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)

[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

We examined changes in guanosine triphosphate-dependent signal transduction mechanisms in the retina from the early stages of the streptozotocin-diabetic rat, a model for Type 1 (insulin-dependent) diabetes mellitus. Guanosine triphosphate binding, guanosine triphosphatase activity, and binding of (azido) guanosine triphosphate decreased significantly in the retina as early as 2 weeks after the induction of diabetes. The ability of guanosine triphosphate to inhibit forskolin-stimulatable adenyl cyclase was also abolished. These data suggest functional deterioration of G-proteins, especially Gi, in diabetic retina. Further studies using retinal rod outer segments revealed deterioration in light-sensitive, guanosine triphosphate-dependent functions of transducin in diabetic rats. Pertussis toxin-catalysed ADP ribosylation of the alpha subunit of transducin, a heterotrimeric G-protein of rod outer segments, was also reduced in diabetes. No functional effects were seen in purified subunits of transducin subjected to non-enzymatic glycation in vitro. On the other hand, incubation of non-diabetic rod outer segments with (12-0-tetradeconyl) phorbol-13-acetate, a protein kinase C agonist, in the presence of magnesium and adenosine triphosphate resulted in the reduction of guanosine triphosphate-binding and hydrolysis, thus indicating that protein kinase C may be involved in the regulation of these activities. The significance of these observations in the early visual abnormalities associated with diabetes is discussed.
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PMID:Functional alterations of G-proteins in diabetic rat retina: a possible explanation for the early visual abnormalities in diabetes mellitus. 132 50

To account for infiltration of the periodontal tissues by neutrophils, the present study was undertaken to examine whether Porphyromonas gingivalis fimbriae, important structures involved in attachment of the bacteria to periodontal tissues, induce gene expression of the neutrophil chemoattractant KC in macrophages. The fimbriae induced expression of the KC gene of mouse peritoneal macrophages in a dose-dependent fashion. The peak of KC gene expression was observed as early as 1 h after initiation of the treatment. However, the gene expression was short lived, with the expression decreasing gradually after 6 h. A nuclear transcriptional assay showed that the fimbriae regulated the KC gene expression at a posttranscriptional level. We observed that the fimbria-induced KC gene expression was not regulated by endogenous or exogenous prostaglandin. Furthermore, forskolin, a potent activator of adenyl cyclase, and dibutyryl cyclic AMP were incapable of inducing KC gene expression of the peritoneal macrophages. H-8 and HA 1004, inhibitors of cyclic nucleotide-dependent protein kinases, had little effect on the fimbria-induced KC gene expression. On the other hand, the fimbria-induced KC gene expression was inhibited markedly by treatment with H-7, a potent inhibitor of protein kinase C. We also observed that phorbol 12-myristate 13-acetate, a specific activator of protein kinase C, induced KC gene expression of peritoneal macrophages in a dose-dependent fashion. In addition, the fimbria-induced KC gene expression was suppressed in the peritoneal macrophages pretreated for 24 h with phorbol 12-myristate 13-acetate. These results suggest that the KC gene expression was mediated through activation of protein kinase C and not through that of cyclic nucleotide-dependent protein kinases. The present study indicates that P. gingivalis fimbriae can induce gene expression of the neutrophil chemotactic factor KC by macrophages via protein kinase C and suggests that this factor may be involved in infiltration of neutrophils into the periodontal tissues of adult periodontal patients.
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PMID:Porphyromonas gingivalis fimbriae induce expression of the neutrophil chemotactic factor KC gene of mouse peritoneal macrophages: role of protein kinase C. 137 96

