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)

The effects of the selective metabotropic glutamate receptor agonist 1-aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) on forskolin-stimulated cyclic AMP formation in guinea-pig cerebral cortex slices were determined. t-ACPD inhibited the accumulation of [3H]cyclic AMP by approximately 80%, with an IC50 value of 35 +/- 4 microM. The effect was reversible and stereoselective, with the 1S,3R isomer being approximately 400-fold more potent than the 1R,3S isomer. L-Glutamate (over a restricted concentration range) also partially inhibited the response to forskolin, but quisqualate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and N-methyl-D-aspartate (NMDA) were ineffective. The effect of t-ACPD was not blocked by antagonists of the phospholipase C-linked metabotropic glutamate receptor, the AMPA ionotropic glutamate receptor, or the NMDA receptor. In summary, our results indicate the presence of a glutamate receptor in guinea-pig brain that is activated selectively by t-ACPD and that is negatively linked to adenylyl cyclase.
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PMID:Inhibition of forskolin-stimulated cyclic AMP formation by 1-aminocyclopentane-trans-1,3-dicarboxylate in guinea-pig cerebral cortical slices. 131 57

The amino acids L-glutamic and L-aspartic acids form the most widespread excitatory transmitter network in mammalian brain. The excitation produced by L-glutamic acid is important in the early development of the nervous system, synaptic plasticity and memory formation, seizures and neuronal degeneration. The receptors activated by L-glutamic acid are a target for therapeutic intervention in neurodegenerative diseases, brain ischaemia and epilepsy. There are two types of receptors for the excitatory amino acids, those that lead to the opening of cation-selective channels and those that activate phospholipase C (ref. 11). The receptors activating ion channels are NMDA (N-methyl-D-aspartate) and kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive receptors. The complementary DNAs for the kainate/AMPA receptor and for the metabotropic receptor have been cloned. We report here on the isolation and characterization of a protein complex of four major proteins that represents an intact complex of the NMDA receptor ion channel and on the cloning of the cDNA for one of the subunits of this receptor complex, the glutamate-binding protein.
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PMID:Cloning of cDNA for the glutamate-binding subunit of an NMDA receptor complex. 183 48

The effect of phospholipase C (PLC) treatment of rat brain membranes on the binding properties of excitatory amino acid receptors was investigated using both a phosphsphatidylcholine-hydrolyzing PLC from Clostridium perfringens and a phosphatidylinositol-specific PLC from Bacillus thuringiensis. PLC from C. perfringens produced an increased affinity of the quisqualate/DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor for its ligand, whereas kainate receptor binding was not affected. Both kinetic analysis and equilibrium saturation experiments indicated that PLC treatment produced a decrease in affinity for [3H]N-(1-[thienyl]cyclohexyl)-piperidine [( 3H]TCP), a ligand for the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel, when the channel was fully activated by high concentrations of glutamate and glycine but increased its binding under conditions in which the channel was presumably closed. This latter component of the binding was not due to an interaction of [3H]TCP with non-glutamate receptor sites, such as sigma opioid and histamine H3 receptors. Binding of [3H]glutamate and [3H] glycine to the NMDA receptors was not modified by PLC treatment, but there was a large decrease in the binding of the NMDA antagonist [3H]3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Stimulation by glycine of [3H]glutamate binding was also abolished following PLC treatment. In contrast to PLC from C. perfringens, phosphatidylinositol-specific PLC treatment did not detectably modify the binding properties of the quisqualate/AMPA receptor or the NMDA receptor channel. These data indicate that alterations in the lipid microenvironment of the glutamate receptors modulate both the conformation and the function of the receptors and suggest a possible role for phospholipases in the regulation of synaptic transmission at excitatory synapses.
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PMID:N-Methyl-D-aspartate and quisqualate/DL-alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors: differential regulation by phospholipase C treatment. 215 75

In primary cultures of cerebellar granule cells, glutamate, aspartate, and N-methyl-D-aspartate (NMDA) induced a dose-dependent release of [3H]arachidonic acid ([3H]AA) which was selective for these agonists and was inhibited by NMDA receptor antagonists. The agonist-induced [3H]AA release was reduced by quinacrine at concentrations that inhibited phospholipase A2 (PLA2) but affected neither the activity of phospholipase C (PLC) nor the hydrolysis of phosphoinositides induced by glutamate or quisqualate. Thus, the increased formation of AA was due to the receptor-mediated activation of PLA2 rather than to the action of PLC followed by diacylglycerol lipase. The receptor-mediated [3H]AA release was dependent on the presence of extracellular Ca2+ and was mimicked by the Ca2+ ionophore ionomycin. Pretreatment of granule cells with either pertussis or cholera toxin failed to inhibit the receptor-mediated [3H]AA release. Hence, in cerebellar granule cells, the stimulation of NMDA-sensitive glutamate receptors leads to the activation of PLA2 that is mediated by Ca2+ ions entering through the cationic channels functioning as effectors of NMDA receptors. A coupling through a toxin-sensitive GTP-binding protein can be excluded.
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PMID:N-methyl-D-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. 217 63

