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 effect of quisqualate, an excitatory amino acid agonist, on the breakdown of exogenously added phosphatidylinositol was investigated in a membrane preparation from the cerebellum of young rats. Quisqualate stimulated phospholipase C activity in a dose-dependent manner in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). Half-maximal activation of the quisqualate response required 0.15 microM GTP gamma S and was optimal at a free Ca2+ concentration of 300 nM. Phosphoinositide breakdown was also stimulated by quisqualate using either exogenous phosphatidylinositides 4,5-bisphosphate or endogenous labeled phosphoinositides as the substrate for phospholipase C in cerebellar membranes. In the presence of guanine nucleotides, other excitatory amino acid agonists, such as L-glutamate, trans-D,L-1-aminocyclopentyl-1,3-dicarboxylic acid, and ibotenate, but not N-methyl-D-aspartate, stimulated phosphatidylinositol breakdown. However, quisqualate displayed the highest response among these excitatory amino acid agonists. These data indicate that there is a direct activation of phosphoinositide-specific phospholipase C by excitatory amino acids through a process dependent on the presence of guanine nucleotides.
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PMID:Quisqualate-stimulated phosphatidylinositol breakdown in rat cerebellar membranes. 130 70

A vasodepressor phospholipid fraction purified from a lipid extract of bovine brain was found to contain novel phospholipids with both a long-chain acyl group and an aliphatic dicarboxylic acid residue. This was shown by analyzing the fraction as tert-butyldimethylsilyl derivatives of glyceride by capillary GC-MS after hydrolysis with phospholipase C. Six molecular species with a palmitoyl group and an aliphatic dicarboxylate (chain length C4-C9), and two species with both a stearoyl group and a succinate or glutarate residue were detected.
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PMID:Novel phospholipids with aliphatic dicarboxylic acid residues in a lipid extract from bovine brain. 342 72

We have reported previously that a selective metabotropic glutamate receptor agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), caused two primary postsynaptic membrane changes, namely, a slow membrane depolarization, and burst firing in rat dorsolateral septal nucleus neurons. In addition, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid also potentiates a slow after depolarization in rat dorsolateral septal nucleus neurons. We now report that, among all the postsynaptic membrane changes induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, only the burst firing was selectively blocked by pertussis toxin pretreatment. Thus, aminocyclopentane-1,3-dicarboxylic acid induced burst firing was mediated by a metabotropic receptor coupled to a pertussis toxin-sensitive GTP-binding protein, while the other induced cellular responses may be mediated by metabotropic glutamate receptors insensitive to pertussis toxin. We further characterized this receptor pharmacologically. This metabotropic receptor is activated by several metabotropic glutamate receptor agonists, but is insensitive to L-glutamate or L-aspartate. On the basis of its agonist activity profile, particularly the ineffectiveness of glutamate as an agonist, we have tentatively assigned the name aminocyclopentane-1,3-dicarboxylic acid metabotropic receptor, to this native, pertussis toxin-sensitive metabotropic receptor in the dorsolateral septal nucleus. Furthermore, this receptor is coupled to protein kinase C, probably via a phospholipase C independent pathway.
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PMID:(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced burst firing is mediated by a native pertussis toxin-sensitive metabotropic receptor at rat dorsolateral septal nucleus neurons. 747 53

The effect of ionotropic excitatory amino acids and potassium on the formation of inositol phosphates elicited by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) was studied in mouse cerebellar granule cells. In Mg(2+)-containing buffers, NMDA (50-100 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 10-1,000 microM), and high potassium (10-30 mM) enhanced synergistically the response to a maximally effective concentration of 500 microM trans-ACPD. Potentiation of the trans-ACPD response was blocked by higher concentrations of NMDA (> 500 microM) and potassium (> 35 mM) but not by AMPA (up to 1 mM). The potentiation by NMDA of the trans-ACPD-stimulated phosphoinositide hydrolysis was blocked by D,L-2-amino-5-phosphonopentanoic acid (APV), a competitive NMDA-receptor antagonist. Under Mg(2+)-free conditions, the accumulation of inositol phosphates in the presence of trans-ACPD alone was equal to that attained by trans-ACPD in Mg(2+)-containing buffers when costimulated with maximally enhancing concentrations of NMDA (50 microM). trans-ACPD potentiated synergistically the NMDA-evoked increases in cytosolic free-Ca2+ levels in Mg(2+)-containing but not in Mg(2+)-free solutions, and moreover did not enhance the AMPA-evoked increases in cytosolic free-Ca2+ levels. The calcium ionophore A23187 caused a dose-dependent increase in inositol phosphate accumulation but did not enhance the response stimulated by trans-ACPD alone. These results demonstrate the existence of cross talk between metabotropic and ionotropic glutamate receptors in cerebellar granule cells. The exact mechanism remains unclear but appears to involve interplay of G protein-coupled phospholipase C activation and regulated elevation of cytosolic free-Ca2+ levels. This study may provide a framework for future investigations at the cellular and molecular level that clarify the functional relevance and molecular mechanisms that are described.
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PMID:Modulation by ionotropic excitatory amino acids and potassium of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid-stimulated phosphoinositide hydrolysis in mouse cerebellar granule cells. 759 41

