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)

We have isolated a full-length cDNA for human carbonic anhydrase IV (CA IV) from a lambda gt10 human kidney cDNA library. The 1105-base-pair (bp) cDNA contains a 47-bp 5' untranslated region, a 936-bp open reading frame, and a 122-bp 3' untranslated region. The deduced amino acid sequence is colinear with the N-terminal sequence and the sequence of several tryptic peptides of human lung CA IV. It includes an 18-amino acid signal sequence, a 260-amino acid region that shows 30-36% similarity with the 29-kDa cytoplasmic CAs (CA I, CA II, and CA III), and an additional 27-amino acid C-terminal sequence that ends in a 21-amino acid hydrophobic domain. Of the 17 "active site" residues that are highly conserved in other human CAs, 16 are also present in CA IV. Expression of the cDNA in COS cells produced a 35-kDa enzyme that was membrane associated, resistant to inactivation by SDS, contained no carbohydrate, and reacted on Western blots with antiserum to the 35-kDa CA IV from human lung. Treatment of membranes from transfected COS cells with phosphatidylinositol-specific phospholipase C released 20-30% of the expressed enzyme from membranes, indicating that at least 20-30% of the expressed enzyme was anchored to membranes by a glycosyl-phosphatidylinositol linkage.
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PMID:Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes. 131 Oct 94

A new class of G-proteins, the Gq family, has been recently identified and found to be involved in phospholipase C activation. The alpha subunits of the Gq and G11 members of this family are separate polypeptides but appear to have the same function. In this study, the cellular distribution in the adult rat brain of these G-proteins, Gq alpha/G11 alpha, was determined by immunohistochemistry using an antipeptide antiserum directed against the predicted C-terminal decapeptide which is conserved between these polypeptides. The specificity of the antiserum was verified by Western blot analysis using rat brain homogenates. Immunoreactivity was detected in neurons, where it was localized in the dendrites and at the periphery of the cell bodies. The staining was abundant in the dendrites of cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. Staining was also found in neurons in the olfactory bulb, minor and major islets of Calleja, anterior olfactory nuclei and piriform cortex; the different cortical areas especially in their superficial layers; caudate-putamen, accumbens and olfactory tubercle; lateral septum and amygdala; hippocampal CA2-4 sectors of Ammon's horn, dentate gyrus and hilus; hypothalamic supraoptic nucleus; cerebellar granular layer; colliculi and superficial layers of the dorsal horn of the spinal cord. In conclusion, the brain neuronal localizations of Gq alpha/G11 alpha match that of phospholipase C, 1,4,5-triphosphate receptor and, to a lesser extent 1,4,5-triphosphate-3-kinase.
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PMID:Immunohistochemical distribution of neurons containing the G-proteins Gq alpha/G11 alpha in the adult rat brain. 146 95

Bath application of the inhibitors of phospholipases, nordihydroguaiaretic acid (NDGA) and p-bromo-phenacyl bromide (BPB), to the rat hippocampal slices suppressed long-term potentiation (LTP) in Schaffer/commissural-CA1 pyramidal synapses. On the other hand, neither of the two inhibitors suppressed LTP in mossy fiber-CA3 pyramidal cell synapses. BPB did not suppress phosphatidylinositol-specific phospholipase C (PI-PLC) activity of the slices. These results suggested that the mechanisms of LTP were quite different in the CA1 and CA3 subfields of rat hippocampus: in CA1, the involvement of an arachidonate metabolism was strongly suggested, whereas in CA3, an arachidonic acid cascade may not be necessary for LTP.
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PMID:Differential effects of phospholipase inhibitors in long-term potentiation in the rat hippocampal mossy fiber synapses and Schaffer/commissural synapses. 276 61

Patch clamp in the whole cell configuration was used to examine the effects of a variety of agents that influence arachidonic acid metabolism on vesicular glutamate release in CA1 neurons of rat hippocampal slices. As previously demonstrated, anoxia induced a significant increase in the frequency of spontaneous glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) during the first 5 min following anoxia. This increase in frequency was almost completely abolished if slices were preincubated in artificial cerebral spinal fluid (ACSF) containing the phospholipase C/A2 inhibitor, bromophenacyl-bromide (BPB; 20 microM) or the cyclooxygenase inhibitors, indomethacin (20 microM) and piroxicam (10 microM). This observation may be important to our understanding of the neuroprotective action of these agents. These data suggest that arachidonic acid (AA) and its cyclooxygenase products or by-products (oxygen free radicals) contribute to vesicular glutamate release during the early phase of anoxia.
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PMID:Arachidonic acid participates in the anoxia-induced increase in mEPSC frequency in CA1 neurons of the rat hippocampus. 802 79