We found in cultured glioma (C6BU-1) cells that excitatory amino acids (EAAs) such as glutamate, N-methyl-D-aspartate (NMDA), aspartate, and metabotropic glutamate receptor agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate caused an increase in the inositol 1,4,5-trisphosphate formation and the intracellular Ca2+ concentration ([Ca2+]i) in the absence of extracellular Mg2+ and Ca2+. Pertussis toxin treatment abolished this glutamate-induced [Ca2+]i increase. Various antagonists against NMDA receptor-ion channel complex, such as Mg2+, D-2-amino-5-phosphonovalerate (D-APV), HA-966, and MK-801, also inhibited the increase in [Ca2+]i induced by glutamate. These results indicate that these metabotropic EAA receptors coupled to pertussis toxin-susceptible GTP-binding protein and phospholipase C system in C6BU-1 glioma cells have the pharmacological properties of NMDA receptor-ion channel complexes. We also found that in the presence of Mg2+ these metabotropic receptors resemble the NMDA receptor-ion channel complex interacted with 5-hydroxytryptamine2 (5-HT2) receptor signaling. EAAs inhibited 5-HT2 receptor-mediated intracellular Ca2+ mobilization and inositol 1,4,5-trisphosphate formation in a concentration-dependent manner. The inhibitory effect of glutamate was reversed by various NMDA receptor antagonists (D-APV, MK-801, phencyclidine, and HA-966), but L-APV failed to block the inhibitory effect of glutamate. The same result was observed in the absence of extracellular Ca2+. In addition, this inhibitory effect on 5-HT2 receptor-mediated signal transduction was abolished by treatment of C6BU-1 cells with pertussis toxin, whereas 5-HT2 receptor-mediated [Ca2+]i increase was not abolished by pertussis toxin treatment. We can, therefore, conclude that the inhibitory effect of glutamate is not a result of the influx of Ca2+ through the ion channel and that it operates via metabotropic glutamate receptors, having NMDA receptor-ion channel complex-like properties and being coupled with pertussis toxin-sensitive GTP-binding protein and phospholipase C.
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PMID:Metabotropic glutamate receptor in C6BU-1 glioma cell has NMDA receptor-ion channel complex-like properties and interacts with serotonin2 receptor-stimulated signal transduction. 752 90

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
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PMID:Modulation of nerve and glial function by adenosine--role in the development of ischemic damage. 753 56

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. It was previously demonstrated that an antibody to an isozyme of PLC, PLC-delta, produces intense staining of neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores and neuropil threads in the brains of patients with Alzheimer's disease (AD). Although the etiology of neuronal degeneration in AD is still to be defined, excitotoxic glutamate might be a candidate. In the present study, an anti-PLC-delta antibody was used to examine the influence of glutamate on PLC-delta immunoreactivity in cultured rat cortical neurons. Exposure to glutamate caused the death of cultured cortical neurons and exhibited increased immunostaining with the anti-PLC-delta antibody. Subtoxic doses of glutamate also increased PLC-delta immunoreactivity in a dose-dependent manner. Both glutamate-induced neuronal degeneration and the increases in PLC-delta immunoreactivity were prevented by removal of extracellular Ca2+ or the application of an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The glutamate-induced increase in PLC-delta immunoreactivity was also prevented by N omega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor. These results suggest that NO formation secondary to Ca2+ influx by NMDA receptor activation leads to similar modifications of PLC-delta to those seen in AD.
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PMID:Glutamate-induced antigenic changes of phospholipase C-delta in cultured cortical neurons. 756 35

