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)

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

The membrane electrical properties and resting ionic conductances of frog semitendinosus muscle fibres were studied in vitro at 25 degrees C with the two-micro-electrode cable technique, in the presence of an activator or inhibitor of protein kinase C (PKC) or in the presence of an activator of adenylate cyclase. The PKC activator, 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB), reduced chloride conductance (GCl) at concentrations greater than 1 microM and did not affect potassium conductance (GK). At 150 microM, the maximum concentration of 4 beta-PDB tested, GCl was reduced by 42%. The "inactive" phorbol ester 4 alpha-phorbol 12,13-dibutyrate did not affect GCl or GK. The inhibitory effect of 4 beta-PDB on GCl was prevented by pretreatment of the muscle preparation with the PKC inhibitor staurosporine. The adenylate cyclase activator forskolin (1.5-8 microM) significantly increased the GK of the fibres, without affecting GCl. Thus, we conclude that frog skeletal muscle GCl, unlike rat muscle GCl, is relatively insensitive to activators of PKC. Moreover, in frog muscle, protein kinase A is a likely modulator of GK, but not GCl.
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PMID:Regulation of resting ionic conductances in frog skeletal muscle. 832 21

Lipopolysaccharide (LPS) treatment impairs cardiac myocyte contractility in a nitric oxide synthase (NOS)-dependent manner. The objective of this study was to assess whether protein kinase C (PKC) transduces the LPS signal into an enhanced NOS activity in rat cardiac myocytes. LPS (100 ng/ml) stimulated myocyte PKC activity, inducible NOS (iNOS) expression, and NOS activity in a time- and protein synthesis-dependent fashion. Directly activating PKC with beta-phorbol 12,13-dibutyrate (beta-PDB) also induced myocyte iNOS synthesis and NOS activity and reduced electrically stimulated contractility, while the inactive alpha-PDB was ineffectual. Contractility could be restored to beta-PDB-incubated cells by superfusion with the NOS inhibitor N omega-nitro-L-arginine methyl ester. PKC blockade with sphingosine, chelerythrine, or calphostin-C precluded LPS- and beta-PDB-induced increases in NOS activity and protected contractility. Depletion of PKC by 18 h of incubation with beta-PDB in the presence of chelerythrine also blocked acquisition of enhanced NOS activity and contractile dysfunction when the myocytes were subsequently exposed to LPS. These findings suggest that PKC is a significant intracellular mediator for the effects of LPS on cardiac cell NOS activity and contractile function.
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PMID:PKC mediates LPS- and phorbol-induced cardiac cell nitric oxide synthase activity and hypocontractility. 859 96

The hypothesis that the increase in Ca2+ sensitivity on norepinephrine-induced contraction of smooth muscles and also the decrease of the norepinephrine-induced sustained level of intracellular Ca2+ concentration are produced by the activation of protein kinase C was tested. Phorbol 12,13-dibutyrate (PDB; 10(-6) M) relaxed the norepinephrine-induced sustained contraction in a concentration-dependent manner. On pretreatment with PDB a transient contraction was produced by the application of norepinephrine, but the sustained contraction was significantly reduced. The sustained elevations of intracellular Ca2+ concentration ([Ca2+]i) and the contraction induced by norepinephrine in fura-2-loaded preparations were decreased by the application of PDB. These inhibitory effects were antagonized by potent protein kinase inhibitors, 2-(1-(3-dimethylaminopropyl)-indol-3-yl)-3-(-indol-3-yl)-maleimide (GF 109203X) (10 (-6) M) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) (10 (-6) M), but were not affected by a protein kinase A/G inhibitor, N-(2-cinnamylaminoethyl)-5-isoquinolinesulfonamide (H-88) (10(-6) M). The slope of the regression line for norepinephrine for [Ca2+]i and tension was significantly steeper than those obtained with high K+. Also, on pretreatment with PDB the Ca2+ sensitivity of the K(+)-induced contraction was decreased, but the Ca2+ sensitivity of norepinephrine-induced contraction tended to be increased. These observations indicate that PDB induces a decrease of [Ca2+]i on Ca2+ mobility and an increase of Ca2+ sensitivity on contraction of smooth muscle through the activation of protein kinase C.
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PMID:Inhibitory effect of phorbol 12,13-dibutyrate on norepinephrine-induced contraction in rabbit iris dilator muscle. 884 Jan 25

