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)

In this study, we investigated the putative roles of certain protein kinase C (PKC) isoenzymes in the regulation of proliferation and arachidonic acid (AA) release in the human monocytoid MonoMac-6 cell line. Experiments employing specific PKC inhibitors and molecular biological methods (RNA-interference, recombinant overexpression) revealed that the two dominantly expressed isozymes, i.e., the "conventional" cPKCbeta and the "novel" nPKCdelta, promote AA production and cellular proliferation. In addition, using different phospholipase A(2) (PLA(2)) inhibitors, we were able to show that the calcium-independent iPLA(2) as well as diacylglycerol lipase (but not the cytosolic PLA(2)) function as "downstream" targets of cPKCbeta and nPKCdelta. In addition, we have also found that, among the other existing PKC isoforms, cPKCalpha plays a minor inhibitory role, whereas nPKCvarepsilon and aPKCzeta apparently do not regulate these cellular processes. In conclusion, in this paper we provide the first evidence that certain PKC isoforms play pivotal, specific, and (at least partly) antagonistic roles in the regulation of AA production and cellular proliferation of human monocytoid MonoMac-6 cells.
 ...
PMID:Protein kinase C-beta and -delta isoenzymes promote arachidonic acid production and proliferation of MonoMac-6 cells. 1754 42

We showed in our previous study that in hippocampal CA1 neurons the stimulation of muscarinic receptors inhibited the GIRK current (I(GIRK)) via a PLC/PKC pathway, whereas group I metabotropic glutamate receptors (mGluR) inhibited I(GIRK) via a PLA(2)/arachidonic acid pathway. In this study, we present evidence that receptor-mediated signalling pathways activated by the two G(q)-coupled receptors (G(q)PCRs) converge on the inhibition of GIRK channel-PIP(2) interaction. I(GIRK) was activated in acutely isolated hippocampal CA1 neurons by repetitive application of baclofen, a GABA(B) receptor agonist, with a 2-3 min interval. When both CCh and DHPG were pretreated before the second I(GIRK) activation, the magnitude of the second I(GIRK) was 52.2 +/- 2.5% of the first I(GIRK), which was not significantly different from the magnitude of inhibition by CCh or DHPG alone. This result shows that the effects of muscarinic receptor and group I mGluR stimulation on I(GIRK) are not additive but occlusive, suggesting that each pathway may converge to a common mechanism that finally regulates I(GIRK). To test the involvement of PIP(2) in this mechanism, the effect of CCh and DHPG on I(GIRK) was tested in cells loaded with exogenous PIP(2). The inhibition of I(GIRK) by CCh or DHPG was almost completely abolished in PIP(2)-loaded cells. We confirmed that the inhibition of I(GIRK) by direct application of phorbol ester or arachidonic acid was also completely reversed in PIP(2)-loaded cells. These results indicate that the decrease in PIP(2)-channel interactions is the final common mechanism responsible for G(q)PCR-induced inhibitions of I(GIRK) mediated by PKC and arachidonic acid.
 ...
PMID:Decrease in PIP(2) channel interactions is the final common mechanism involved in PKC- and arachidonic acid-mediated inhibitions of GABA(B)-activated K+ current. 1758 38

Activation of the urotensin II (U-II) receptor, GPR14, leads to an increase in Ca(2+), activation of phospholipase A(2) (PLA(2)) and an increase in arachidonic acid. The signaling pathway for guanylin peptides in the kidney involves an unknown G-protein coupled receptor which activates PLA(2) and increases arachidonic acid as well. To test if guanylin peptides could be, as U-II, agonists for the GPR14 receptor in the kidney, we used HEK293 and CHO cells transfected with hGPR14 (HEK293+hGPR14, CHO+hGPR14, respectively). Effects of guanylin peptides and U-II were studied by slow-whole-cell patch-clamp analysis and microfluorimetric measurements of intracellular Ca(2+). Guanylin peptides and U-II depolarized HEK293+hGPR14 significantly more than wild type cells. These effects were inhibited in the presence of Ba(2+) or PLA(2) inhibition (AACOCF(3)), suggesting that guanylin peptides and U-II increase arachidonic acid and inhibit ROMK channels in these cells. However, only U-II was capable to increase the cellular Ca(2+), suggesting different mechanism of GPR14 activation by guanylin peptides and U-II. This signaling pathway of U-II involves PKC, because U-II effects in HEK293+hGPR14 cells were inhibited by calphostin C. Guanylin peptides activate PLA(2) and inhibit ROMK channels in HEK293 cells transfected with the human GPR14 receptor. Since GPR14 is present in mouse and human CCD it is a candidate for the guanylate cyclase independent receptor for guanylin peptides.
 ...
PMID:Ligands and signaling of the G-protein-coupled receptor GPR14, expressed in human kidney cells. 1759 27

