Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Emerging evidence indicates that group I metabotropic glutamate receptors (mGluRs) play a significant role in the addictive plasticity of striatal neurons. The plasticity is probably mediated by altered cellular gene expression in relation to stimulation of group I mGluRs and associative signaling proteins. In this study, we investigated the signaling linkage of surface group I mGluRs to the nuclear transcription factor cAMP response element-binding protein (CREB) in cultured primary striatal neurons. We found that selective activation of group I mGluRs (primarily the mGluR5 subtype) was able to up-regulate CREB phosphorylation in neurochemically identified gamma-aminobutyratergic neurons but not glia. The CREB phosphorylation was independent of kainate/AMPA receptors but partially dependent of concomitant NMDA receptor activation. Because L-type voltage-operated Ca(2+) channel inhibitors substantially blocked the CREB phosphorylation, group I receptors are believed to lead to activation of L-type Ca(2+) channels, resulting in the CREB phosphorylation. Indeed, further studies on signaling pathways showed that group I mGluRs, by activating phospholipase C, induced a rapid and transient Ca(2+) release from the 1,4,5-triphosphate-sensitive rather than ryanodine-sensitive Ca(2+) store. The transient Ca(2+) rise in turn triggered the opening of L-type Ca(2+) channels, resulting in a progressively larger increase in cytoplasmic Ca(2+) levels that is responsible for subsequent CREB phosphorylation. These results indicate that Ca(2+)-coupled group I mGluRs possess the ability to up-regulate CREB phosphorylation via the intracellular Ca(2+) release-induced activation of L-type Ca(2+) channels and, to a lesser extent, NMDA receptors in primary striatal neurons.
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PMID:Glutamate cascade to cAMP response element-binding protein phosphorylation in cultured striatal neurons through calcium-coupled group I metabotropic glutamate receptors. 1218 23

The ability of activation of group I metabotropic glutamate receptor (mGluR) to induce depotentiation was investigated at Schaffer collateral-CA1 synapses of rat hippocampal slices. Brief bath application (5 min) of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) (10 microm) induced a long-term depression of synaptic transmission or depotentiation (DEP) of previously established long-term potentiation (LTP), which was independent of NMDA or A(1) adenosine receptor activation. This DHPG-DEP was observed when DHPG was delivered 3 min after LTP induction. However, when DHPG was applied at 10 or 30 min after LTP induction, significantly less depotentiation was found. DHPG-DEP (1) is reversible and has the ability to unsaturate LTP, (2) is synapse specific, (3) does not require concurrent synaptic stimulation, (4) is mechanistically distinct from NMDA receptor-dependent depotentiation, (5) requires mGluR5 activation, (6) requires rapamycin-sensitive mRNA translation signaling, (7) does not require phospholipase C or protein phosphatase activation, and (8) is not associated with a change in paired-pulse (PP) facilitation. In addition, the ability of DHPG to reverse LTP was mimicked by a long train of low-frequency (1 Hz/15 min) PP stimulation. Moreover, the expression of DHPG-DEP is associated with a reduction in the increase of the surface expression of AMPA receptors seen with LTP. These results suggest that the activation of mGluR5 and in turn the triggering of a protein synthesis-dependent internalization of synaptic AMPA receptors may contribute to the DHPG-DEP in the CA1 region of the hippocampus.
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PMID:The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. 1238 90

The Galphaq protein-coupled metabotropic glutamate receptor subtype-5 (mGluR5) is densely expressed in medium spiny projection neurons of striatum. Emerging evidence suggests a significant role of mGluR5 in the addictive plasticity of striatal neurons that is likely derived from inducible cellular gene expression related to stimulation of mGluR5 and associative signaling proteins. In this study, we found that activation of mGluR5 with a selective agonist (RS)-2-chloro-5-hydroxy-phenylglycine (CHPG) induced a rapid and transient phosphorylation of a transcription regulator Elk-1 in cultured striatal neurons from rat E19 embryos or neonatal day-1 pups. The Elk-1 phosphorylation was dose-dependent and occurred in neurochemically identified GABAergic neurons, but not glia. A series of experiments further demonstrated that the CHPG-stimulated Elk-1 phosphorylation was mediated through selective activation of mGluR5-regulated phospholipase C and associative second messenger system, i.e. 1,4,5,-triphosphate-sensitive Ca2+ release. Moreover, the Elk-1 phosphorylation was partially dependent on mGluR5-mediated co-activation of NMDA, but not kainate/AMPA receptors and L-type voltage-operated Ca2+ channels. Using an immediate early gene c-fos as a report of inducible gene expression, we found that CHPG induced marked c-fos mRNA expression. The c-fos induction kinetically corresponded to the Elk-1 phosphorylation and was attenuated by antisense oligonucleotides that selectively knocked down Elk-1 proteins. These results indicate that glutamatergic tone on mGluR5 is positively coupled to Elk-1 phosphorylation in striatal neurons via multiple signaling mechanisms involving Ca2+ release and NMDA activation, and the mGluR5-mediated Elk-1 phosphorylation facilitates gene transcription.
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PMID:Metabotropic glutamate receptor 5-regulated Elk-1 phosphorylation and immediate early gene expression in striatal neurons. 1271 32