Different neurotransmitter receptor agonists [carbachol, serotonin, noradrenaline, histamine, endothelin-1, and trans-(1S,3R)-aminocyclopentyl-1,3-dicarboxylic acid (trans-ACPD)], known as stimuli of phospholipase C in brain tissue, were tested for phospholipase D stimulation in [32P]Pi-prelabeled rat brain cortical and hippocampal slices. The accumulation of [32P]phosphatidylethanol was measured as an index of phospholipase D-catalyzed transphosphatidylation in the presence of ethanol. Among the six neurotransmitter receptor agonists tested, only noradrenaline, histamine, endothelin-1, and trans-ACPD stimulated phospholipase D in hippocampus and cortex, an effect that was strictly dependent of the presence of millimolar extracellular calcium concentrations. The effect of histamine (EC50 18 microM) was inhibited by the H1 receptor antagonist mepyramine with a Ki constant of 0.7 nM and was resistant to H2 and H3 receptor antagonists (ranitidine and tioperamide, respectively). Endothelin-1-stimulated phospholipase D (EC50 44 nM) was not blocked by BQ-123, a specific antagonist of the ETA receptor. Endothelin-3 and the specific ETB receptor agonist safarotoxin 6c were also able to stimulate phospholipase D with efficacies similar to that of endothelin-1, and EC50 values of 16 and 3 nM, respectively. These results show that histamine and endothelin-1 stimulate phospholipase D in rat brain through H1 and ETB receptors, respectively.
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PMID:Histamine H1 and endothelin ETB receptors mediate phospholipase D stimulation in rat brain hippocampal slices. 761 43

In the fluid percussion model of traumatic brain injury (TBI), we examined muscarinic and metabotropic glutamate receptor-stimulated polyphosphoinositide (PPI) turnover in rat hippocampus. Moderate injury was obtained by displacement and deformation of the brain within the closed cranial cavity using a fluid percussion device. Carbachol and (+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD)-stimulated PPI hydrolysis was assayed in hippocampus from injured and sham-injured controls at both 1 hour and 15 days following injury. At 1 hour after TBI, the response to carbachol was enhanced in injured rats by up to 200% but the response to trans-ACPD was diminished by as much as 28%. By contrast, at 15 days after TBI, the response to carbachol was enhanced by 25% and the response to trans-ACPD was enhanced by 73%. The ionotropic glutamate agonists N-methyl-D-aspartate (NMDA), and alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionate (AMPA), did not increase PPI hydrolysis in either sham or injured rats and injury did not alter basal hydrolysis. Thus, hippocampal muscarinic and metabotropic receptors linked to phospholipase C are differentially altered by TBI.
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PMID:Differential modulation of carbachol and trans-ACPD-stimulated phosphoinositide turnover following traumatic brain injury. 765 77

The possible roles of G-protein coupled metabotropic glutamate receptors in central nervous function are currently the focus of intensive investigation. The complexity of effects produced by agonists at these receptors probably reflects the activity of a range of sub-types. The metabotropic glutamate receptors first described are linked to phospholipase C, mediating phosphoinositide hydrolysis and release of Ca2+ from intracellular stores. A substance generally considered to be a selective agonist for these receptors is (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). This substance not only stimulates phosphoinositide hydrolysis, but also inhibits cyclic AMP formation. A family of metabotropic glutamate receptors, incorporating both phospholipase C- and adenylcyclase-linked sub-types has been cloned. Various effects of metabotropic glutamate receptor agonists on membrane ion fluxes and synaptic events have been reported, including neuronal depolarization and/or excitation, hyperpolarization, inhibition of Ca(2+)-dependent and voltage-gated K+ currents, potentiation of N-methyl-D-aspartate-induced responses, depression of synaptic excitation and either induction or augmentation of long-term potentiation. To clarify the role of metabotropic glutamate receptors in central nervous activity and to aid the characterization of the various receptor types that may be involved, a range of highly selective agonists and antagonists is required. To date, currently available antagonists such as L-2-amino-3-phosphonopropionate and L-aspartic acid-beta-hydroxamate appear to be unselective and insufficiently potent. We report here the actions of three phenylglycine derivatives, the particular agonist and/or antagonist properties of which may help to elucidate the roles of metabotropic glutamate receptors in central nervous activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system. 768 Jul 90

