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)

Cyclic AMP affects microvascular smooth muscle contraction and growth. Therefore, it is important to elucidate mechanisms regulating cyclic AMP production in microvascular smooth muscle. In this study, we determined whether several signal transduction pathways regulate receptor-induced cyclic AMP in isolated preglomerular microvessels and microvascular smooth muscle cells. Preglomerular microvessels were incubated with isoproterenol (beta-adrenoceptor agonist) and with and without U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), 1-butanol (phospholipase D inhibitor), CGP77675 (c-src inhibitor), HA1077 (Rho kinase inhibitor), Y27632 (Rho kinase inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), dipenyleneiodonium (NADPH oxidase inhibitor), or Tempol (superoxide dismutase mimetic). Cultured preglomerular microvascular smooth muscle cells were incubated with isoproterenol or forskolin (direct activator of adenylyl cyclase) and with or without U73122, C(2)-ceramide (phospholipase D inhibitor), or PP1 [src family inhibitor, 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine]. All studies were conducted with 3-isobutyl-1-methylxanthine (broad-spectrum phosphodiesterase inhibitor) to eliminate changes in cyclic AMP degradation. In microvessels isoproterenol-induced cyclic AMP was not affected by Y27632, HA1007, LY294002, dipenylene-iodonium, or Tempol; was increased by U73122 and GF109203X; and was decreased by 1-butanol and CGP77675. In cells, U73122 increased and C(2)-ceramide and PP1 decreased isoproterenol-induced cyclic AMP. Forskolin-induced cyclic AMP was not altered. These results indicate that receptor-mediated activation of adenylyl cyclase is 1) not modulated by Rho kinase, phosphatidylinositol-3-kinase, NADPH oxidase, or superoxide; 2) is attenuated by phospholipase C and protein kinase C; and 3) is augmented by phospholipase D and src. Phospholipase C, phospholipase D, and src modulate receptor-induced cyclic AMP by affecting beta-adrenoreceptor/G protein/adenylyl cyclase coupling rather than by directly affecting adenylyl cyclase activity.
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PMID:Modulation of cyclic AMP production by signal transduction pathways in preglomerular microvessels and microvascular smooth muscle cells. 1508 74

Tissue transglutaminase (TG2) affects cell-matrix interactions in cell spreading, migration and extracellular matrix (ECM) reorganisation. Using fibroblasts deficient in TG2 or overexpressing normal or crosslinking-deficient enzyme, we show that the extracellular crosslinking activity and intracellular G-protein function in signal transduction contribute differentially to regulation of cell-matrix interactions. TG2-deficient cells displayed normal attachment but delayed spreading on ECM substrata and defects in motility unrelated to crosslinking. Blocking antibodies to TG2 failed to induce similar defects in normal fibroblasts. TG2-deficient fibroblasts had defects in focal adhesion turnover and stress fibre formation, showed changes in focal adhesion kinase (FAK) phosphorylation and failed to activate protein kinase C alpha (PKCalpha). Phospholipase C (PLC) and PKCalpha inhibitors blocked spreading of normal fibroblasts whilst PKC activators induced spreading in TG2-deficient cells. In contrast, ECM remodelling was not only compromised by TG2 deficiency but also by overexpression of dominant negative enzyme and TG inhibitors. TG2 activity increased matrix tension and was required for membrane type 1-MMP (MT1-MMP)-dependent activation of MMP-2. Our results demonstrate that TG2 is involved in the control of dynamic adhesion formation in cell spreading and migration via regulation of phospholipase C activity. By virtue of its crosslinking activity, the enzyme plays a central role in regulating ECM remodelling.
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PMID:Crosslinking and G-protein functions of transglutaminase 2 contribute differentially to fibroblast wound healing responses. 1519 98