The endogenous polyamines spermidine and spermine enhanced guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S)-stimulated phosphoinositide turnover with EC50 values of 100 +/- 30 and 50 +/- 15 microM, respectively, whereas the synthetic polyamines N,N'-bis(3-aminopropyl)-1,3-propanediamine and -ethylenediamine inhibited GTP-gamma-S-stimulated phosphoinositide turnover, with maximal inhibition at 1 mM. Kinetic analysis of GTP-gamma-S-stimulated phosphoinositide turnover in the absence and presence of spermidine showed that the Km for GTP-gamma-S was not changed (1,303 +/- 270 and 1,069 +/- 214 nM, respectively), whereas the Vmax was increased by 206% (1,566 +/- 141 and 4,792 +/- 84 cpm, respectively), indicating that spermidine and GTP-gamma-S acted at different sites. Spermidine also enhanced Ca(2+)-stimulated phosphoinositide turnover in the absence of GTP-gamma-S by decreasing the Ca2+ requirement of the phosphoinositide-specific phospholipase C. Arcaine and agmatine, polyamine antagonists at the NMDA receptor complex, did not block the effects of spermidine on GTP-gamma-S- and Ca(2+)-induced phosphoinositide turnover, suggesting that the spermidine effects are not mediated through these specific polyamine sites. Furthermore, spermidine increased the level of [3H]phosphatidylinositol 4-phosphate (EC50 = 120 +/- 10 microM), without affecting significantly the levels of [3H]-phosphatidylinositol and [3H]phosphatidylinositol 4,5-bis-phosphate. Collectively these data indicate that the enhanced phosphoinositide turnover induced by spermidine in the presence of GTP-gamma-S or Ca2+ is mediated through multiple levels of the phosphoinositide turnover cascade.
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PMID:Regulation of the phosphoinositide cascade by polyamines in brain. 793 Dec 84

Beginning at therapeutic concentrations (1-1.5 mM), the anti-manic-depressive drug lithium stimulated the release of glutamate, a major excitatory neurotransmitter in the brain, in monkey cerebral cortex slices in a time- and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] accumulation. (+/-)-3-(2-Carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP), dizocilpine (MK-801), ketamine, and Mg(2+)-antagonists to the N-methyl-D-aspartate (NMDA) receptor/channel complex selectively inhibited lithium-stimulated Ins(1,4,5)P3 accumulation. Antagonists to cholinergic-muscarinic, alpha 1-adrenergic, 5-hydroxytryptamine2 (serotoninergic), and H1 histaminergic receptors had no effect. Antagonists to non-NMDA glutamate receptors had no effect on lithium-stimulated Ins(1,4,5)P3 accumulation. Possible reasons for this are discussed. Similar results were obtained in mouse cerebral cortex slices. Carbetapentane, which inhibits glutamate release, inhibited lithium-induced Ins(1,4,5)P3 accumulation in this model. It is concluded that the primary effect of lithium in the cerebral cortex slice model is stimulation of glutamate release, which, presumably via activation of the NMDA receptor, leads to Ca2+ entry. Ins(1,4,5)P3 accumulation increases due to the presumed increased influx of intracellular Ca2+, which activates phospholipase C. These effects may have relevance to the therapeutic action of lithium in the treatment of manic depression as well as its toxic effects, especially at lithium blood levels above 1.5 mM.
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PMID:Lithium stimulates glutamate "release" and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices. 807 88

It is known that the activation of N-methyl-D-aspartate (NMDA) receptors leads to an increase in extracellular taurine concentration in different brain regions. The mechanism that mediates this effect is not totally understood. In this study, rat hippocampal slices were used to determine the dependence of NMDA-induced taurine release on extracellular calcium and/or on calcium mobilization from intracellular stores. NMDA was administered through a microdialysis probe inserted into the slice, at the level of CA1 stratum radiatum, which was also used to collect amino acids from the extracellular space. Field potentials evoked by stimulation of the Schaffer collaterals and recorded in the stratum pyramidale of CA1 were used as a control of NMDA receptor activation. NMDA induced a marked increase in extracellular taurine levels and a decrease in field potential amplitude, and both effects were suppressed in the presence of MK-801, a blocker of the NMDA receptor-linked channel. Dantrolene, an inhibitor of calcium release from intracellular stores, partially inhibited the extracellular taurine increase, while 2-nitro-4-carboxyphenyl-N,N-diphenyl carbamate (NCDC), an inhibitor of phosphatidylinositol-specific phospholipase C activation, had no effect. Removal of extracellular calcium diminished, but did not abolish, the extracellular taurine increase caused by NMDA. The remaining taurine response was totally suppressed by dantrolene, and also by NCDC. These results demonstrate that the release of taurine induced by NMDA receptor activation is triggered by the increase in cytoplasmic calcium concentration. We suggest that, under physiological conditions, calcium influx provides the signal for NMDA-induced taurine release, which is amplified by calcium-dependent calcium mobilization from intracellular stores.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Taurine release evoked by NMDA receptor activation is largely dependent on calcium mobilization from intracellular stores. 827 29


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