Carbonic anhydrase (CA) was purified from the gills of the shore crab Carcinus maenas using affinity chromatography and HPLC. The predominantly membrane-bound CA was found to share several features with mammalian CA IV. Its apparent molecular weight of 36 kDa was reduced to 33 kDa by treatment with PNGase F, suggesting that crab CA is a glycoprotein with one N-linked oligosaccharide chain. More than half of the membrane-bound crab CA was released from membranes by treatment with a phosphatidylinositol-specific phospholipase C, indicating that the branchial CA is anchored to membrane surfaces by a phosphatidylinositol-glycan linkage. The enzyme also resembles mammalian CA IV in its relative sensitivity to inhibition by sulfonamides and the resistance to inhibition by halide ions. Amino acid composition of the HPLC-purified crab CA was examined and CNBr cleavage was carried out followed by N-terminal amino acid sequencing. Amino-terminal sequence of the native enzyme differed considerably from those of mammalian isozymes (human CA I and CA II, bovine CA III, human and rat CA IV). However, antisera raised against rat CA IV, CA II, and CA I all cross-reacted weakly with crab CA. Unlike mammalian CA IVs, crab gill CA was sensitive to 0.2% sodium dodecyl sulfate, suggesting that although crab gill CA is like mammalian CA IVs in many ways, it is less stabilized by intramolecular disulfide bonds.
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PMID:Membrane-associated carbonic anhydrase from the crab gill: purification, characterization, and comparison with mammalian CAs. 803 56

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

Hippocampal slices were transiently exposed to an oxygen- and glucose-free environment which causes a pronounced drop of both ATP and creatine phosphate, an anoxic depolarization, and an incomplete recovery of synaptically evoked population spike in the CA1 region after 1 h (48.5 +/- 3.6% of baseline values). This recovery could be markedly enhanced by the application of N-methyl-D-aspartate receptor antagonists. To examine the influence of metabotropic glutamate receptors on neuronal recovery from hypoxia/hypoglycemia, we applied various antagonists and agonists of the metabotropic glutamate receptors to the bath during the interval from 20 min before to 10 after hypoxia/hypoglycemia. The metabotropic glutamate receptor antagonists (+)-alpha-methyl-4-carboxyphenylglycine and L-2-3- amino-phosphonopropionic acid were both able to enhance the population spike recovery significantly. However, the mixed metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid also exhibited a protective effect on population spike recovery, leaving the anoxic depolarization and N-methyl-D-aspartate responses during the hypoxia/hypoglycemia untouched. With the help of more subtype-specific agonists, we found that an activation of phospholipase C coupled (class 1) metabotropic glutamate receptors prior to hypoxia/hypoglycemia may be responsible for the protective effect seen with 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid, because the specific class 1 metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid appeared to be highly protective, but only if it was applied 20 min before the hypoxia/hypoglycemia. An activation of class 2 metabotropic glutamate receptors by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, which inhibits adenylyl cyclase activity, led to a marked deterioration of the population spike recovery and even to a total prevention of the protective effect of the N-methyl-D-aspartate agonist D-2-amino-5-phosphonopentanoic acid. Our data suggest that prior activation of class 1 metabotropic glutamate receptors is beneficial, while their activation during hypoxia/hypoglycemia is detrimental. Furthermore, the activation of class 2 metabotropic glutamate receptors decreases the recovery from hypoxia/hypoglycemia.
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PMID:Metabotropic glutamate receptor subtypes differentially influence neuronal recovery from in vitro hypoxia/hypoglycemia in rat hippocampal slices. 854 5

