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)

[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

It has been suggested that the therapeutic action of lithium in affective disorders may be due to its inhibition of signal transduction and second messenger synthesis, in particular of the phosphoinositide (PI) pathway. Yet, previous work in neuronal cell lines indicates that lithium has an enhancing effect on gene expression mediated by protein kinase C, which is activated by the PI pathway. In this report, we have analyzed the effect of lithium on two neuropeptide encoding genes that are regulated by second messenger systems; neuropeptide Y (NPY) and proenkephalin (Enk). We find that acute treatment with lithium, resulting in serum levels that are within the therapeutic range effective in patients with mood disorders, significantly enhances basal expression of the NPY gene in rat hippocampus. In contrast, no effect on Enk expression was detected. This selective effect in a limbic structure supports the hypothesis that gene expression may be an important target of lithium's therapeutic action.
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PMID:Acute lithium treatment enhances neuropeptide Y gene expression in rat hippocampus. 137 67

Previous results from our laboratory suggest that long-term treatment of primary cultured bovine adrenal medullary (BAM) chromaffin cells with nicotine or phorbol 12-myristate 13-acetate, either of which directly activates protein kinase C (PKC), increases the mRNA levels encoding catecholamine-synthesizing enzymes and proenkephalin. In the present study, we have examined the effects of nicotine on BAM cell PKC activity with special emphasis on long-term effects. Nicotine increased particulate PKC activity in a concentration-dependent manner when measured using in vitro enzyme assay with histone as the substrate. This effect is mediated through nicotinic cholinergic receptors, because 1,1-dimethylphenylpiperazinium, a nicotinic agonist, had a similar effect. In addition, chlorisondamine, a specific nicotine-receptor blocking drug, antagonized the effect of nicotine. Nicotine also increased specific [3H]phorbol 12,13-dibutyrate ([3H]PdBu) binding within 1 min, the effect of which was maximal between 3 and 12 min. This effect was reversed by chlorisondamine similarly after 12 min and after 18 h of nicotine treatment, indicating that continual nicotinic-receptor occupancy is required for persistent PKC activation. Compared to PKC activation, the onset of nicotine-stimulated diacylglycerol production was slow, and it was observed after 12 min of incubation with nicotine. The diacylglycerol levels, specific [3H]PdBu binding, and PKC activity remained significantly elevated for at least 18 h with continuous nicotine incubation. Furthermore, nicotine increased the PKC immunoreactivity of a particulate protein with a molecular mass of 82 kDa in the western blot. These results suggest that nicotinic-receptor activation increases PKC activity and immunoreactivity in BAM cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Long-term activation of protein kinase C by nicotine in bovine adrenal chromaffin cells. 156 Feb 24

Proenkephalin, a classically defined opioid encoding gene, is transiently expressed in nondifferentiated mesodermal cells during organogenesis. We examined the hypothesis that this expression is associated with mesenchymal cell proliferation. For this purpose, we established a cell culture derived from fetal skin mesenchyme that specifically expresses proenkephalin mRNA in correlation with hypodermis development. These mesenchymal cells also produce and secrete significant amounts of proenkephalin-derived peptides. Using this model system, we observed a marked increase in proenkephalin mRNA expression in response to serum. This effect is time dependent and reaches peak levels during the G1/S transition. Similarly, 12-O-tetradecanoyl-phorbol-13-ester, whose biological actions have been shown to be mediated by the activity of protein kinase C (PKC), up-regulates proenkephalin expression. Desensitization of PKC by prolonged exposure of cells to 12-O-tetradecanoyl-phorbol-13-ester attenuates the serum induction of proenkephalin. The results presented in this report demonstrate that proenkephalin expression in mesenchymal cells is regulated by serum factors via mechanisms that involve PKC activity. A possible association between proenkephalin expression and cell proliferation is suggested.
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PMID:Regulation of proenkephalin expression in cultured skin mesenchymal cells. 158 16