The contribution of ionotropic and metabotropic glutamate receptors to inositol polyphosphate accumulation in carp retinal slices was investigated using myo-[2-3H]inositol prelabelling. In the presence of the glutamate agonists quisqualate, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and trans-(+/-)-1-amino-1,3-cyclopentane-dicarboxylic acid (t-ACPD), formation of [3H]inositol phosphate was significantly increased in a dose-dependent manner, with EC50 values of 350 nM, 1.5 microM and 10 microM respectively. The complete AMPA-induced response and a large component of the quisqualate-induced response were inhibited in a competitive manner when the ionotropic antagonist 6-cyano-7-nitroquinoxalin- 2,3-dione (CNQX) was present. Furthermore, the remaining level of quisqualate-induced [3H]inositol phosphate formation closely matched that produced by ACPD alone, and coincubation of AMPA and ACPD showed additive effects, suggesting that the quisqualate-induced response resulted from coactivation of metabotropic and ionotropic glutamate receptors. The ionotropic component was partially reduced in the presence of cobalt, suggesting indirect effects resulting from synaptic interactions. We could exclude indirect effects through depolarization-induced release of other neurotransmitters. Only serotonin (EC50 1 microM) and carbachol (at a concentration of 1 mM) stimulated [3H]inositol phosphate formation, but their antagonists did not affect the quisqualate response and coactivation with quisqualate and serotonin or carbachol resulted in additive effects. The ionotropic component was completely suppressed when Ca2+ was omitted from the medium and cobalt was present. This makes it likely that the ionotropic component resulted from Ca2+ entry through AMPA-gated channels and subsequent Ca(2+)-dependent activation of phospholipase C.
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PMID:Involvement of metabotropic and ionotropic glutamate receptors in inositol polyphosphate formation in carp retinal slices. 770 99

Phosphoinositide breakdown, as stimulated by six different neurotransmitter receptor agonists (carbachol, serotonin, norepinephrine, trans-(+/-)-aminocyclopentyl-1,3-dicarboxylic acid, endothelin-1 and histamine), has been studied in rat brain cortical slices. The accumulation was monitored of total 3H-inositol phosphates (InsPs) and [3H]CDP-diacylglycerol (CDP-DAG) in [3H]inositol or [3H]cytidine-prelabeled tissue, respectively, and the profile of the major InsPs was quantified as the index log [(inositol 4-monophosphate + inositol 1,4-bisphosphate)/inositol 1-monophosphate]. The efficacy of the six agonists to stimulate the accumulation of CDP-DAG, relative to that of InsPs, was not constant, which revealed varying degrees of defective recycling of DAG to CDP-DAG. The value of the index for the profile of InsPs was not constant either but was characteristic of each agonist. Both parameters (ratio of efficacies CDP-DAG/InsPs and InsPs profile) were not independent and defined two groups of agonists as follows: group a, carbachol and serotonin, with balanced CDP-DAG and InsPs responses, and Ins1P prevailing against inositol 4-monophosphate + inositol 1,4-bisphosphate and group b, norepinephrine, trans-(+/-)-aminocyclopentyl-1,3-dicarboxylic acid, endothelin-1 and histamine, with weak CDP-DAG responses and high accumulation of inositol 4-monophosphate + inositol 1,4-bisphosphate compared with that of inositol 1-monophosphate. In a membrane preparation from brain cortex, only agonists in group a stimulated phospholipase C in the presence of guanosine 5'-O-(3-thiotriphosphate) and in a receptor antagonist-sensitive fashion, which indicated that brain cortical alpha-1, H1, endothelin and glutamate metabotropic receptors stimulate phospholipase C indirectly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurotransmitter-specific profiles of inositol phosphates in rat brain cortex: relation to the mode of receptor activation of phosphoinositide phospholipase C. 781 67

The effects of acute and chronic ethanol exposures on the stimulation of inositol specific phospholipase C by metabotropic glutamate receptor activation were determined in primary cultures of rat cortical astrocytes. Phospholipase C activity was monitored by the formation of [3H]inositol phosphates in the presence of lithium in cells prelabelled with [3H]inositol. Acute exposure to 200 mM ethanol had no significant effect on either basal or L-glutamate stimulated [3H]inositol phosphate formation. In cells chronically exposed to ethanol for 4 days, the [3H]inositol phosphate responses to L-glutamate, quisqualate, and the selective metabotropic receptor agonist, 1S,3R-1-amino-cyclopentane-1,3 dicarboxylic acid (trans-ACPD), were significantly inhibited when compared to control (untreated) cells. In contrast, chronic ethanol exposure had no significant effect on the [3H]inositol phosphate response to endothelin-1, a peptide structurally and functionally unrelated to L-glutamate. Similarly, the stimulation of [3H]inositol phosphate formation by the stable GTP analog, guanine 5'-(gamma-thiotrisphosphate), was also unaffected by chronic ethanol exposure. The results suggest that chronic ethanol exposure does not affect the coupling of GTP binding proteins to phospholipase C, but rather acts in a selective manner to either alter the metabotropic receptor number or to disrupt the normal coupling of this receptor to its GTP binding protein, which may in turn affect receptor affinity.
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PMID:Selective effects of ethanol exposure on metabotropic glutamate receptor and guanine nucleotide stimulated phospholipase C activity in primary cultures of astrocytes. 781 99


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