Platelet-derived growth factor (PDGF) is a multifunctional protein that plays important roles in many tissues, including the mammalian central nervous system. PDGF and PDGF receptors (PDGFRs) are expressed in virtually every region of the central nervous system where they are involved in the development, survival, growth, and differentiation of both neuronal and glial cells. We now report that a brief activation of PDGFRs produced a long-lasting inhibition of N-methyl-D-aspartate (NMDA)-dependent excitatory postsynaptic currents in CA1 pyramidal neurons in rat hippocampal slices. PDGF also inhibited NMDA receptors (NMDA-Rs) in cultured hippocampal neurons by a mechanism that involves a decrease in single channel open probability. Non-NMDA receptor function was not affected by PDGF in hippocampal neurons. Experiments with mutant PDGFRs and chelation of intracellular Ca2+ in Xenopus oocytes indicate that this inhibition depends on a phospholipase C-gamma-induced elevation of intracellular Ca2+ levels. The PDGF-induced inhibition of NMDA-Rs is produced by a mechanism different than the well characterized phenomenon of Ca2+-dependent NMDA-R run down because the effect of PDGF was blocked by the phosphatase inhibitor, calyculin A, and was not affected by the microtubule polymerizing agent, phalloidin. Because elevations of PDGF levels are associated with neurological trauma or disease, we propose that PDGF can exert neuroprotective effects by inhibiting NMDA-R-dependent excitotoxicity.
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PMID:Platelet-derived growth factor induces a long-term inhibition of N-methyl-D-aspartate receptor function. 866 18

In the CA1 region of hippocampal slices prepared from young adult rats, we studied the ability of several specific agonists of metabotropic glutamate receptors (mGluRs) to depress excitatory synaptic transmission at the CA3-CA1 pyramidal cell synapses. Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase. We found that the broad-spectrum agonist (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate and the group 1-specific agonist (R,S)-dihydroxyphenylglycine both reversibly inhibited evoked field excitatory postsynaptic potentials, indicating the involvement of group 1 mGluRs. (R,S)-3,5-dihydroxyphenylglycine presumably inhibited transmission via a presynaptic mechanism, as whole-cell voltage-clamp recordings revealed that inhibition of the synaptic transmission was always accompanied with an increase in paired-pulse facilitation. Treatment with a specific blocker of mGluR1 receptors, the phenylglycine derivative (S)-4-carboxyphenylglycine, was without effect on the (1S,3R)-1-amino-cyclopentyl-1,3-dicarboxylate-induced depression of the field excitatory postsynaptic potentials, strongly suggesting that mGluR5 receptors are responsible for the (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate effect. Two selective agonists of group 2 mGluRs, (2S,1's,2's)-2-(2'-carboxycyclopropyl)glycine and 4-carboxy-3-hydroxyphenylglycine, were totally ineffective in blocking CA3-CA1-evoked synaptic transmission, excluding the involvement of mGluR2/3 subtypes at this developmental stage.
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PMID:Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus. 884 58

Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFRs) are ubiquitously expressed in the mammalian central nervous system, where they exert trophic actions on both neuronal and glial cells. However, the acute actions of PDGF on synaptic transmission are unknown. We report a novel regulatory action of PDGF/PDGFR. Activation of PDGFRs inhibited the function of native type A gamma-aminobutyric acid (GABAA) receptors (GABAA-RS) in rat hippocampal CA1 pyramidal neurons and mouse brain membrane vesicles. The mechanism of this inhibition was studied with a panel of mutant PDGFRS-beta coexpressed with cloned human GABAA-Rs in Xenopus oocytes. These experiments revealed that phospholipase C-gamma is the protein that relays the inhibitory signal from PDGFRS to GABAA-Rs. Experiments with microinjected EGTA and inositol-1, 3, 4-triphosphate demonstrated that inhibition of GABAA-Rs depended on a phospholipase C-gamma-mediated increase in intracellular Ca(2+)-levels. The PDGFR-induced inhibitory effect was independent of the subunit composition of GABAA-RS. Moreover, GABAA-RS composed of alpha 1 beta 1 S409A subunits, which do not contain any known protein kinase C phosphorylation sites, were inhibited by PDGF to the same extent as wild-type GABAA-RS. Inhibitors of protein kinase C, CA2+/calmodulin-dependent protein kinase II, calcineurin, and tyrosine phosphatases did not affect the modulatory actions of PDGFR. In conclusion, our results suggest that PDGFRs exert potent modulatory actions on GABAA-R-dependent inhibitory synaptic transmission. These regulatory actions of PDGF could play important roles in the function of the mammalian central nervous system during physiological and pathophysiological conditions.
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PMID:Platelet-derived growth factor receptor is a novel modulator of type A gamma-aminobutyric acid-gated ion channels. 884 10


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