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)

This paper provides evidence that central sensitization and persistent nociception following formalin-induced tissue injury in rats is dependent on the production of protein kinase C. Persistent nociceptive behavior in rats induced by subcutaneous formalin injection was significantly reduced by intrathecal pretreatment with a phospholipase C inhibitor (neomycin), and an inhibitor of protein kinase C (W-7), and was significantly enhanced by a phorbol ester (phorbol 12-myristate 13-acetate, PMA) and a stimulator of protein kinase C (SC-10). It is expected that noxious inputs associated with tissue injury produce a release of aspartate and glutamate within the spinal dorsal horn which by acting at ionotropic (NMDA) and metabotropic excitatory amino acid receptors produce an increase in intracellular messengers such as calcium and diacylglycerol which stimulate protein kinase C.
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PMID:Contribution of protein kinase C to central sensitization and persistent pain following tissue injury. 150 74

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

It is well known that levels of free fatty acids (FFA) in the brain rapidly increase during ischemia. FFA release during ischemia is generally due to the disturbance of reacylation by ATP depletion and deacylation from membrane phospholipids by the action of phospholipase. The present study examined the regional difference in brain FFA levels and also the action of phospholipase from the effect of NMDA antagonist (MK-801) and phospholipase C inhibitor (PMSF) on FFA release during complete ischemia in rat brain. Complete brain ischemia was induced with cardiac arrest by intracardiac injection of KCI. A focused microwave was irradiated to the head of rats 0, 2, 4 and 8 minutes after cardiac arrest. Samples of the neocortex, striatum, hippocampus and thalamus were dissected. FFA were measured in each sample. In the vulnerable regions such as neocortex, hippocampus and striatum, arachidonic acid and other FFA levels rapidly increased from the onset of ischemia. All FFA levels in the thalamus were significantly lower than those in the other regions during ischemia. The regional difference of FFA levels during ischemia seemed to be responsible for the regional difference of the vulnerability to ischemia. MK-801 inhibited the FFA release mainly from phosphatidylcholine and phosphatidylethanolamine between 2 and 4 minutes of ischemia. On the other hand, PMSF inhibited the FFA release mainly from phosphatidylinositol during the first 2 minutes of ischemia and from phosphatidylcholine and phosphatidylethanolamine until 8 minutes of ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Regional difference in free fatty acids release and the action of phospholipase during ischemia in rat brain]. 228 77

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

1. The effect of NMDA-receptor stimulation on phosphoinositide signalling in response to the metabotropic glutamate receptor agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) has been examined in neonatal rat cerebral cortex slices. 2. Total [3H]-inositol phosphate ([3H]-InsPx) accumulation, in the presence of 5 mM LiCl, in [3H]-inositol pre-labelled slices was concentration-dependently increased by 1S,3R-ACPD (EC50 16.6 microM) and, at a maximally effective concentration, 1S,3R-ACPD (300 microM) increased [3H]-InsPx accumulation by 12.8 fold over basal values. 3. [3H]-InsPx accumulation stimulated by 1S,1R-ACPD was enhanced by low concentrations of NMDA (3-30 microM), but not by higher concentrations (> 30 microM). [3H]-InsPx accumulations stimulated by 1S,3R-ACPD in the absence or presence of 10 microM NMDA were linear with time, at least over the 15 min period examined; however, in the presence of 100 microM NMDA the initial enhancement of 1S,3R-ACPD-stimulated phosphoinositide hydrolysis progressively decreased with time. 4. In the presence of a maximal enhancing concentration of NMDA (10 microM), the response to 1S,3R-ACPD (300 microM) was increased 1.9 fold and the EC50 for agonist-stimulated [3H]-InsPx accumulation decreased about 4 fold. The enhanced response to the metabotropic agonist was concentration-dependently inhibited by competitive and uncompetitive antagonists of NMDA-receptor activation. 5. 1S,3R-ACPD also stimulated inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) mass accumulation with an initial peak response (5-6 fold over basal) at 15 s decaying to a smaller (2 fold), but persistent elevated accumulation (1-10 min). 6. Co-addition of 10 or 100 MicroM NMDA enhanced the initial peak Ins(1,4,5)P3 response to 1S,3RACPD.However, the enhancing effect was only maintained over 10 min in the presence of 1O Micro MNMDA, whilst in contrast, 100 MicroM NMDA ceased to cause a significant enhancement of the metabotropic response by 5 min and completely suppressed lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation at 10 min.7. Both basal and 1S,3R-ACPD-stimulated Ins(1,4,5)P3 accumulations were reduced when slices were incubated in nominally Ca2"-free medium. Under these conditions only a concentration-dependent enhancement of the response was observed (EC50 for NMDA facilitation of lS,3R-ACPD-stimulated Ins(1,4,5)P3 accumulation of 32 MicroM).8. These experiments have revealed that at low concentrations, NMDA can dramatically potentiate1S,3R-ACPD-stimulated phosphoinositide hydrolysis, probably by a Ca2"-dependent facilitation of agonist-stimulated phosphoinositide-specific phospholipase C activity. Higher concentrations of NMDA result in time-dependent inhibition of the metabotropic agonist-stimulated response. We believe the former effect could be fundamental in glutamate receptor 'cross-talk', whereas the latter may reflect a Ca2+-dependent neurotoxic effect of NMDA on the neonatal cerebral cortex slices.
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PMID:Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R-ACPD in neonatal rat cerebral cortex. 791 80