The anti-inflammatory properties of three flavanones isolated from Inula viscosa, sakuranetin, 7-O-methylaromadendrin, and 3-acetyl-7-O-methylaromadendrin, have been tested both in vitro and in vivo. Acute inflammation in vivo was induced by means of topical application of 12-O-tetradecanoylphorbol 13-acetate (TPA) to mouse ears or by subcutaneous injection of phospholipase A(2) (PLA(2)) into mouse paws. The test compounds were evaluated in vitro for their effect on both the metabolism of arachidonic acid and on the release and/or activity of enzymes involved in the inflammatory response such as elastase, myeloperoxidase (MPO), and protein kinase C (PKC). The most active compounds in vivo against PLA(2)-induced paw oedema were 7-O-methylaromadendrin (ED(50)=8 mg/kg) and sakuranetin (ED(50)=18 mg/kg). In contrast, the most potent compound against TPA-induced ear oedema was 3-acetyl-7-O-methylaromadendrin (ED(50)=185 microg/ear), followed by sakuranetin (ED(50)=205 microg/ear). In vitro, the latter compound was the most potent inhibitor of leukotriene (LT) B(4) production by peritoneal rat neutrophils (IC(50)=9 microM) and it was also the only compound that directly inhibited the activity of 5-lipoxygenase (5-LOX). 3-Acetyl-7-O-methylaromadendrin also inhibited LTB(4) production (IC(50)=15 microM), but had no effect on 5-LOX activity. The only flavanone that inhibited the secretory PLA(2) activity in vitro was 7-O-methylaromadendrin. This finding may partly explain the anti-inflammatory effect observed in vivo, although other mechanisms such as the inhibition of histamine release by mast cells may also be implicated. Sakuranetin at 100 microM was found to inhibit elastase release, although this result is partly due to direct inhibition of the enzyme itself. At the same concentration, 7-O-methylaromadendrin only affected the enzyme release. Finally, none of the flavanones exhibited any effect on MPO or PKC activities. Taken together, these findings indicate that sakuranetin may be a selective inhibitor of 5-LOX.
 ...
PMID:Effects of naturally occurring dihydroflavonols from Inula viscosa on inflammation and enzymes involved in the arachidonic acid metabolism. 1765 57

Biomphalaria spp. serve as obligate intermediate hosts for the human blood fluke Schistosoma mansoni. Following S. mansoni penetration of Biomphalaria glabrata, hemocytes of resistant snails migrate towards the parasite, encasing the larva in a multicellular capsule resulting in its destruction via a cytotoxic reaction. Recent studies have revealed the importance of hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) in parasite killing [Hahn UK, Bender RC, Bayne CJ. Killing of Schistosoma mansoni sporocysts by hemocytes from resistant Biomphalaria glabrata: role of reactive oxygen species. J Parasitol 2001;87:292-9; Hahn UK, Bender RC, Bayne CJ. Involvement of nitric oxide in killing of Schistosoma mansoni sporocysts by hemocytes from resistant Biomphalaria glabrata. J Parasitol 2001;87:778-85]. It is assumed that H(2)O(2) and NO production is tightly regulated although the specific molecules involved remain largely unknown. Consequently, the potential role of cell signaling pathways in B. glabrata hemocyte H(2)O(2) production was investigated by evaluating the effects of specific inhibitors of selected signaling proteins. Results suggest that both ERK and p38 MAPKs are involved in the regulation of B. glabrata H(2)O(2) release in response to stimulation by PMA and galactose-conjugated BSA. However, the involvement of the signaling proteins PKC, PI(3) kinase and PLA(2) differs between PMA- and BSA-gal-induced H(2)O(2) production.
 ...
PMID:Regulation of hydrogen peroxide release in circulating hemocytes of the planorbid snail Biomphalaria glabrata. 1798 29

