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)

1. Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD-coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2. The mGluR-selective agonist (1S,3R)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 microM) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3. The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-ACPD > L-cysteine sulphinic acid > L-aspartate > L-glutamate. L-(+)-2-Amino-4-phosphonobutyric acid and the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate failed to activate PLD. (RS)-3,5-dihydroxyphenylglycine (100300 microM), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 microM (1S,3R)-ACPD. 4. (+)-alpha-Methyl-4-carboxyphenylglycine (0.1-1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L-(+)-2-Amino-3-phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 microM (1S,3R)-ACPD-induced PLC response but produced a robust stimulation of PLD. 5. 12-O-Tetradecanoylphorbol 13-acetic acid and phorbol 12,13-dibutyrate (PDBu), activators of protein kinase C, at 1 microM had a stimulatory effect on mGluRs linked to PLD but depressed (1S,3R)-ACPD-induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 microM) reduced PLD activation induced by 1 microM PDBu but not by 100 microM (1S,3R)-ACPD. 6. Our results suggest that PLD-linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC-independent mechanism.
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PMID:Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. 879 79

The amyloid precursor protein (APP) can be cleaved by a beta-secretase to generate a beta-amyloid peptide, which has been implicated in the pathogenesis of Alzheimer's disease. However, APP can also be cleaved by an alpha-secretase to form a non-amyloidogenic secreted form of APP (APP-S). APP-S secretion can be physiologically regulated. This study examined the glutamatergic regulation of APP in the human neuronal Ntera 2 (NT2N) cell line. Metabotropic glutamate receptor subtypes 1alpha/beta and 5alpha were identified in the NT2N neurons by reverse transcription-polymerase chain reaction. Stimulation of these phosphatidylinositol-linked receptors with glutamate or specific receptor agonists resulted in a dose- and time-dependent increase in the secretion of the amyloid precursor protein (APP-S), measured by the immunoprecipitation of APP-S from the medium of [35S]methionine-labeled NT2N neurons. The glutamate-induced APP-S secretion was maximal at 30 min and at a concentration of 1 mM glutamate. Glutamate-induced APP-S secretion required activation of phospholipase C, which resulted in inositol 1, 4,5-trisphosphate production, as shown by the rapid glutamate-induced accumulation of inositol 1,4,5-trisphosphate. Glutamate also caused an increase in intracellular Ca2+. The protein kinase C activator phorbol 12-myristate 13-acetate, a phorbol ester, as well as 1-oleoyl-2-acetoyl-3-glycerol, a cell-permeable diacylglycerol analog, also stimulated APP-S secretion. These findings suggest that APP-S secretion from NT2N neurons can be regulated by the activation of phosphatidylinositol-linked metabotropic glutamate receptor signaling pathway.
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PMID:Regulation of amyloid precursor protein secretion by glutamate receptors in human Ntera 2 neurons. 959 52

1. Glutamate suppressed high-voltage-activated barium currents (IBa, HVA) in tiger salamander retinal ganglion cells. Both ionotropic (iGluR) and metabotropic (mGluR) receptors contributed to this calcium channel inhibition. 2. Trans-ACPD (1-aminocyclopentane-trans-1S,3R-dicarboxylic acid), a broad-spectrum metabotropic glutamate receptor agonist, suppressed a dihydropyridine-sensitive barium current. Kainate, an ionotropic glutamate receptor agonist, reduced an omega-conotoxin GVIA-sensitive current. 3. The relative effectiveness of selective agonists indicated that the predominant metabotropic receptor was the L-2-amino-4-phosphonobutyrate (L-AP4)-sensitive, group III receptor. This receptor reversed the action of forskolin, but this was not responsible for calcium channel suppression. l-AP4 raised internal calcium concentration. Antagonists of phospholipase C, inositol trisphosphate (IP3) receptors and ryanodine receptors inhibited the action of metabotropic agonists, indicating that group III receptor transduction was linked to this pathway. 4. The action of kainate was partially suppressed by BAPTA, by calmodulin antagonists and by blockers of calmodulin-dependent phosphatase. Suppression by kainate of the calcium channel current was more rapid when calcium was the charge carrier, instead of barium. The results indicate that calcium influx through kainate-sensitive glutamate receptors can activate calmodulin, which stimulates phosphatases that may directly suppress voltage-sensitive calcium channels. 5. Thus, ionotropic and metabotropic glutamate receptors inhibit distinct calcium channels. They could act synergistically, since both increase internal calcium. These pathways provide negative feedback that can reduce calcium influx when ganglion cells are depolarized.
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PMID:Metabotropic and ionotropic glutamate receptors regulate calcium channel currents in salamander retinal ganglion cells. 966 Aug 96