Changes in cytosolic free Ca2+ concentration ([Ca2+]i) induced by ATP and other P2 purinoceptor agonists were investigated using indo 1 microspectrofluorimetry in single smooth muscle cells of the rat pulmonary artery. ATP (100 microM, 30 s) induced 3-4 cyclic rises in [Ca2+]i of decreasing amplitude. The first peak reached 743 +/- 24 nM from the resting value of 103 +/- 5 nM (n = 86). In approximately 50% of the cells, the ATP-induced [Ca2+]i oscillations were accompanied by a small but maintained rise in [Ca2+]i. In a series of 10 cells, the amplitude of this rise averaged 41 +/- 9 nM. The small rise 1) was also induced by 2-methylthio-ATP (2-MeS-ATP) and alpha,beta-methylene-ATP (alpha,beta-MeATP), 2) was insensitive to thapsigargin (TG, 1 microM), and 3) was abolished by the removal of external Ca2+. ATP-induced [Ca2+]i oscillations 1) were not abolished in the absence of external Ca2+, 2) were suppressed by treatment of the cells with TG (1 microM), and 3) were mimicked by UTP but not by 2-MeS-ATP or alpha,beta-MeATP. Both the number of cells that responded by [Ca2+]i oscillations and the maximal amplitude of the response depended on the agonist (ATP or UTP) concentration. The ATP-induced [Ca2+]i oscillations were not modified by tetracaine (500 microM) but were inhibited by forskolin (1 microM) and by phorbol 12,13-dibutyrate (PDB, 0.03 microM). The effect of PDB was reversed by the protein kinase C antagonist calphostin C (0.01 microM). These results suggest that the ATP-induced [Ca2+]i rise is mediated by the activation of P2x and P2u purinoceptors. Ca2+ entry through the P2x receptor channels produces a small and maintained [Ca2+]i rise. [Ca2+]i rise. Stimulation of P2u purinoceptor induces [Ca2+]i oscillations due to cyclic Ca2+ release from intracellular stores through inositol trisphosphate receptor channels.
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PMID:Effect of extracellular ATP on cytosolic Ca2+ concentration in rat pulmonary artery myocytes. 884 94

1. The effects of various protein kinase C (PKC) activators on the stimulation-induced (S-I) release of noradrenaline and dopamine was studied in rat cortical slices pre-incubated with [3H]-noradrenaline or [3H]-dopamine. The aim was to investigate a possible structure-activity relationship for these agents on transmitter release. 2. 4 beta-Phorbol 12,13-dibutyrate (4 beta PDB, 0.1-3.0 microM), enhanced S-I noradrenaline and dopamine release in a concentration-dependent manner whereas the structurally related inactive isomer 4 alpha-phorbol 12, 13-dibutyrate (4 alpha PDB, 0.1-3.0 microM) and phorbol 13-acetate (PA, 0.1-3.0microM) were without effect on noradrednaline release. Another group of phorbol 12, 13-diesters containing a common 13-ester substituent (phorbol 12, 13-diacetate, PDA, 0.1-3.0 microM; phorbol 12-myristate 13-acetate, PMA, 0.1-3.0 microM; phorbol 12-methylaminobenzoate 13-acetate, PMBA, 0.03-3.0 microM) also enhanced S-I noradrenaline and dopamine release in a concentration-dependent manner with PMA being the least potent. 3. The 12-deoxyphorbol 13-substituted monoesters, 12-deoxyphorbol 13-acetate (dPA, 0.1-3.0 microM), 12-deoxyphorbol 13-angelate (dPAng, 0.1-3.0 microM), 12-deoxyphorbol 13-isobutyrate (dPiB, 0.03-3.0 microM) and 12-deoxyphorbol 13-phenylacetate (dPPhen, 0.1-3.0 microM) enhanced S-I noradrenaline and dopamine release in a concentration-dependent manner. In contrast, 12-deoxyphorbol 13-tetradecanoate (dPT, 0.1-3.0 microM) was without effect. 4. The involvement of PKC in mediating the effects of the various phorbol esters was further investigated. PKC was down-regulated by 20 h exposure of the cortical slices to 4 beta-phorbol 12,13-dibutyrate (1 microM). In this case the facilitatory effect of 4 beta PDB and dPA was abolished whilst that of dPAng was significantly attenuated. This indicates that these agents were acting selectively at PKC. In support of this the PKC inhibitors, polymyxin B (21 microM) and bisindolylmaleimide I (3 microM), attenuated the facilitatory effect of 4 beta PDB and dPAng although that of dPA was not significantly altered. 5. The effects of these agents on transmitter release were not correlated with their in vitro affinity and isozyme selectivity for PKC. Short chain substituted mono- and diesters of phorbol were more potent enhancers of action-potential evoked noradrenaline and dopamine release than the long chain esters. Interestingly, these former agents are the least potent or non effective (e.g. dPA, PDA) tumour promoters. We suggest that the reason for the poor effects of lipophilic long chain phorbol esters (PMA, dPT) on transmitter release is that they are sequestered in the plasmalemma and do not access the cell cytoplasm where the PKC may be located.
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PMID:The structural requirements for phorbol esters to enhance noradrenaline and dopamine release from rat brain cortex. 887 64

The high affinity GTPase activity in the mouse spinal cord was increased in a concentration-dependent manner by a selective delta 2-opioid receptor agonist, [D-Ala2]deltorphin II (0.1-1 microM). This increase of GTPase activity induced by [D-Ala2]deltorphin II was completely blocked by co-incubation with a selective delta 2-opioid receptor antagonist, naltriben (0.1 microM). A protein kinase C activator, phorbol 12,13-dibutyrate (PDB; 0.1-10 microM), which given alone had no effect on basal GTPase activity, blocked dose-dependently the increase of GTPase activity induced by [D-Ala2]deltorphin II (1 microM). Our results indicate the possibility that activation of protein kinase C by phorbol ester uncouples the delta 2-opioid receptor from G-proteins in the spinal cord.
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PMID:Phorbol ester blocks the increase of a high affinity GTPase activity induced by delta 2-opioid receptor agonist in the mouse spinal cord. 888 28

