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)

Several model systems have been used to test the hypothesis that the release of FFA in the brain is regulated by depolarization of neurons. This FFA release is likely the result of the activation of phospholipase A2. The increased neuronal activity that occurs due to synchronous depolarization during seizures causes activation of phospholipase A2. Decreasing neuronal activity by administering the anxiolytic, diazepam, appears to decrease the activity of phospholipase A2. The GABA antagonist, bicuculline, which causes depolarization by negating the hyperpolarizing tone imposed on neurons by GABA, causes FFA release in synaptosomes and in neurons in tissue culture. Likewise, the glutamate agonist, kainic acid, which depolarizes neurons by opening sodium channels, increases the activity of phospholipase A2. PC-specific phospholipase C, another enzyme important in the generation of the second messenger, DG, is also activated by depolarization. Several important questions remain to be answered. The site of FFA release, in terms of the pre-vs. postsynaptic membrane, is not clear, although the experiments with synaptosomes support the hypothesis that activation of phospholipase A2 may be an important regulator of presynaptic events. This idea has also been suggested by studies on the phenomenon of long-term potentiation, where free 20:4 or its metabolites may be involved in presynaptic facilitation of neurotransmitter release (Freeman et al., 1990; Massicotte et al., 1990; Williams et al., 1989; also see Dorman, this volume). The activation of the PI cycle and subsequent stimulation of protein kinase C may be a postsynaptic event important in the integration of inputs at the dendrite and soma or a presynaptic event involved in the modulation of neurotransmitter release (Taniyama et al., 1990; El-Fakahany et al., 1990; also see Nishizuka, this volume). Therefore the stimulation of a PC-specific phospholipase C, which is capable of generating large amounts of DG over a prolonged period of time (Exton, 1990; Martinson et al., 1990; Diaz-Laviada et al., 1990), could occur at either site. Another important question is the role of FFA and DG in affecting cell-cell signaling events, particularly with regard to ion fluxes. Modulation of an acetylcholine-linked K+ channel in the heart by FFA and their oxygenation products has been reported (Kim and Clapham, 1989). The cardiac muscarinic receptor is linked to a hyperpolarizing K+ channel via a G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reciprocal regulation of fatty acid release in the brain by GABA and glutamate. 135 87

The effects of GABA on catecholamine release and phosphoinositide metabolism were studied in cultured bovine adrenal chromaffin cells. GABA and muscimol, a specific agonist for the GABAA receptor, each evoked a gradual secretion of catecholamines from the cells in the presence of ouabain, an inhibitor of Na+, K(+)-ATPase. This release was inhibited by bicuculline, a specific antagonist for the GABAA receptor, or by picrotoxin, a blocker of GABA-gated Cl- channels, and was potentiated by diazepam or pentobarbital. GABA or muscimol induced a concentration-dependent formation of inositol phosphates. This accumulation of inositol phosphates was also inhibited by bicuculline, picrotoxin or removal of extracellular Ca2+, and also potentiated by diazepam and pentobarbital. Nicardipine suppressed GABA-induced catecholamine release in the presence of ouabain and accumulation of inositol phosphates, while verapamil, diltiazem, and omega-conotoxin failed to inhibit these responses to GABA. The phosphoinositide-specific phospholipase C inhibitor neomycin also inhibited both GABA-induced accumulation of inositol phosphates and stimulation of catecholamine release in the presence of ouabain. These results taken together indicate that GABA evoked catecholamine release from the chromaffin cells in the presence of ouabain by stimulation of phosphoinositide metabolism in a Ca2(+)-sensitive manner via activation of GABAA receptor-coupled Cl- channels.
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PMID:Involvement of phosphoinositide metabolism in GABA-induced catecholamine release from cultured bovine adrenal chromaffin cells. 217 9

gamma-Hydroxybutyric acid (GHB) is a natural compound of mammalian brain synthesized from GABA. The characteristics of its synthesis, transport, release, distribution and turnover, in addition to the presence of a high affinity binding site for this substance in brain are in favor of a modulator role for GHB. The effects of hydrolytic enzymes on the specific binding capacity of GHB have been studied in the present work. Phospholipases A2 and C, neuraminidase and Pronase markedly decrease GHB binding to crude synaptosomal membranes from rat brain. This effect is time and enzyme concentration dependent. Trypsin, under the conditions employed, is less active. The inhibitory effects of phospholipases is correlated with phospholipid hydrolysis. Lysophospholipids, in the absence of bovine fatty acid free serum albumin partially inhibit GHB binding. The action of neuraminidase has been followed by sialic acid release and modifications of the ganglioside profile. The effects of phospholipase C and of neuraminidase are completely different to those on GABA binding sites. These results represent further data concerning the molecular existence of specific GHB binding sites on rat brain membranes.
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PMID:Effects of phospholipases, proteases and neuraminidase on gamma-hydroxybutyrate binding sites. 218 47