The effects of L-glutamate, acetylcholine, and serotonin (5HT) were examined on generation of inositol 1,4,5-triphosphate [Ins(1,4,5)P3], in membrane preparations of the cestode Hymenolepis diminuta. Only L-glutamate and acetylcholine stimulated a significant elevation in Ins(1,4,5)P3. The response to L-glutamate was stereospecific; D-glutamate or L-aspartate were not as potent. A role for G-protein(s) was supported by the observations that sodium fluoride stimulated Ins(1,4,5)P3 generation, and the L-glutamate response was potentiated by GTP and GTP-S and was suppressed by GDPS. However, studies with pertussis and cholera toxins indicated that the putative G-protein(s) was not pertussis or cholera toxin sensitive. The pharmacological profile of the L-glutamate response was examined partially. Trans-ACPD was a very effective agonist at 10(-5)M. While 10(-3)M L-glutamate, NMDA, and AMPA significantly elevated Ins(1,4,5)P3 levels, quisqualate and kainate did not. The elevation of Ins(1,4,5)P3 levels by L-glutamate and NMDA was antagonized by the specific glutamatergic antagonists AP-5, AP-7, CNQX, and CPP. While the response to ACPD was antagonized by AP5, CPP and CPG, CNQX was without effect. Collectively, the data support the hypothesis that in the cestode H. diminuta, L-glutamate activation of a metabotropic (ACPD) and/or ionotropic-like AMPA/NMDA receptor subtypes proceeds via a G protein(s) to enhance phospholipase C activity, ultimately resulting in the elevation of Ins(1,4,5)P3 levels in the tissues.
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PMID:The stimulatory effect of L-glutamate and related agents on inositol 1,4,5-trisphosphate production in the cestode Hymenolepis diminuta. 869 99

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78

The activation of the glutamatergic NMDA receptor has no effect on arachidonic acid release from cortical synaptoneurosomal lipids prelabeled with [1-14C]arachidonic acid ([14C]AA). However, activation of NMDA receptor leads to the reduction of AA incorporation into rat brain cortex synaptoneurosomal membrane phosphatidylinositol (PI). The competitive NMDA receptor antagonist, 2-amino-5-phosphovaleric acid (APV), completely eliminates the effect of NMDA on this process. More precise analysis of the sequence of events leading to NMDA-induced decrease of AA incorporation indicates that this process is significantly blocked by voltage-gated sodium and calcium channels inhibitors, such as tetrodotoxin (TTX) and omega-conotoxin (CTX), respectively. Then the antagonist of inositol trisphosphate receptor, TMB-8, totally abolishes the effect of NMDA on AA incorporation into PI. The lowering of AA incorporation evoked by NMDA is significantly diminished by nitric oxide (NO) synthase inhibitor, NG-nitro-L- arginine (NNLA). Further studies were carried out with NO donor(s) to explain the mechanism of NO action in the inhibition of AA incorporation into PI. Our results suggest the following sequence of events: opening of voltage-dependent sodium and calcium channels, subsequent activation of PI-4,5-bisphosphate-specific phospholipase C (PLC), elevation of inositol trisphosphate (IP3)-sensitive calcium ions, stimulation of NO production and NO-mediated S-nitrosylation, or free radical effect on enzymes involved in AA incorporation. Our data suggest that NO-mediated events may be responsible for NMDA-evoked inhibition of AA incorporation into PI of synaptoneurosomal membrane.
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PMID:Nitric oxide responsible for NMDA receptor-evoked inhibition of arachidonic acid incorporation into lipids of brain membrane. 888 42