To explore the functional effects of hormone-sensitive lipase (HSL) in diacylglycerol (DAG) metabolism, Chinese hamster ovary cells were stably transfected with rat HSL cDNA (wt-HSL), inactive mutant S423A-HSL cDNA (S423A) and pcDNA3 vector alone (Ct). [(14)C]Glucose-incorporation into triglyceride (TG) was 75% lower in the presence or absence of insulin in cells expressing wt-HSL compared to Ct or S423A. [(14)C]Glucose-incorporation into DAG was 33% lower without insulin and 51% lower with insulin in cells expressing wt-HSL compared to Ct or S423A. Insulin stimulated glucose-incorporation into DAG 2.2-fold in S423A and Ct cells, whereas only a 50% increase was observed in cells expressing wt-HSL. Phospholipase C-mediated release of DAG from membrane phospholipids was reduced 70% in cells expressing wt-HSL compared to Ct or S423A. Western blot analysis showed that membrane-bound protein kinase C (PKC)-alpha and -epsilon were decreased 40-50% in cells expressing wt-HSL grown in high glucose with insulin. These data show that HSL potentially hydrolyzes cellular DAG generated either by de novo synthesis from glucose or release from membrane phospholipids by phospholipase C, resulting in a reduction in the translocation of DAG-sensitive PKCs.
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PMID:Function of hormone-sensitive lipase in diacylglycerol-protein kinase C pathway. 1533 Dec

We have demonstrated before that exposure of neuronal cultures to poisoning by iodoacetic acid, followed by "reperfusion" (iodoacetate-"reperfusion" insult; IAA-R insult), results in severe cytotoxicity. This insult was found to be associated with ATP depletion and generation of reactive oxygen species. The cultured neurons could be protected against the insult by activation of the adenosine A1 receptors and by presence of antioxidants. Previous studies in our laboratory demonstrated that the adenosine-activated signal transduction pathway (Ado-STP) conferring protection against the IAA-R insult, involves activation of protein kinase C-epsilon (PKCepsilon) and opening of ATP sensitive potassium (K(ATP)) channels. In this respect, the adenosine-activated protective mechanism against the IAA-R insult is similar to the Ado-STP in the neurons and in cardiomyocytes against ischemia-reperfusion injury. Phospholipase C (PLC) is an additional component demonstrated recently to participate in the myocardial Ado-STP protecting against ischemia-reperfusion. Here we provide proof for the involvement of PLC also in the neuronal Ado-STP protecting against the IAA-R insult. Primary rat neuronal cultures were exposed to the IAA-R insult. The neurons could be protected against this insult by activation of the adenosine A1 receptors by N6-(R)-phenylisopropyladenosine (R-PIA), a specific A1 adenosine receptor agonist. Exposure of the cultures to the PLC inhibitor U73122, abrogated the protection. The exposure of the cultures to R-PIA was found to enhance PLC activity, an effect that could be abrogated by presence of U73122. The R-PIA-induced increase in PLC activity was short-lived, in the range of minutes. These results demonstrate that activation of PLC is a vital step in the neuronal protective Ado-STP, but that it does not contribute directly to the relatively long time window of the protection signal shown previously to characterize the neuronal mechanism. The results also support the suggestion that the Ado-STP protecting against the IAA-R insult and that protecting against ischemia-reperfusion may represent the same mechanism.
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PMID:Phospholipase C is involved in the adenosine-activated signal transduction pathway conferring protection against iodoacetic acid-induced injury in primary rat neuronal cultures. 1561 46

Calcium is a key regulator of cardiac function and is modulated through the Ca2+-sensor protein S100A1. S100 proteins are considered to exert both intracellular and extracellular functions on their target cells. Here we report the impact of an increased intracellular S100A1 protein level on Ca2+-homeostasis in neonatal ventricular cardiomyocytes in vitro. Specifically, we compare the effects of exogenously added recombinant S100A1 to those resulting from the overexpression of a transduced S100A1 gene. Extracellularly added S100A1 enhanced the Ca2+-transient amplitude in neonatal ventricular cardiomyocytes (NVCMs) through a marked decrease in intracellular diastolic Ca2+-concentrations ([Ca2+]i). The decrease in [Ca2+]i was independent of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity and was probably the result of an increased sarcolemmal Ca2+-extrusion through the sodium-calcium exchanger (NCX). At the same time the Ca2+-content of the sarcoplasmic reticulum (SR) decreased. These effects were dependent on the uptake of extracellularly added S100A1 protein and its subsequent routing to the endosomal compartment. Phospholipase C and protein kinase C, which are tightly associated with this subcellular compartment, were found to be activated by endocytosed S100A1. By contrast, adenoviral-mediated intracellular S100A1 overexpression enhanced the Ca2+-transient amplitude in NVCMs mainly through an increase in systolic [Ca2+]i. The increased Ca2+-load in the SR was based on an enhanced SERCA2a activity while NCX function was unaltered. Overexpressed S100A1 colocalized with SERCA2a and other Ca2+-regulatory proteins at the SR, whereas recombinant S100A1 protein that had been endocytosed did not colocalize with SR proteins. This study provides the first evidence that intracellular S100A1, depending on its subcellular location, modulates cardiac Ca2+-turnover via different Ca2+-regulatory proteins.
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PMID:Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes. 1565 19