1. [3H]Noradrenaline (NA) AND [14C]acetylcholine (ACh) released by electrical field stimulation were measured simultaneously in strips from the body of rat urinary bladder. 2. [3H]NA and [14C]ACh release was greater during continuous stimulation (CS; 10 Hz, 100 shocks) or in the presence of eserine than during intermittent train stimulation (IS; 10 Hz, 10 shocks every 5 s, 10 times). Atropine (1 microM) or pirenzepine (0.05-0.1 microM) blocked the CS- or eserine-facilitated release. 3. The protein kinase C (PKC) activator phorbol dibutyrate (PDB; 0.05 and 0.5 microM) increased the release of both [3H]NA and [14C]ACh in a concentration-dependent manner. Atropine blocked the PDB-induced facilitation of ACh release but not the facilitation of NA release. 4. The protein kinase A (PKA) activator 8-Br-cAMP did not affect ACh release but enhanced NA release. 5. The PKC inhibitor H-7 (50-100 microM) inhibited the CS- or eserine-facilitated release of both ACh and NA, but did not affect the non-facilitated release evoked by IS. H-7 also inhibited 0.5 microM PDB-induced facilitation of ACh release but not NA release. 6. Down-regulating PKC by pretreatment for 30 min with 5 microM PDB decreased the facilitated release of ACh and the eserine-induced facilitation of NA release. 7. Electrically evoked contractions of the bladder strips exhibited a biphasic response to PDB (2.5 microM), which consisted of an initial enhancement of the peak amplitude and area followed after 20 min by an inhibition of contractions. H-7 inhibited the electrically evoked contractions in a dose-dependent fashion. 8. It is concluded that a phospholipase C-PKC signal transduction pathway is essential for muscarinic receptor-induced facilitation of ACh and NA release but is not involved in the non-facilitated release of transmitters in the rat urinary bladder.
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PMID:M1 muscarinic receptor-induced facilitation of ACh and noradrenaline release in the rat bladder is mediated by protein kinase C. 891 Feb 12

Protein kinase D (PKD) is a serine/threonine protein kinase that is directly stimulated in vitro by phorbol esters and diacylglycerol in the presence of phospholipids. Here, we examine the regulation of PKD in living cells. Our results demonstrate that tumour-promoting phorbol esters, membrane-permeant diacylglycerol and serum growth factors rapidly induced PKD activation in immortalized cell lines (e.g. Swiss 3T3 and Rat-1 cells), in secondary cultures of mouse embryo fibroblasts and in COS-7 cells transiently transfected with a PKD expression construct. PKD activation was maintained during cell disruption and immunopurification and was associated with an electrophoretic mobility shift and enhanced 32P incorporation into the enzyme, but was reversed by treatment with alkaline phosphatase. PKD was activated, deactivated and reactivated in response to consecutive cycles of addition and removal of PDB. PKD activation was completely abrogated by exposure of the cells to the protein kinase C inhibitors GF I and Ro 31-8220. In contrast, these compounds did not inhibit PKD activity when added directly in vitro. Co-transfection of PKD with constitutively activated mutants of PKCs showed that PKCepsilon and eta but not PKCzeta strongly induced PKD activation in COS-7 cells. Thus, our results indicate that PKD is activated in living cells through a PKC-dependent signal transduction pathway.
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PMID:Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. 894 45

Broussochalcone A, a prenylated chalcone isolated from Broussonetia papyrifera (L.) VENT. (Moraceae), inhibited O2 consumption in formylmethionyl-leucyl-phenylalanine (fMLP)- and phorbol 12-myristate 13-acetate (PMA)-stimulated rat neutrophils in a concentration-dependent manner with IC50 values of 70.3 +/- 4.9 and 63.9 +/- 7.1 microM, respectively. Broussochalcone A did not affect the fMLP-induced increase of cellular inositol trisphosphate (IP3) and [Ca2+]i. However, the enzyme activity of neutrophil cytosolic protein kinase C was effectively suppressed by broussochalcone A. Broussochalcone A had no effect on either [3H]phorbol 12,13-dibutyrate ([3H]PDB) binding to neutrophil cytosolic protein kinase C or on PMA-induced membrane translocation of protein kinase C-beta in neutrophils. Broussochalcone A suppressed the enzyme activity of trypsin-treated rat brain protein kinase C in a concentration-dependent manner. In PMA-activated neutrophil particulate NADPH oxidase, broussochalcone A attenuated superoxide anion radical (O2.-) generation with an IC50 value of 61.8 +/- 5.4 microM. These results show that the inhibitory effect of broussochalcone A on respiratory burst in neutrophils is not mediated by the reduction of phospholipase C activity, but is mediated partly by the suppression of protein kinase C activity through interference with the catalytic region and by the attenuation of O2.- generation from the NADPH oxidase complex.
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PMID:Investigation of the inhibitory effect of broussochalcone A on respiratory burst in neutrophils. 905 55


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