Preproenkephalin metabolism, in the rat, was studied in primary striatal neurons maintained in a chemically defined medium. Acute treatment (30 min) with forskolin (10(-5) M) or phorbol 12 myristate 13 acetate (10(-7) M) resulted, respectively, in a two- and seven-fold increase in methionine-enkephalin secretion. Chronic treatment with forskolin or phorbol 12 myristate 13 acetate (24 h) induced a 100% increase in methionine-enkephalin content (forskolin) and on the other hand a 50% decrease in methionine-enkephalin (phorbol 12 myristate 13 acetate). Both treatments increased preproenkephalin mRNA levels in a time-dependent manner, this augmentation being observable after 180 min by Northern blot analysis and in situ hybridization. These data indicate that under chronic stimulation, with either forskolin or phorbol 12 myristate 13 acetate, proenkephalin turnover is accelerated. However, after stimulation with phorbol 12 myristate 13 acetate, the more potent methionine-enkephalin secretagogue, increased peptide synthesis is not sufficient to replenish methionine-enkephalin intracellular stores. Preproenkephalin gene transcription was analysed by introducing the preproenkephalin gene promoter fused to the bacterial acetyl chloramphenicol transferase reporter gene into primary neurons. Chronic stimulation (48 h) by forskolin (10(-5) M) or phorbol 12 myristate 13 acetate (10(-7) M) of striatal neurons transfected with this fusion gene increased chloramphenicol acetyltransferase activity six-fold and the two effects were additive. These data suggest that the cyclic AMP and the protein kinase C pathways directly activate preproenkephalin gene transcription.
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PMID:Striatal proenkephalin turnover and gene transcription are regulated by cyclic AMP and protein kinase C-related pathways. 165 16

Unilateral injections of 6-hydroxydopamine (6-OHDA) cause significant bilateral increases in striatal proenkephalin (PEK) mRNA in rat brain. We have tested the possibility that implantation of fetal mesencephalic cells can normalize these changes. Two types of grafts were used: 1) embryonic day-15 mesencephalic cells and 2) embryonic day-15 cells which have been modified with a retroviral vector containing a cDNA for protein kinase C (PKC). At two months after grafting, both cell types cause significant attenuation of the increases which occurred on the side of the lesion. However, only the PKC-modified cells cause normalization of the changes on the contralateral side. These observations indicate that, in addition to normalizing supersensitive striatal dopamine (DA) D2 receptors, embryonic cells can also attenuate the alterations in PEK mRNA observed after lesions of the nigrostriatal DA system. The finding that the PKC-modified cells caused bilateral effects in the striatum suggests that second messenger systems may play a role in the bilateral improvement reported in parkinsonian patients who had gotten unilateral intrastriatal transplants.
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PMID:Intrastriatal implants of fetal mesencephalic cells attenuate the increases in striatal proenkephalin mRNA observed after unilateral 6-hydroxydopamine-induced lesions of the striatum. 175 90

Previous studies from our laboratory suggest that protein kinase C (PKC) is involved in the angiotensin II (AII)-induced increase in the expression of genes encoding proenkephalin and catecholamine biosynthesizing enzymes in primary cultured bovine adrenal medullary (BAM) cells. The purpose of this study was to examine the effects of [Sar1]-AII (S1-AII), an AII agonist, on PKC activity in BAM cells. Thirty-minute incubation with S1-AII produced a dose-dependent activation of PKC. The particulate PKC activity was significantly increased by 2 nM S1-AII after both 30 min and 12 h of incubation. A high concentration of S1-AII (200 nM) caused an increase in particulate PKC activity after 30 min of incubation and this increase was still observed after 18 h of continuous incubation. [Sar1, Thr8]-angiotensin II (S1, T8-AII) (100 microM), an AII antagonist, inhibited the effect of S1-AII (20 nM) on PKC activity, suggesting a specific AII receptor-mediated effect. An increase in BAM cell particulate PKC immunoreactivity after 18 h of S1-AII treatment was observed in Western blot analysis of PKC-immunoreactive protein (82 kDa). The persistent activation of PKC seen in this study is consistent with our hypothesis that PKC may mediate the S1-AII-induced increase in the expression of genes encoding proenkephalin and catecholamine synthesizing enzymes in BAM cells.
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PMID:Long-term activation of protein kinase C by angiotensin II in cultured bovine adrenal medullary cells. 200 41