Quantitative in situ hybridization revealed that following the induction of hippocampal long-term potentiation (LTP) in the dentate gyrus of freely moving rats, specific increases in the expression of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor and mGluR1c, a short splice variant of the metabotropic glutamate receptors that are linked intracellularly to phospholipase C (PLC) and protein kinase C (PKC), were seen in the postsynaptic dentate granule cells. There were no changes in the expression of NR2A; NR2C and NR2D NMDA receptor subunits; or mGluR1a, mGluR1b, mGluR5a, and mGluR5b PLC-associated metabotropic receptors. The elevations in NR2B and mGluR1c mRNA were delayed, occurring days after LTP induction. NR2B expression was enhanced significantly by 48 hr after LTP but was starting to decrease toward basal levels by 96 hr. The transient increase in the expression of NR2B mirrored the increase in the expression of PKC-sensitive isoforms of the NR1 subunits of the NMDA receptor we observed previously (Thomas et al. 1994a). The increase in mGluR1c expression was more persistent, showing a significant increase 96 hr after LTP. This study demonstrates that not only are there changes in the expression of individual glutamate receptor subunits but the increases in their expression occur days after the induction of LTP and may reflect so-called late-onset genes that may be important for the maintenance of LTP.
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PMID:Alterations in the expression of specific glutamate receptor subunits following hippocampal LTP in vivo. 1045 90

HIV-1 infection commonly leads to neuronal cell death and a debilitating syndrome known as AIDS-related dementia complex. The HIV-1 protein Tat is neurotoxic, and because cell survival is affected by the intracellular calcium concentration ([Ca2+]i), we determined mechanisms by which Tat increased [Ca2+]i and the involvement of these mechanisms in Tat-induced neurotoxicity. Tat increased [Ca2+]i dose-dependently in cultured human fetal neurons and astrocytes. In neurons, but not astrocytes, we observed biphasic increases of [Ca2+]i. Initial transient increases were larger in astrocytes than in neurons and in both cell types were significantly attenuated by antagonists of inositol 1,4,5-trisphosphate (IP3)-mediated intracellular calcium release [8-(diethylamino)octyl-3,4,5-trimethoxybenzoate HCI (TMB-8) and xestospongin], an inhibitor of receptor-Gi protein coupling (pertussis toxin), and a phospholipase C inhibitor (neomycin). Tat significantly increased levels of IP3 threefold. Secondary increases of neuronal [Ca2+]i in neurons were delayed and progressive as a result of excessive calcium influx and were inhibited by the glutamate receptor antagonists ketamine, MK-801, (+/-)-2-amino-5-phosphonopentanoic acid, and 6,7-dinitroquinoxaline-2,3-dione. Secondary increases of [Ca2+]i did not occur when initial increases of [Ca2+]i were prevented with TMB-8, xestospongin, pertussis toxin, or neomycin, and these inhibitors as well as thapsigargin inhibited Tat-induced neurotoxicity. These results suggest that Tat, via pertussis toxin-sensitive phospholipase C activity, induces calcium release from IP3-sensitive intracellular stores, which leads to glutamate receptor-mediated calcium influx, dysregulation of [Ca2+]i, and Tat-induced neurotoxicity.
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PMID:Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein tat. 1050 Nov 79

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1alpha. The mGluR1 agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1alpha-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor thapsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated by the broad spectrum kinase inhibitor staurosporine. ACPD produced no further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with a role for cytoskeletal protein(s) in the signaling pathway. As Group I mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.
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PMID:mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. 1137 56

The neuroprotectant fructose-1,6-bisphosphate (FBP) preserves cellular [ATP] and prevents catastrophic increases in [Ca2+]i during hypoxia. Because FBP does not enter neurons or glia, the mechanism of protection is not clear. In this study, we show that FBP's capacity to protect neurons and stabilize [Ca2+]i during hypoxia derives from signaling by a phospholipase-C-intracellular Ca2+-protein kinases pathway, rather than Ca2+ chelation or glutamate receptor inhibition. FBP reduced [Ca2+]i changes in hypoxic hippocampal neurons, regardless of [Ca2+]e, and preserved cellular integrity as measured by trypan blue or propidium iodide exclusion and [ATP]. FBP also prevented hypoxia-induced increases in [Ca2+]i when glucose was absent and when [Ca2+]e was increased to negate Ca2+ chelation by FBP. These protective effects were observed equally in postnatal day 2 (P2) and P16 neurons. Inhibiting glycolysis with iodoacetate eliminated the protective effects of FBP in P16 neurons. FBP did not alter Ca2+ influx stimulated by brief applications of NMDA or glutamate during normoxia or hypoxia, but did reduce the increase in [Ca2+]i produced by 10 min of glutamate exposure during hypoxia. Because FBP increases basal [Ca2+]i and stimulates membrane lipid hydrolysis, we tested whether FBP's protective action was dependent on phospholipase C signaling. The phospholipase C inhibitor U73122 prevented FBP-induced increases in [Ca2+]i and eliminated FBP's ability to stabilize [Ca2+]i and increase survival during anoxia. Similarly, FBP's protection was eliminated in the presence of the mitogen/extracellular signal protein kinase (MEK) inhibitor U0126. We conclude that FBP may produce neuroprotection via activation of neuroprotective signaling pathways that modulate Ca2+ homeostasis.
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PMID:Neuroprotection and intracellular Ca2+ modulation with fructose-1,6-bisphosphate during in vitro hypoxia-ischemia involves phospholipase C-dependent signaling. 1164 Sep 1