There is general agreement that activation of the N-methyl-D-aspartate receptor is involved in thermal hyperalgesia. However, there is less agreement on the specific intracellular events subsequent to receptor activation and the involvement of other excitatory amino acid receptors in thermal hyperalgesia. In the present study, we found that the intrathecal administration of N-methyl-D-aspartate produced a dose- (1 fmol-1 pmol) and time-dependent thermal hyperalgesia. In contrast, over the dose range tested, intrathecal administration of either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA; 10 fmol-100 pmol), 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (10 fmol-100 pmol), quisqualate (10 pmol-5 nmol) or a 1:1 combination of AMPA and 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (total dose 20 fmol-200 pmol) did not produce any evidence of thermal hyperalgesia; greater doses produced a caudally-directed biting and scratching behavior that precluded testing in the paradigm used. A fixed dose of 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (100 pmol) did, however, potentiate the effects of N-methyl-D-aspartate (1-100 fmol). Thermal hyperalgesia produced by N-methyl-D-aspartate (1 pmol) was attenuated by intrathecal administration of the N-methyl-D-aspartate receptor-selective antagonist 2-amino-5-phosphonopentanoate (100 pmol), but not by the AMPA receptor-selective antagonist 6,7-dinitroquinoxaline-2,3-dione (1 nmol) or the metabotropic receptor antagonist 2-amino-3-phosphonoproprionate (10 nmol). In a second series of experiments, we examined the role of different signal transduction systems in acute N-methyl-D-aspartate-produced thermal hyperalgesia. N-Methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was attenuated by intrathecal hemoglobin (1-100 pmol) and dose-dependently by intrathecal N(G)-nitro-L-arginine methyl ester (10 pmol-l nmol), Methylene Blue (10 pmol-l nmol) and chelerythrine (1-100 pmol), suggesting that acute N-methyl-D-aspartate-mediated thermal hyperalgesia involves activation of nitric oxide synthase and protein kinase C. In contrast, N-methyl-D-aspartate-produced thermal hyperalgesia was unaffected by intrathecal administration of the phospholipase A2 inhibitor mepacrine (10 nmol) or the phospholipase C inhibitor neomycin (10 nmol). While prostaglandins and leukotrienes have been suggested to play a role in hyperalgesia, N-methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was unaffected by the non-selective eicosanoid inhibitor nordihydroguaiarate (1 nmol), the cyclo-oxygenase selective inhibitor indomethacin (10 nmol) or the lipoxygenase selective inhibitor baicalein (1 nmol). The results of the present study suggest that acute thermal hyperalgesia can be produced by activation of N-methyl-D-aspartate receptors. Activation of AMPA, metabotropic or co-activation of AMPA and metabotropic glutamate receptors, at the doses tested, did not produce an acute thermal hyperalgesia. The thermal hyperalgesia produced by N-methyl-D-aspartate is mediated by activation of nitric oxide synthase and protein kinase C, but not by phospholipase C, phospholipase A2, cyclo-oxygenase or lipoxygenase. Collectively, the results are consistent with a role for spinal N-methyl-D-aspartate receptors, nitric oxide and protein kinase C in thermal hyperalgesia.
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PMID:Acute thermal hyperalgesia in the rat is produced by activation of N-methyl-D-aspartate receptors and protein kinase C and production of nitric oxide. 905 88

The molecular identity and structure of imidazoline receptors is still poorly understood. For example the I1-imidazoline binding site (I1-site) is localised to the plasma membrane, but it is not clear if this represents a conventional receptor. The I1-site reportedly has both high and low affinity binding states. Again it is not clear if these sites represent different states of the same receptor, or distinct molecular entities. The signal transduction mechanisms of I1-imidazoline receptors are beginning to be unravelled. There is clear evidence that ligands with high affinity for I1-sites stimulate phosphatidylcholine-selective phospholipase C in the rat adrenal medullary tumour cell line PC-12, but this may not be the case in all cell types. We investigated the possible role of this novel pathway in bovine adrenal medullary cells. Radioligand binding studies with [3H]clonidine confirmed the presence of I1-sites in membranes from these cells. Using microphysiometry, a recently developed technique for determining cellular activation, the extracellular acidification rates of cultured bovine adrenal medullary cells were unaffected by a number of imidazolines considered to be agonists at the I1-site. This suggests that there is no I1-site mediated stimulation of phosphatidylcholine specific phospholipase C in these cells. However, nicotine-stimulated increases in extracellular acidification were blocked by 100 microM clonidine. Ion channels have been suggested as another possible I1-imidazoline 'receptor' family, and may represent the low affinity I1-site detected in binding studies. I1-Site ligands can be shown to bind to, or block, several members of the ligand-gated ion channel superfamily, including the 5HT3, K+ATP, NMDA and nicotinic acetylcholine receptors. The I1-site ligands appear to be binding to, and acting at, the previously described phencyclidine binding site in these channels. Furthermore, molecular modelling suggests that I1-site selective ligands share a common three-dimensional structure with phencyclidine, and that I2-site selective ligands do not have this structure. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-site ligands, and a search for receptors based on this motif may reveal novel imidazoline 'receptors'.
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PMID:Investigation of I1-imidazoline receptors using microphysiometry and molecular modelling. 985 62


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