In the present study we investigated the role of protein kinase C (Ca2+/phospholipid-dependent enzyme)-mediated processes in the regulation of proenkephalin gene expression in primary cultures of bovine adrenal chromaffin cells. Activators of protein kinase C such as 1-oleoyl-2-acetylglycerol, mezerein, and the phorbol esters phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-didecanoate induced a time-dependent increase in proenkephalin mRNA levels, whereas the inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate had no effect. The increase in phorbol ester-induced proenkephalin mRNA was potentiated by low concentrations of the Ca2+ ionophore A23187, suggesting an interaction between protein kinase- and Ca2+-mediated processes in the regulation of proenkephalin mRNA. The phorbol ester-induced stimulation does not appear to be mediated by an interaction with the cAMP-generating system or increases in Ca2+ uptake. However, when proenkephalin mRNA levels were stimulated by KCl (10 mM) and the dihydropyridine BayK8644, PMA exhibited an inhibitory effect on proenkephalin mRNA, which was detectable at a 10-fold lower concentration of PMA than the stimulatory effect. This inhibitory effect appears to be mediated by an inhibition of Ca2+ entry through voltage-dependent Ca2+ channels, as suggested by 45Ca2+ uptake experiments. Thus, the net effect of PMA depends on and varies with the state of voltage-dependent Ca2+ channel activity. A third mode of action by protein kinase C to modulate proenkephalin gene expression is by interaction with the phosphatidylinositol second messenger system. Stimulation of phosphoinositide hydrolysis and proenkephalin mRNA by histaminic H1-receptor activation was inhibited by low concentrations of PMA. We suggest that protein kinase C may act as a positive and negative regulator of proenkephalin gene expression by interacting with at least three receptor-coupled second messenger systems.
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PMID:Multiple regulation of proenkephalin gene expression by protein kinase C. 244 1

Many cellular processes are regulated by hormones and neurotransmitters which interact with cell-surface receptors to produce intracellular second messengers that activate protein kinases. Cyclic (c) AMP is a second messenger whose intracellular level is determined by receptor-mediated activation or inhibition of adenylate cyclase. Phorbol esters directly activate protein kinase C, a Ca2+ and phospholipid-dependent protein kinase and a component of a different second messenger system, the phosphatidylinositol pathway. Proenkephalin messenger RNA levels are regulated in response to cAMP analogues, activators of adenylate cyclase, nicotinic agonists and depolarization, suggesting that expression of the gene encoding proenkephalin is regulated by trans-synaptic events involving cell-surface-receptor activation. Here we report that cAMP analogues and activators of adenylate cyclase regulate a proenkephalin-chloramphenicol acetyl transferase fusion gene when transiently expressed in tissue culture cells. Phorbol ester regulates the fusion gene in a similar fashion, but requires the presence of phosphodiesterase inhibitors for large effects. The DNA sequences required for regulation by both cAMP and phorbol ester map to the same 37-base pair (bp) region located 107-71 bp 5' to the mRNA cap site of the proenkephalin gene. This highly conserved region is composed of three closely related 12-bp sequences and has properties similar to those of previously characterized transcriptional enhancers.
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PMID:A cyclic AMP- and phorbol ester-inducible DNA element. 302 Apr 28

Treatment of bovine adrenal medullary chromaffin (BAMC) cells with staurosporine for 24 h caused the cells to elongate and flatten, and induced the formation of neurite-like outgrowth from BAMC cells; superficially the cells resembled those treated with the protein kinase C (PKC) agonist phorbol myristate acetate (PMA, 10(-7) M). The intracellular concentration of [Met5]-enkephalin (ME) was significantly increased in staurosporine-treated cells whereas the secretion of ME into the medium was significantly less than that from control cells. In addition, pretreatment of cells with staurosporine effectively inhibited the long-term stimulatory effects of other secretagogues on ME secretion. Furthermore, a 24 h exposure to staurosporine greatly increased the levels of both proenkephalin A (proENK) and its messenger RNA (mRNA). Both staurosporine and PMA increased AP-1 DNA binding activity to a similar extent. In contrast to the results with staurosporine, the structurally similar compound, K252a (10(-8) M) did not show these effects. Moreover, other PKC inhibitors, H7 (10(-5) M) and sphingosine (3.6 x 10(-5) M), did not duplicate those effects, suggesting that these long-term effects of staurosporine are independent of PKC inhibition. Staurosporine acts at the ATP binding site on many other kinases, but it is presently unclear whether the observed effects on cell morphology, proENK mRNA induction and ME secretion result from inhibition of only a single particular kinase. However, the uncoupling of proENK mRNA induction from ME secretion in these cells is unique to staurosporine and, therefore, this compound may be useful for further studies on secretion-transcription coupling.
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PMID:Effects of staurosporine on cell morphology, expression of the proenkephalin gene and the secretion of [Met5]-enkephalin in bovine adrenal medullary chromaffin cells. 770 5


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