The possible roles of cyclic AMP and protein kinase C in the release of renin from human decidual cells were investigated by examining renin release from monolayers of decidual cells exposed for 72 h to agents that increase intracellular cAMP or activate protein kinase C. Dibutyryl cAMP (10-1000 microM caused a dose-dependent stimulation of renin release after a 24-h exposure. Maximal stimulation, 410 per cent greater than that of control cells, occurred at 72 h, and 98 per cent of the renin released into the medium was in the form of prorenin. Forskolin (10-1000 microM) and cholera toxin (CT. 20-1000 ng/ml), both of which stimulate adenyl cyclase, also stimulated prorenin release. Phorbol myristate acetate (PMA), an activator of protein kinase C, had little effect on basal prorenin release at 100 nM but potentiated the stimulation of prorenin release by cAMP and CT. The effects on prorenin release were paralleled by stimulation of active renin release. The results of this study therefore implicate cAMP and protein kinase C in the regulation of prorenin release from decidual cells and suggest that prorenin release from the decidua and other tissues is regulated by the same second messengers.
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PMID:Cyclic AMP as a second messenger for prorenin release from human decidual cells. 166 20

Recent evidence has suggested that cAMP plays a role as a second messenger in the decrease in nociceptive threshold (or hyperalgesia) produced by agents acting on primary afferent terminals. In support of this hypothesis we report that intradermal injection of a direct activator of adenyl cyclase, forskolin, produces a dose-dependent hyperalgesia in the rat. The duration of this hyperalgesia was prolonged by the phosphodiesterase inhibitors, isobutylmethylxanthine and rolipram. Forskolin hyperalgesia was antagonized by the Rp isomer of cyclic adenosine-3'5'-monophosphothioate, an analog of cAMP that prevents the phosphorylation of the cAMP protein kinase. The Rp isomer of cyclic adenosine-3'5'-monophosphothioate also inhibited the hyperalgesia induced by a membrane-permeable analogue of cAMP, 8-bromocyclic adenosine monophosphate, as well as the hyperalgesia induced by agents that are presumed to act directly on primary afferent nociceptors: prostaglandin E2, prostaglandin I2, (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid; and the adenosine A2-agonist 2-phenylaminoadenosine. Although the cAMP second messenger system contributes to primary afferent hyperalgesia, we found no evidence for a contribution of protein kinase C. Thus, hyperalgesia induced by prostaglandin E2, prostacyclin (prostaglandin I2), (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid, the adenosine A2-agonist 2-phenylaminoadenosine, 8-bromocyclic adenosine monophosphate and the direct activator of adenyl cyclase, forskolin, were not significantly attenuated by the selective inhibition of protein kinase C by the 19-31 fragment of protein kinase C. Two other inhibitors of protein kinase C, sphingosine and staurosporine, also failed to attenuate prostaglandin E2-induced hyperalgesia.
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PMID:Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. 172 88

Human peripheral blood mononuclear cells (H-PBMC) from 10 healthy donors were stimulated to proliferate with phytohemagglutinin lectin (PHA), anti-CD3 monoclonal antibody (mAb), and anti-CD3 mAb plus phorbol 12, myristate 13 acetate (TPA), a protein kinase C (PKC) agonist. Anti-CD3 mAb-mediated mitogenesis was 35-75% of that observed with PHA. When TPA was added to a dose of mAb that by itself did not cause mitogenesis, proliferation equal to 50-90% of the maximally mitogenic dose occurred. TPA did not enhance proliferation with maximally mitogenic doses of antibody. Dimethyl-prostaglandin E2, dibutyryl cyclic AMP, and forskolin (an adenyl cyclase agonist) inhibited PHA, anti-CD3, and anti-CD3/PMA-mediated mitogenesis. Cyclosporine (CSA) inhibited anti-CD3 and anti-CD3/TPA mitogenesis in a dose-dependent fashion. While CSA inhibited anti-CD3 and anti-CD3/TPA mitogenic signals, it did not affect PGE2 production by anti-CD3 mAb-stimulated H-PBMC. In the presence of CSA, PGE2 production in PHA-stimulated H-PBMC was increased. PGE2 inhibits lymphocyte proliferation via a cyclic AMP-mediated mechanism and may enhance maturation of suppressor cells. CSA inhibits anti-CD3 mAb and anti-CD3/TPA proliferative signals in H-PBMC yet has no effect or may even enhance production of suppressive PGE2. The maturation of antigen-specific suppressor cells elicited by CSA may involve active down-regulation of CD3 receptor and PKC-dependent events while PGE2 production continues.
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PMID:Cyclosporine effect on anti-CD3 monoclonal antibody-stimulated mitogenesis, phorbol ester comitogenesis, and PGE2 production. 182 79