In order to establish an immortalized granulosa cell line and to investigate the potential mechanisms of immortalized cell proliferation, simian virus (SV) 40 was used to infect porcine granulosa cells from small follicles (1-2 mm in diameter), and one colony was selected after four weeks of culture. The colony was digested with trypsin and the cells were cultured for more than 300 days (named PGV). The SV40 large T antigen gene and its products were confirmed in immortalized cells by Southern blotting and immunohistochemistry. Progesterone production was not detected in the conditioned culture media with follicle-stimulating hormone (FSH) and forskolin, possibly due to the lack of P450scc gene transcription as examined by Northern blotting. PGV cells responded significantly to the stimulation of sera (fetal bovine and horse sera) and protein kinase C (PKC) stimulators (PMA and OAG), while PKC inhibitors (staurosporine and calphostin C) blocked both sera and PKC stimulation. Phospholipase C (PLC) and phosphatidic acid phosphatase (PAP) inhibitors (U73122 and propranolol) significantly reduced PGV cell proliferation, while PMA restored PLC and PAP inhibition. These data suggest that diacylglycerol (DAG) is produced in PGV cells by PLD as well as by PLC, and that DAG then activates PKC stimulating the PGV cell cycle through yet unknown mechanisms. Thus, an immortalized granulosa cell line is very useful to study granulosa cells in vitro, as the cells are homogeneous and are a functionally defined population.
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PMID:Establishment of an immortalized porcine granulosa cell line (PGV) and the study on the potential mechanisms of PGV cell proliferation. 1583 78

Acylation stimulating protein (ASP; C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes/adipocytes through C5L2, a G-protein-coupled receptor. Here, ASP signaling is compared with insulin in 3T3-L1 cells. ASP stimulation is not Galpha(s) or Galpha(i) mediated (pertussis and cholera toxin insensitive), suggesting G(alphaq) as a candidate. Phospholipase C (PLC) is required, because the Ca(2+) chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester and the PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (P < 0.0.001) and 86.1% (P < 0.004), respectively. Wortmannin and LY294002 blocked ASP effect by 69% (P < 0.001) and 116.1% (P < 0.003), respectively, supporting phosphatidylinositol 3-kinase (PI3K) involvement. ASP induced rapid, transient Akt phosphorylation (maximal, 5 min; basal, 45 min), which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, mamalian target of rapaycin (mTOR) is required for insulin but not ASP action. By contrast, both ASP and insulin activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK(1/2)) pathway, with rapid, pronounced increases in ERK(1/2) phosphorylation, effects partially blocked by PD98059 (64.7% and 65.9% inhibition, respectively; P < 0.001). Time-dependent (maximal, 30 min) transient calcium-dependent phospholipase A(2) (cPLA(2))(-Ser505) phosphorylation (by MAPK/ERK(1/2)) was demonstrated by Western blot analysis. ASP signaling involves sequential activation of PI3K and PLC, with downstream activation of protein kinase C, Akt, MAPK/ERK(1/2), and cPLA(2), all of which leads to an effective and prolonged stimulation of TGS.
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PMID:Targeting the signaling pathway of acylation stimulating protein. 1633 41