Regulatory mechanisms in bradykinin (BK) activated release of arachidonate (ARA) and synthesis of prostaglandin (PG) and platelet activating factor (PAF) were studied in bovine pulmonary artery endothelial cells (BPAEC). A role for GTP binding protein (G-protein) in the binding of BK to the cells was determined. Guanosine 5-O- (thiotriphosphate), (GTPtauS), lowered the binding affinity for BK and increased the Kd for the binding from 0.45 to 1.99 nM. The Bmax remained unaltered at 2.25 x 10(-11) mole. Exposure of the cells to aluminium fluoride also reduced the affinity for BK. Bradykinin-induced release of ARA proved pertussis toxin (PTX) sensitive, with a maximum sensitivity at 10 ug/ml PTX. GTPtauS at 100 muM increased the release of arachidonate. The effect of GTPtauS and BK was additive at suboptimal doses of BK up to 0.5 nM but never exceeded the levels of maximal BK stimulation at 50 nM. PTX also inhibited the release of ARA induced by the calcium ionophore, A23187. Phorbol 12-myristate 13-acetate or more commonly known as tetradecanoyl phorbol acetate (TPA) itself had little effect on release by the intact cells. However, at 100 nM it augmented the BK activated release. This was downregulated by overnight exposure to TPA and correlated with down-regulation of protein kinase C (PKC) activity. The down-regulation only affected the augmentation of ARA release by TPA but not the original BK activated release. TPA displayed a similar, but more potent amplification of PAF synthesis in response to both BK or the calcium ionophore A23187. These results taken together point to the participation of G-protein in the binding of BK to BPAEC and its activation of ARA release. Possibly two types of G-protein are involved, one associated with the receptor, the other activated by Ca(2+) and perhaps associated with phospholipase A(2) (PLA(2)). Our results further suggest that a separate route of activation, probably also PLA(2) related, takes place through a PKC catalysed phosphorylation.
 ...
PMID:Mechanisms in bradykinin stimulated arachidonate release and synthesis of prostaglandin and platelet activating factor. 1847 53

The phospholipase A(2) (PLA(2))-prostanoid cascade is involved in cannabinoid receptor-mediated neuronal functions. We investigated the signaling mechanism for the release of arachidonic acid by cannabinoids, 2-arachidonoyl glycerol (2-AG) and HU210, in rat PC12 cells and in primary cultured cells from the mouse cerebellum. The effect of selective inhibitors for signaling pathways and/or enzymes (alpha type cytosolic PLA(2) (cPLA(2)alpha), G protein, Src kinases, phospholipase C, protein kinase C) was assessed. Methods included translocation of the chimeric protein GFP-cPLA(2)alpha, the activities of Src family kinases, Ca(2+)-dependent fluorescence and cyclic AMP accumulation. Treatment with 2-AG and HU210 at greater concentrations than 3 muM caused the release of arachidonic acid, and the response was inhibited by AM251 (an antagonist of cannabinoid CB(1) receptor) and by pyrrophenone (a selective inhibitor of cPLA(2)alpha) in PC12 cells. The cannabinoid treatment caused the intracellular translocation of cPLA(2)alpha and an increase in the intracellular Ca(2+) level. Treatment with HU210 caused tyrosine phosphorylation of Src and Fyn, and increased their kinase activities. Pretreatment with inhibitors of tyrosine kinases or phospholipase C abolished the cannabinoids-induced release of arachidonic acid and Ca(2+) response, and protein kinase C inhibitor reduced the release of arachidonic acid. 2-AG caused the release of arachidonic acid from cultured cells of the mouse cerebellum via similar mechanisms. These data reveal that cannabinoids activated cPLA(2)alpha in a Src-phospholipase C-protein kinase C-dependent manner probably via cannabinoid CB(1) receptor and/or CB(1)-like receptor in neuronal cells.
 ...
PMID:Release of arachidonic acid by 2-arachidonoyl glycerol and HU210 in PC12 cells; roles of Src, phospholipase C and cytosolic phospholipase A(2)alpha. 1853 71

Gonadotropin-releasing hormone (GnRH) is the first key hormone of reproduction. GnRH analogs are extensively used in in vitro fertilization, and treatment of sex hormone-dependent cancers, due to their ability to bring about 'chemical castration'. The interaction of GnRH with its cognate type I receptor (GnRHR) in pituitary gonadotropes results in the activation of Gq/G(11), phospholipase Cbeta (PLCbetaI), PLA(2), and PLD. Sequential activation of the phospholipases generates the second messengers inositol 1, 4, 5-trisphosphate (IP(3)), diacylglycerol (DAG), and arachidonic acid (AA), which are required for Ca(2+) mobilization, the activation of various protein kinase C isoforms (PKCs), and the production of prostaglandin (PG) and other metabolites of AA, respectively. PKC isoforms are the major mediators of the downstream activation of a number of mitogen-activated protein kinase (MAPK) cascades by GnRH, namely: extracellular signal-regulated kinase (ERK), jun-N-terminal kinase (JNK), and p38MAPK. The activated MAPKs phosphorylate both cytosolic and nuclear proteins to initiate the transcriptional activation of the gonadotropin subunit genes and the GnRHR. While Ca(2+) mobilization has been found to initiate rapid gonadotropin secretion, Ca(2+), together with various PKC isoforms, MAPKs and AA metabolites also serve as key nodes, in the GnRH-stimulated signaling network that enables the gonadotropes to decode GnRH pulse frequencies and translating that into differential gonadotropin synthesis and release. Even though pulsatility of GnRH is recognized as a major determinant for differential gonadotropin subunit gene expression and gonadotropin secretion very little is yet known about the signaling circuits governing GnRH action at the 'Systems Biology' level. Direct apoptotic and metastatic effects of GnRH analogs in gonadal steroid-dependent cancers expressing the GnRHR also seem to be mediated by the activation of the PKC/MAPK pathways. However, the mechanisms dictating life (pituitary) vs. death (cancer) decisions made by the same GnRHR remain elusive. Understanding these molecular mechanisms triggered by the GnRHR through biochemical and 'Systems Biology' approaches would provide the basis for the construction of the dynamic connectivity maps, which operate in the various cell types (endocrine, cancer, and immune system) targeted by GnRH. The connectivity maps will open a new vista for exploring the direct effects of GnRH analogs in tumors and the design of novel combined therapies for fertility control, reproductive disorders and cancers.
 ...
PMID:Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. 1870 85