The effects of endogenous hypothalamic neurohormones and activators of second messenger signalling systems on the secretion of GH and on cell content of GH mRNA of cultured bovine adenohypophysial cells were studied. Synthetic bovine GH-releasing factor (bGRF; 100 nmol/l) increased secretion of GH by bovine adenohypophysial cells five-fold relative to control. Forskolin (an adenyl cyclase activator; 10 mumol/l) and the synthetic cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) increased secretion of GH by 1.9- and 1.7-fold respectively, relative to control. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA), provided at 1 mumol/l or 10 nmol/l, increased GH secretion by 6.6- and four-fold respectively, relative to control. Somatostatin-14 (SRIF-14) attenuated basal, bGRF-, forskolin- and dbcAMP-stimulated secretion of GH by 40, 49, 47 and 67% respectively, but did not, however, diminish PMA-stimulated GH secretion. The content of GH mRNA in cultured bovine adenohypophysial cells increased 2.2-, 1.7- and 3.2-fold by administration of bGRF, forskolin and PMA respectively, relative to control. Although GH mRNA content was unchanged by SRIF-14 treatment relative to control, SRIF-14 did reduce bGRF-stimulated bGH mRNA content by 67%. This study demonstrates that mechanisms subserving GH secretion in bovine adenohypophysial cells (e.g. adenyl cyclase and protein kinase C) may be coupled with mechanisms which regulate expression of the GH gene or with factors affecting message stability.
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PMID:Modulation of growth hormone (GH) secretion and GH mRNA levels by GH-releasing factor, somatostatin and secretagogues in cultured bovine adenohypophysial cells. 197 Oct 2

Platelet-activating factor (PAF or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is the most potent lipid mediator yet discovered. It is known to stimulate a wide span of biological responses ranging from aggregation and degranulation of platelets and neutrophils to a variety of cellular effects involving the stimulation of chemotaxis; chemokinesis; superoxide formation; protein phosphorylation; activation of protein kinase C, arachidonic acid, and phosphoinositide metabolites; glycogenolysis; and tumor necrosis factor production. Obviously, with such a diversity of biological activities, it is not surprising that PAF has been considered to be a key component in numerous diseases related to hypersensitivity and inflammatory responses. Evidence has also been presented for the role of PAF in physiological processes, particularly those involving reproduction and fetal development. Furthermore, because of its potent hypotensive action, PAF has been implicated as a contributing factor in blood pressure regulation. PAF is produced by two independent enzymatic pathways. The remodeling route involves the structural modification of a membrane lipid (1-alkyl-2-acyl-sn-glycero-3-phosphocholine) by replacement of the acyl moiety with an acetate group. An alternate route is the de novo synthesis of PAF from an O-alkyl analogue of a lysophosphatidic acid that requires a reaction sequence of acetylation, dephosphorylation, and phosphocholine addition steps. Hypersensitivity and other pathophysiological reactions are thought to be caused by activation of the remodeling pathway, whereas the de novo route is believed to be the source of endogenous levels of PAF required for physiological functions. Inactivation of PAF occurs when the acetate group is hydrolyzed by an acetylhydrolase that is present in both extra- and intracellular compartments, although the catalytic activity of the two forms of acetylhydrolase are identical, some of their properties differ. The control of PAF metabolism is very complex, but acetylhydrolase, Ca2+, phosphorylation/dephosphorylation of enzymes, and fatty acids (especially polyunsaturates) appear to be important regulatory factors. Specific PAF receptors have clearly been demonstrated on several different types of cells, and although the mechanism of PAF actions is poorly understood, it appears that the PAF/receptor-induced responses are closely associated with the signal transduction process; both G proteins and adenyl cyclase appear to be involved. Because significant quantities of PAF are often retained within certain cells, the possibility of PAF serving as an intracellular mediator has also been proposed.
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PMID:Platelet-activating factor and related acetylated lipids as potent biologically active cellular mediators. 224 Jan 90