We have previously reported that dopamine (DA) depresses non-NMDA receptor-mediated glutamatergic transmission in the rat parabrachial nucleus (PBN), an interface between brainstem and forebrain that is implicated in autonomic regulation. This work examined cellular signalling pathways that might underlie this DA-induced synaptic depression. Direct activation of adenylyl cyclase with 10 microM forskolin increased the evoked EPSC but did not occlude DA-induced EPSC depression. Similarly, a preferential protein kinase A inhibitor, H-7 (10 microM), did not block DA's synaptic effects. Incubation of slices with cholera toxin (CTX; 1 microgram/ml) or pertussis toxin (PTX; 0.5 microgram/ml) for 20 h, procedures used to irreversibly activate or disable the G(s) and G(i) proteins, respectively, did not change DA's effects. The putative phospholipase C inhibitor, U-73122 (10 microM) and its inactive analogue U-73343 (10 microM) did not alter DA-induced reduction in the EPSCs. Alterations in signalling molecules downstream of phospholipase C including depleting internal calcium stores by thapsigargin and cyclopiazonic acid and blocking protein kinase C with chelerythrine, had no effect on DA-induced synaptic depression. Furthermore, DA's depression of the non-NMDA response was not blocked by APV, an NMDA receptor antagonist. Finally, DA depressed evoked, pharmacologically isolated NMDA receptor-mediated synaptic responses while increasing NMDA-induced inward currents in the PBN. These results indicate that DA-induced synaptic effects in the PBN are not through the activation of cholera or pertussis toxin sensitive G proteins. Furthermore, it does not employ the adenylyl cyclase-cAMP-PKA cascade, the phospholipase C signalling pathway and NMDA receptor-coupled mechanisms to depress excitatory synaptic transmission in the PBN.
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PMID:Dopamine-induced synaptic depression in the parabrachial nucleus is independent of CTX- and PTX-sensitive G-proteins, PKA and PLC signalling pathways. 1467 13

Primary cultures of neocortical neurons exhibit spontaneous Ca(2+) oscillations under zero or low extracellular [Mg(2+)] conditions. We find that mature murine neocortical neurons cultured for 9 days also produce spontaneous Ca(2+) oscillations in the presence of physiological [Mg(2+)]. These Ca(2+) oscillations were action potential mediated inasmuch as tetrodotoxin eliminated their occurrence. AMPA receptors were found to regulate the frequency of Ca(2+) oscillations. In contrast, Ca(2+) oscillations were independent of activation of L-type Ca(2+) channels, and NMDA receptors provided only a minor contribution. Release of intracellular Ca(2+) stores was involved in the oscillatory activity since thapsigargin reduced the amplitude and frequency of the oscillations. S-4-carboxyphenylglycine (S)-4CPG), an antagonist of group I metabotropic glutamate receptor (mGluR), also reduced the amplitude of oscillations. In addition, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), a group I mGluR agonist, increased the oscillation frequency, suggesting a critical role for mGluR in the generation of Ca(2+) oscillations. The mGluR-mediated release of intracellular Ca(2+) stores appeared to be mediated by phospholipase C (PLC) since the PLC inhibitor U73122 eliminated the Ca(2+) oscillations. These results indicate that Ca(2+) oscillations in neocortical cultures in the presence of physiologic [Mg(2+)] are primarily initiated by excitatory input from AMPA receptors and involve mobilization of intracellular Ca(2+) stores following activation of mGluR.
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PMID:Spontaneous synchronized calcium oscillations in neocortical neurons in the presence of physiological [Mg(2+)]: involvement of AMPA/kainate and metabotropic glutamate receptors. 1504 19