We investigated the effects of the human immunodeficiency virus-1 transactivator of transcription (Tat) on the release of norepinephrine (NE) from human and rat brain synaptosomes. Tat could not evoke directly release of [3H]NE. In the presence of Tat (1 nM), N-methyl-D-aspartate (NMDA) concentrations unable to release (human synaptosomes) or slightly releasing (rat synaptosomes) [3H]NE became very effective. The NMDA/Tat-evoked release depends on NMDA receptors (NMDARs) since it was abolished by MK-801 (dizocilpine). Tat binding at NMDARs was excluded. The NMDA-induced release of [3H]NE in the presence of glycine was further potentiated by Tat. The release evoked by NMDA/glycine/Tat depends on metabotropic glutamate receptor 1 (mGluR1) activation, since it was halved by mGluR1 antagonists. Tat seems to act at the glutamate recognition site of mGluR1. Recently, Tat was shown to release [3H]acetylcholine from human cholinergic terminals; here, we demonstrate that this effect is also mediated by presynaptic mGluR1. The peptide sequence Tat41-60, but not Tat61-80, mimicked Tat. Phospholipase C, protein kinase C, and cytosolic tyrosine kinase are involved in the NMDA/glycine/Tat-evoked [3H]NE release. To conclude, Tat can represent a potent pathological agonist at mGlu1 receptors able to release acetylcholine from human cholinergic terminals and up-regulate NMDARs mediating NE release from human and rat noradrenergic terminals.
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PMID:The human immunodeficiency virus-1 protein transactivator of transcription up-regulates N-methyl-D-aspartate receptor function by acting at metabotropic glutamate receptor 1 receptors coexisting on human and rat brain noradrenergic neurones. 1648 29

The pressure-induced constriction in the rat ophthalmic artery was characterized. Ophthalmic arteries were isolated, cannulated in an arteriograph, and pressurized. Arteries developed 25% constriction at 70 mmHg of intraluminal pressure. Arteries maintained almost similar diameter over the range of pressures 50-210 mmHg, and forced dilatation was observed at pressures >210 mmHg. Denudation of endothelium increased the sensitivity of arteries to pressure-induced constriction, and significantly higher myogenic tone was observed in the pressure range of 10-100 mmHg. Indomethacin and cyclooxygenase-2 inhibition by SC-236 decreased myogenic tone, whereas cyclooxygenase-1 inhibition by SC-560 potentiated myogenic tone in a lower concentration range and decreased at a higher concentration. Pressure-induced constriction was completely blocked by 1 microM nifedipine. Phospholipase C inhibition by 6 microM U-73122 decreased myogenic tone by 39%, whereas PKC inhibitor GF-109203X (3 microM) had no effect. Constriction to phenylephrine was significantly decreased by U-73122 (1 microM) and GF-109203X (3 microM) at an intraluminal pressure of 10 mmHg. Rho-kinase inhibition by Y-27632 (30 microM) and HA-1077 (30 microM) decreased myogenic tone by 75% and 73%, respectively, and 1 microM Y-27632 significantly decreased myogenic tone developed in response to graded increases in pressure. These results suggest that rat ophthalmic artery has an efficient pressure-dependent autoregulatory function that is modulated by endothelium. Contribution of phospholipase C-activation to myogenic tone is minimal, whereas Rho-kinase activation plays a predominant role in the myogenic reactivity in this artery.
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PMID:Characteristics of myogenic tone in the rat ophthalmic artery. 1692 Aug 4

Fibroblasts isolated from jaw cysts expressed calcium-sensing receptor (CasR). In the fibroblasts elevated extracellular Ca(2+) ([Ca(2+)](o)) increased fluo-3 fluorescence intensity, and the production of inositol(1,4,5)trisphosphate and active protein kinase C. Phospholipase C inhibitor U-73122 attenuated the Ca(2+)-induced increase in fluo-3 fluorescence intensity. Elevated [Ca(2+)](o) enhanced the expression of cyclooxygenase-2 (COX-2) mRNA and protein, and the secretion of prostaglandin E(2) in the fibroblasts. CasR activator neomycin also increased the expression of COX-2 mRNA, and U-73122 attenuated the Ca(2+)-induced expression of COX-2 mRNA. Elevated [Ca(2+)](o)-induced phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK), and U-73122 inhibited the Ca(2+)-induced phosphorylation. The inhibitors for each kinase, PD98059, SB203580, and SP600125, attenuated the Ca(2+)-induced expression of COX-2 mRNA. These results suggest that in jaw cyst fibroblasts elevated extracellular Ca(2+) may enhance COX-2 expression via the activation of ERK1/2, p38 MAPK, and JNK through CasR.
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PMID:Ca2+ stimulates COX-2 expression through calcium-sensing receptor in fibroblasts. 1709 11


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