Adenylate cyclase (ATP-pyrophosphate lyase (cyclizing); EC 4.6.1.1) in the human keratinocyte cell line SCC 12F was potentiated by 12-O-tetradecanoyl-phorbol-13-acetate (TPA), phorbol-12,13-diacetate, and 1,2-dioctanoylglycerol. Keratinocytes exposed to TPA showed a 2-fold enhancement of adenylate cyclase activity when assayed in the presence of isoproterenol or GTP. The half-maximal effective concentration (EC50) for both isoproterenol and GTP were unaltered by TPA treatment of the cells. Basal adenylate cyclase activity in membranes from TPA-treated cultures was also increased 2-fold relative to activity in control membranes. Potentiation of adenylate cyclase activity was dependent on the concentration of TPA to which the keratinocytes were exposed (EC50 for TPA = 3 nM). TPA actions on adenylate cyclase were maximal after 15 min of incubation of the cells with the compound, correlating well with the time course of translocation of protein kinase C (Ca2+/phospholipid-dependent enzyme) from cytosol to membrane. The action of cholera toxin on adenylate cyclase was additive with TPA. In contrast, pertussis toxin actions on adenylate cyclase were not additive with TPA. Treatment of control cells with pertussis toxin activated adenylate cyclase 1.5-fold, whereas cells exposed to pertussis toxin for 6 h followed by TPA for 15 min showed the same 2-fold increase in adenylate cyclase activity as observed in membranes from cells exposed to TPA without prior exposure to pertussis toxin. Pertussis toxin catalyzed ADP-ribosylation was increased 2-fold in membranes from SCC 12F cells exposed to TPA, indicating an increase in the alpha beta gamma form of Gi. These data suggest that exposure of human keratinocytes to phorbol esters increases adenylate cyclase activity by a protein kinase C-mediated increase in the heterotrimeric alpha beta gamma form of Gi resulting in decreased inhibition of basal adenylate cyclase activity.
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PMID:Modulation of adenylate cyclase in human keratinocytes by protein kinase C. 246 Apr 60

A transcriptional trans-acting factor p40tax of human T-cell leukemia virus type I (HTLV-I) functions as an inducer for expression of HTLV-I provirus via activation of the enhancer in the long terminal repeat of HTLV-I. In addition to p40tax and a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, we report here that forskolin, an activator of adenyl cyclase, also induces function of the HTLV-I enhancer. Experiments with mutants of the HTLV-I enhancer revealed that TPA-induced activation was not mediated by solely a 21-base-pair (bp) sequence that is repeated three times in the enhancer, whereas the 21-bp enhancer element can act as a sufficient cis-acting sequence for activation by both p40tax and forskolin. In addition, we found that nuclear factor(s) like the cyclic AMP-responsive element (CRE) binding factor could bind to the HTLV-I 21-bp enhancer element. However, a difference was found in sequences required for activation by p40tax and forskolin. A CRE related sequence present in the 21-bp enhancer element was enough for forskolin-induced activation. On the other hand, p40tax required a much longer sequence that is overlapping but not identical to the CRE related sequence, suggesting that the forskolin-induced cyclic AMP pathway may be partly involved in, but not sufficient for p40tax-mediating trans-activation of the HTLV-I enhancer.
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PMID:Differential activation of the 21-base-pair enhancer element of human T-cell leukemia virus type I by its own trans-activator and cyclic AMP. 254 56


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