As growth plate chondrocytes mature and hypertrophy, they reorganize their proteoglycan-rich type II collagen extracellular matrix (ECM), involving 1,25(OH)(2)D(3)-dependent regulation of matrix metalloproteinases (MMPs). Stromelysin-1 (MMP-3) and 72-kD gelatinase (MMP-2) are found in extracellular matrix vesicles (MVs) and release and activate ECM-bound latent TGF-beta1 and TGF-beta2, respectively. 1,25(OH)(2)D(3) regulates incorporation of MMP-2 and MMP-3 into MVs and release of these enzymes in the ECM. Plasma membranes (PMs) and MVs contain the 1alpha,25(OH)(2)D(3) membrane receptor ERp60 (protein disulfide isomerase A3), phospholipase A(2) (PLA(2)), PLA(2)-activating protein, the nuclear vitamin D receptor and caveolin-1. 1,25(OH)(2)D(3) secreted by chondrocytes binds MV ERp60, activating PLA(2). Resulting lysophospholipids destabilize MV membranes, releasing active MMPs. We examined 1,25(OH)(2)D(3)-dependent activation of latent TGF-beta1 stored in cartilage ECM. Interestingly, TGF-beta1 regulates 1,25(OH)(2)D(3) production. 1alpha,25(OH)(2)D(3) activates PM protein kinase C (PKC)-alpha via ERp60-dependent PLA(2)-signaling, lysophospholipid production and phospholipase C-gamma. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching MVs in PKC-zeta. Direct activation of MV MMP-3 requires ERp60 based on blocking antibodies and PKC based on inhibitor studies. However, treatment of MVs with 1,25(OH)(2)D(3) decreases MV PKC-zeta activity, suggesting more complex feedback mechanisms, potentially involving MV lipid signaling. Our observations indicate that one role of MVs is to provide MMPs at sites distant from the cells. Chondrocytes secrete 1,25(OH)(2)D(3), which acts directly on MV-membranes via ERp60, releasing MMPs. MMP-specific ECM components are hydrolyzed, resulting in release and activation of growth factors that can act back on the cells.
 ...
PMID:1,25-Dihydroxy vitamin D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60-activated matrix vesicle matrix metalloproteinases. 1876 31

Sphingosine 1-phosphate (S1P) is a bioactive lipid, stored and released from activated platelets, macrophages, and other mammalian cells. We previously reported that S1P induces esophageal smooth muscle contraction in freshly isolated intact cells. Here, we measured S1P-induced ERK1/2 activation and upstream signaling in cultured feline esophageal smooth muscle cells. Activation of ERK1/2 by S1P peaked at 5 min, was sustained up to 30 min, and was blocked by PTX. In contrast, S1P did not activate p38 MAPK or JNK. PTX inhibited S1P-induced ERK1/2 activation. We then used phospholipase inhibitors, DEDA for PLA(2), U73122 for PLC, and rhoCMB for PLD, to determine that ERK1/2 activation was downstream of PLC activation. The PKC inhibitors, GF109203X and chelerythrine, also suppressed ERK1/2 activation. Whereas the PTK inhibitor, genistein, partially inhibited ERK1/2 activation, the EGFR tyrosine kinase inhibitor, tyrphostin 51, had no effect. Taken together, S1P-induced ERK1/2 activation in cultured ESMCs requires a PTX-sensitive G protein, stimulation of the PLC pathway, and subsequent activation of the PKC and PTK pathways.
 ...
PMID:Signaling mechanisms of sphingosine 1-phosphate-induced ERK1/2 activation in cultured feline esophageal smooth muscle cells. 1902 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>