suggest, therefore, that PKC is involved in the permeability-enhancing effects of PAF, 5-HT and PDB. Pretreatment with indomethacin (1 x 10(-6) M) as a cyclooxygenase inhibitor did not reduce the response to PDB, indicating that prostaglandin release is of minor importance in the PDB-induced increase in microvascular permeability.
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PMID:Involvement of protein kinase C in the control of microvascular permeability to colloidal carbon. 830 40

We have detected in human platelets two protein kinase C isozymes that have not been reported previously. Using an anti-nPKC theta antibody and Western blotting, we calculated the molecular weight of platelet nPKC theta as 79K. This molecular weight is identical to that described for nPKC theta in skeletal muscle and in COS cells transfected with the nPKC theta-cDNA. Using an anti-nPKC eta antibody, we determined the molecular weight of an immunoreactive protein, which we called nPKC eta', to be 95K. This molecular weight is higher than that of nPKC eta found in lung and skin tissue of 82K and 78K, and it is higher than nPKC eta of COS cells transfected with the nPKC eta-cDNA expression plasmid. Together with previous reports, these findings make the total number of PKC isozymes in human platelets equal to six. These are the PKC isozymes: alpha, beta, delta and zeta, which have been previously described, and eta' and theta which we describe here. To assess the functionality of these new PKC isoforms, we stimulated platelets with PAF. We found a 200% and 175% increase in the levels of membrane-bound nPKC eta' and nPKC theta, respectively, in human platelets stimulated by PAF. A concomitant decrease in the level of these isoforms in the cytoplasm was observed. This PAF-induced translocation was time-dependent, and it reached its peak after a 1 minute incubation of human platelets with PAF for nPKC theta and 30 seconds for nPKC eta'.
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PMID:A new protein kinase C, nPKC eta', and nPKC theta are expressed in human platelets: involvement of nPKC eta' and nPKC theta in signal transduction stimulated by PAF. 844 26

From current information, a brief review was made on the basic properties of a possible process of eosinophil activation and degranulation. The "activated" eosinophils show the following characteristics: diminished cell density, morphologic alterations, increased surface receptors, heightened parasite killing, increased metabolic activity and prolonged survival. Immune complexes (secretory IgA, IgG, IgE) are known as potent triggering stimuli of eosinophil degranulation as well as complement fragments (C3b, C3bi). Cytokines (IL-5, GM-CSF), PAF and peptides (substance P) act both as weak degranulation inducer and degranulation enhancer. Synergism between the two pathways, Ca2+ and protein kinase C, is now recognized as a common feature of control of secretion in eosinophils.
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PMID:[Eosinophil granule proteins (MBP, ECP, EPX/EDN, EPO)--a possible process of eosinophil activation and degranulation]. 849 33

Platelet-agonist interaction results in activation of glycoprotein (GP) IIb-IIIa complex and fibrinogen binding, a prerequisite for platelet aggregation. Fibrinogen binding exposes new antibody binding sites on GPIIb-IIIa (ligand-induced binding sites: LIBS). Signal transduction events, including pleckstrin phosphorylation by protein kinase C (PKC), are considered to regulate GPIIb-IIIa activation. We studied a 16-year-old white male with lifelong mucocutaneous bleeding manifestations and abnormal platelet aggregation and secretion in response to multiple agonists. Pleckstrin phosphorylation was diminished in response to platelet-activating factor (PAF; 4 and 400 nmol/L) and thrombin (0.05 U/mL). Binding of monoclonal antibodies (MoAbs) 10E5 and A2A9, which bind to both resting and activated GPIIb-IIIa, was normal. Binding of MoAb PAC1, which binds to only activated GPIIb-IIIa, was diminished upon activation with PAF, adenosine diphosphate (ADP), thrombin receptor agonist peptide (SFLLRN), A23187, and 1,2-dioctonylglycerol (DiC8). Signal transduction-dependent LIBS expression (studied using MoAb 62) induced by ADP, SFLLRN, and DiC8 and signal transduction-independent LIBS expression induced by RGDS peptide or disintegrin albolabrin were normal or minimally decreased, indicating the presence of intact ligand binding sites. We conclude that the patient's platelets have a defect in inside-out signal transduction-dependent GPIIb-IIIa activation due to an upstream defect in the signal transduction mechanisms rather than in the GPIIb-IIIa complex itself. Our findings extend the spectrum of congenital mechanisms leading to impaired aggregation from defects in GPIIb-IIIa per se to aberrations in signaling mechanisms.
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PMID:Abnormal inside-out signal transduction-dependent activation of glycoprotein IIb-IIIa in a patient with impaired pleckstrin phosphorylation. 860 26


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