Ischemic preconditioning (IPC) promotes brain tolerance against subsequent ischemic insults. Using the organotypic hippocampal slice culture, we conducted the present study to investigate (1) the role of adenosine A1 receptor (A1AR) activation in IPC induction, (2) whether epsilon protein kinase C (epsilonPKC) activation after IPC is mediated by the phosphoinositol pathway, and (3) whether epsilonPKC protection is mediated by the extracellular signal-regulated kinase (ERK) pathway. Our results demonstrate that activation of A1AR emulated IPC, whereas blockade of the A1AR during IPC diminished neuroprotection. The neuroprotection promoted by the A1AR was also reduced by the epsilonPKC antagonist. To determine whether epsilonPKC activation in IPC and A1AR preconditioning is mediated by activation of the phosphoinositol pathway, we incubated slices undergoing IPC or adenosine treatment with a phosphoinositol phospholipase C inhibitor. In both cases, preconditioning neuroprotection was significantly attenuated. To further characterize the subsequent signal transduction pathway that ensues after epsilonPKC activation, mitogen-activated protein kinase kinase was blocked during IPC and pharmacologic preconditioning (PPC) (with epsilonPKC, NMDA, or A1AR agonists). This treatment significantly attenuated IPC- and PPC-induced neuroprotection. In conclusion, we demonstrate that epsilonPKC activation after IPC/PPC is essential for neuroprotection against oxygen/glucose deprivation in organotypic slice cultures and that the ERK pathway is downstream to epsilonPKC.
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PMID:Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. 1518 71

Inositol 1,4,5-trisphosphate (InsP(3)) production in single cerebellar granule neurons (CGNs) grown in culture was measured using the PH domain of phospholipase C delta1 tagged with enhanced green fluorescent protein (eGFP-PH(PLCdelta1)). These measurements were correlated with changes in intracellular free Ca2+ determined by single cell imaging. In control CGNs, intracellular Ca2+ stores appeared replete. However, the refilling state of these stores appeared dependent on the fluorophore used to measure Ca2+-release. Thus, methacholine (MCH), acting via muscarinic acetylcholine-receptors (mAchRs), mobilised intracellular Ca2+ in cells loaded with fluo-3 and fura-4f, but not fura-2. Confocal measurements of single CGNs expressing eGFP-PH(PLCdelta1) demonstrated that MCH stimulated a robust peak increase in InsP(3), which was followed by a sustained plateau phase of InsP(3) production. In contrast, glutamate-induced InsP(3) signals were weak or not detectable. MCH-stimulated InsP(3) production was reduced by chelation of intracellular Ca2+ with BAPTA, and emptying of intracellular stores with thapsigargin, indicated a positive feedback effect of Ca2+ mobilisation onto PLC activity. In CGNs, NMDA- and KCl-mediated Ca2+-entry significantly enhanced MCH-induced InsP(3) production. Furthermore, mAchR-mediated PLC activation appeared sensitive to the full dynamic range of intracellular Ca2+ increases stimulated by 100 microm NMDA. This dynamic regulation was also observed at the level of PKC activation indicated by an enhanced translocation of eGFP-tagged myristoylated alanine-rich C kinase substrate (MARCKS) protein in cells stimulated with MCH. Thus, NMDA-mediated Ca2+ influx and PLC activation may represent a coincident-detection system whereby ionotropic and metabotropic signals combine to stimulate InsP(3) production and PKC-mediated phosphorylation events in CGNs.
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PMID:NMDA-receptor regulation of muscarinic-receptor stimulated inositol 1,4,5-trisphosphate production and protein kinase C activation in single cerebellar granule neurons. 1518 57

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. After release from presynaptic terminals, glutamate binds to both ionotropic and metabotropic receptors to mediate fast, slow, and persistent effects on synaptic transmission and integrity. There are three types of ionotropic glutamate receptors. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate receptors are principally activated by the agonist bearing its name and are permeable to cationic flux; hence, their activation results in membrane depolarization. All ionotropic glutamate receptors are believed to be composed of four distinct subunits, each of which is topologically arranged with three transmembrane-spanning and one pore-lining (hairpin loop) domain. In contrast, metabotropic glutamate receptors are G protein (guanine nucleotide-binding protein) -coupled receptors linked to second-messenger systems. Group I metabotropic glutamate receptors are linked to phospholipase C, which results in phosphoinositide hydrolysis and release of calcium from intracellular stores. Group II and group III metabotropic glutamate receptors are negatively linked to adenylate cyclase, which catalyzes the production of cyclic adenosine monophosphate. Each metabotropic glutamate receptor is composed of seven transmembrane-spanning domains, similar to other members of the superfamily of metabotropic receptors, which includes noradrenergic, muscarinic acetylcholinergic, dopaminergic, serotonergic (except type 3 receptors), and gamma-aminobutyric acid (GABA) type B receptors. This review summarizes the relevant molecular biology and ontogeny of glutamate receptors in the central nervous system and highlights some of the roles that they can play during brain development and in certain disease states.
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PMID:Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. 1522 8