Chronic R-N(6)-phenylisopropiladenosine (R-PIA) subcutaneous injection for 6 days significantly increased total glutamate receptor number (180% of control) in rat brain synaptic plasma membranes (SPM), without affecting receptor affinity. A higher increase in metabotropic glutamate (mGlu) receptor number (258% of control) was also detected, indicating that mGlu is the main type of glutamate receptor affected by this treatment. On the other hand, the observed increase in basal and calcium- and Gpp(NH)p-stimulated phospholipase C (PLC) activity after treatment was associated with a significant increase in PLC beta(1) isoform, detected in SPM by immunoblotting assays. Moreover, an increase in PLC activity stimulation with trans-ACPD, in the absence and in the presence of Gpp(NH)p, was detected after R-PIA treatment. These results show that mGlu receptors and its effector system, PLC activity, are up-regulated by chronic exposure to an adenosine A(1) receptor agonist and suggest the existence of a cross-talk mechanism between both signal transduction pathways in rat brain.
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PMID:Adenosine A1 receptor agonist treatment up-regulates rat brain metabotropic glutamate receptors. 1243 85

The influence of activation of glutamate receptor (GluR) on outward K(+) current in cultured neonate rat hippocampal astrocytes was investigated. Patch-clamp analysis of K(+) channel currents in cultured astrocytes identified the existence of 71 +/- 6 and 161 +/- 11 pS single-channel K(+) currents that were sensitive to changes in voltage and [Ca(2+)](i) and blocked by external TEA but not by charybdotoxin, iberiotoxin, apamin, or 4-aminopyridine. Reverse transcriptase (RT)-PCR and Northern blot analysis revealed transcripts of the Ca(2+)-activated K(+) channel (K(Ca)) beta(4)-subunit (beta4) (KCNMB4) in cultured astrocytes. Expression of the metabotropic glutamate receptor (mGluR) subtypes mGluR1 and mGluR5 and the ionotropic glutamate receptor (iGluR) subtypes iGluR1 and iGluR4 were detected by RT-PCR and immunofluorescence analysis in cultured astrocytes. The mGluR agonists L-glutamate and quisqualate increased the open state probability (NP(o)) of the 71 and 161 pS K(+) channel currents that were prevented by the mGluR receptor antagonists 1-aminoindan-1,5-dicarboxylic acid or L-(+)-2-amino-3-phosphonopropionic acid and not by the iGluR antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate or CNQX. Activation of the two types of K(+) channel currents by mGluR agonists was attenuated by pertussis toxin and by inhibition of phospholipase C (PLC) or cytochrome P450 arachidonate epoxygenase. These results indicate that brain astrocytes contain the KCNMB4 transcript and express two novel types of K(Ca) channels that are gated by activation of a G-protein coupled metabotropic glutamate receptor functionally linked to PLC and cytochrome P450 arachidonate epoxygenase activity.
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PMID:Metabotropic glutamate receptor activation enhances the activities of two types of Ca2+-activated k+ channels in rat hippocampal astrocytes. 1262 72

Group I metabotropic glutamate receptors (mGluRs) are important for hippocampal interneuron function. We used whole-cell recording and confocal imaging to characterize group I mGluR actions in CA1 oriens/alveus interneurons in slices. In tetrodotoxin and ionotropic glutamate receptor antagonists, the group I mGluR specific agonist DHPG increased intradendritic Ca(2+) levels and depolarized interneurons, whereas the group II mGluR specific agonist DCG-IV and the group III mGluR specific agonist L-AP4 did not. DHPG-induced depolarizing and Ca(2+) responses were antagonized by the group I mGluR antagonist 4CPG, but only Ca(2+) responses were significantly inhibited by the mGluR1 antagonist CPCCOEt. DHPG-induced depolarizing responses were not blocked by the inositol-1,4,5-trisphosphate (IP(3)) receptor inhibitor heparin, the protein kinase C (PKC) antagonists GF-109203X, or the inhibitor of phospholipase C (PLC) U73122. Thus, these responses to DHPG may not be transduced by the PLC-->IP(3)/diacylglycerol (DAG) pathway classically linked to group I mGluRs. DHPG-induced depolarizations were not blocked by intracellular GDP beta S or bath-application of N-ethylmaleimide (NEM), suggesting the involvement of a G protein-independent pathway. Our findings indicate that group I mGluRs induce a depolarization of oriens/alveus interneurons via a G protein-independent mechanism different from their classic signalling pathway. Since depolarizations are associated with intracellular Ca(2+) rises, these actions may be important for their synaptic plasticity and vulnerability to excitotoxicity.
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PMID:Group I metabotropic glutamate receptor actions in oriens/alveus interneurons of rat hippocampal CA1 region. 1505 57


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