Pancreastatin (PST), a chromogranin A-derived peptide, has an anti-insulin metabolic effect and inhibits growth and proliferation by producing nitric oxide (NO) in HTC rat hepatoma cells. When NO production is blocked, a proliferative effect prevails due to the activation a Galphaq/11-phospholipase C-beta (PLC-beta) pathway, which leads to an increase in [Ca2+]i, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. The aim of the present study was to investigate the NO synthase (NOS) isoform that mediates these effects of PST on HTC hepatoma cells and the possible roles of cyclic GMP (cGMP) and cGMP-dependent protein kinase. DNA and protein synthesis in response to PST were measured as [3H]-thymidine and [3H]-leucine incorporation in the presence of various pharmacological inhibitors: N-monomethyl-L-arginine (NMLA, nonspecific NOS inhibitor), L-NIO (endothelial nitric oxide synthase (eNOS) inhibitor), espermidine (neuronal nitric oxide synthase (nNOS) inhibitor), LY83583 (guanylyl cyclase inhibitor), and KT5823 (protein kinase G inhibitor, (PKG)). L-NIO, similarly to NMLA, reverted the inhibitory effect of PST on hepatoma cell into a stimulatory effect on growth and proliferation. Nevertheless, espermidine also prevented the inhibitory effect of PST, but there was no stimulation of growth and proliferation. When guanylyl cyclase activity was blocked, there was again a reversion of the inhibitory effect into a stimulatory action, suggesting that the effect of NO was mediated by the production of cGMP. PKG inhibition prevented the inhibitory effect of PST, but there was no stimulatory effect. Therefore, the inhibitory effect of PST on growth and proliferation of hepatoma cells may be mainly mediated by eNOS activation. In turn, the effect of NO may be mediated by cGMP, whereas other pathways in addition to PKG activation seem to mediate the inhibition of DNA and protein synthesis by PST in HTC hepatoma cells.
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PMID:eNOS, nNOS, cGMP and protein kinase G mediate the inhibitory effect of pancreastatin, a chromogranin A-derived peptide, on growth and proliferation of hepatoma cells. 1558 12

Hyperammonemia is responsible for most neurological alterations in patients with hepatic encephalopathy by mechanisms that remain unclear. Hyperammonemia alters phosphorylation of neuronal protein kinase C (PKC) substrates and impairs NMDA receptor-associated signal transduction. The aim of this work was to analyse the effects of hyperammonemia on the amount and intracellular distribution of PKC isoforms and on translocation of each isoform induced by NMDA receptor activation in cerebellar neurons. Chronic hyperammonemia alters differentially the intracellular distribution of PKC isoforms. The amount of all isoforms (except PKC zeta) was reduced (17-50%) in the particulate fraction. The contents of alpha, beta1, and epsilon isoforms decreased similarly in cytosol (65-78%) and membranes (66-83%), whereas gamma, delta, and theta; isoforms increased in cytosol but decreased in membranes, and zeta isoform increased in membranes and decreased in cytosol. Chronic hyperammonemia also affects differentially NMDA-induced translocation of PKC isoforms. NMDA-induced translocation of PKC alpha and beta is prevented by ammonia, whereas PKC gamma, delta, epsilon, or theta; translocation is not affected. Inhibition of phospholipase C did not affect PKC alpha translocation but reduced significantly PKC gamma translocation, indicating that NMDA-induced translocation of PKC alpha is mediated by Ca2+, whereas PKC gamma translocation is mediated by diacylglycerol. Chronic hyperammonemia reduces Ca+2-mediated but not diacylglycerol-mediated translocation of PKC isoforms induced by NMDA.
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PMID:Chronic exposure to ammonia induces isoform-selective alterations in the intracellular distribution and NMDA receptor-mediated translocation of protein kinase C in cerebellar neurons in culture. 1560 4


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