The characteristics of the Na+-independent high-affinity binding of [3H]GABA to various types of crude synaptic membranes (CSM) prepared from rat brain cortex were studied. In freshly prepared CSM the content of GABA was so high that the high-affinity [3H]GABA binding could not be determined. In contrast when the frozen-thawed CSM were incubated at 37 degrees for 30 min with or without Triton X-100 or phospholipase C and then washed repeatedly, there was a virtual disappearance of GABA from the supernatant extracts and the binding constants of [3H]GABA to CSM could be determined. Two apparent populations of [3H]GABA binding sites, one with a low- and the other with a high-affinity constant, were detected. The ratio of the number of high- to low-affinity binding sites varies with the method used to prepare the membranes. The lowest value of this ratio was observed with membranes incubated at 37 degrees for 30 min. However, when frozen-thawed CSM were treated with 0.05% Triton X-100 repeatedly, the ratio of the number of high- to low-affinity binding sites increased progressively. This increase in ratio is due to a selective increase in the number of the high-affinity sites without significant changes in the number of the low-affinity sites. The extent of the increase in the number of sites that bind [3H]GABA with high affinity after repeated Triton X-100 treatments was paralleled by a decrease of an endogenous protein which inhibits GABA binding. The reapplication of this endogenous material to membranes repeatedly treated with Triton X-100 reduces the number of high-affinity binding sites for [3H]GABA to values similar to those measured in membranes that were not treated with Triton X-100. The inhibitory preparation extracted from CSM incubated with Triton X-100 was shown to be free of GABA or phospholipids. The gel filtration chromatography reveals the presence of two molecular forms of the inhibitor; of these, the high-molecular-weight material fails to bind GABA, whereas the low-molecular-weight material appears to bind GABA. The high-molecular-weight endogenous inhibitor has been termed GABA modulin.
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PMID:Endogenous inhibitors of Na+-independent [3H]GABA binding to crude synaptic membranes. 626 13

Triton X-100 treatments produced an extensive depletion of proteins and phospholipids and a marked increase of [3H] GABA binding on synaptic plasma membranes (SPM). Maximal [3H]GABA binding was obtained with three Triton X-100 treatments (+ 174% with respect to control). Phospholipase C, which removes only the phospholipid polar head, induces a 40% increase of [3H]GABA binding only after treatments resulting in extensive protein depletion. In reconstitution experiments phosphatidylethanolamine, the largest phospholipid removed, induced a 30-35% inhibition of [3H]GABA binding in Triton X-100 treated membranes; in contrast phosphatidylserine and phosphatidylcholine did not produce significant changes. The reconstitution of phospholipase C-treated SPM preparations with exogenous phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine or phosphoethanolamine and 1,2-dipalmitoylglycerol, products of phospholipase C activity, did not yield significant changes. This evidence, which argues against a direct role of phospholipids on the regulation of GABA binding, should, however, suggest that the GABA binding component of the receptor site is a lipoprotein or a lipid-depending protein.
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PMID:Regulation of GABA receptor binding to synaptic plasma membrane of rat cerebral cortex: the role of endogenous phospholipids. 627 33

Treatment of rat cerebellar membranes with phospholipase A2 (PLA2) or phospholipase C (PLC) increased basal [3H]diazepam binding at 0 degrees C with concomitant disappearance of the stimulatory effect of Cl- ion on the binding. On the other hand, these treatments did not affect the stimulatory effect of GABA, nor the maximum enhancement obtained in the presence of both GABA and Cl- ion. These results suggest that PLA2 or PLC modified the phospholipids responsible for the interaction between the benzodiazepine receptor and the Cl- ionophore. This assumption was supported by the results of thermodynamic experiments which showed that the changes in thermodynamic parameters occurring after the addition of Cl- ion resembled those after PLA2 or PLC treatment. Since the effect of PLA2 was evident at very low concentrations, and a PLC concentration of at least one order of magnitude higher was required to induce a similar effect, the change of phospholipids especially to lysophospholipids seems to be of particular importance. Protein release from the membrane, which also occurs after PLA2 or PLC treatment, did not appear to be responsible for the present phenomenon.
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PMID:Influence of phospholipase treatments on ligand bindings to a benzodiazepine receptor-GABA receptor-chloride ionophore complex. 630 32

1. The intracellular phosphorylation of bicuculline- and baclofen-insensitive GABAC receptors was investigated in rat retinal bipolar cells. The cells were recorded in organotypic slice cultures by using the whole-cell configuration of the patch-clamp technique. 2. Peak GABA responses recorded in the presence of bicuculline decreased with repetitive GABA applications. Intracellular application of the phorbol ester, phorbol 12-myristate, 13-acetate (PMA) increased this run-down, whilst it was prevented by both tamoxifen and phosphatase. 3. Perfusing the cells extracellularly with L-AP4, trans-(+/-)-1-amino-1,3-cyclopentane dicarboxylate (ACPD) or alpha-methyl serotonin accelerated the run-down of GABAC responses. 4. Modulation of GABAC responses could be induced by intracellular application of GTP gamma S, indicating involvement of G-proteins in the transduction cascade. 5. These results suggest that retinal GABAC receptors in bipolar cells are modulated by protein kinase C. Receptors which stimulate phospholipase C, presumably via Gi or Go, such as some of the metabotropic glutamate receptors or the 5-HT2 receptor, appear to be linked to this regulatory pathway.
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PMID:Modulation of GABAC receptors in rat retinal bipolar cells by protein kinase C. 773 28

The effects of 5 mM NaF + 10 microM AlCl3, a direct activator of guanine nucleotide-binding proteins (G proteins), on the release of [3H]dopamine ([3H]DA), [3H]gamma-aminobutyric acid ([3H]GABA), and [3H]acethylcholine ([3H]ACh) were investigated in slices of rat striatum. When the tissue was exposed to NaF + AlCl3 the release of [3H]DA, [3H]GABA, and [3H]ACh was enhanced significantly. In a calcium-free solution the release of [3H]GABA and [3H]DA was increased by NaF+AlCl3 much more than in the presence of [Ca2+]o. In slice preparations taken from reserpinized animals, in which the vesicular storage of [3H]DA was therefore prevented, NaF + AlCl3 had no effect on [3H]DA release. HPLC analysis of the radioactivity of the perfusate showed that, in the presence of NaF + AlCl3, the content of dihydroxyphenylacetic acid (DOPAC) in perfusate samples increased significantly, while in pargyline-treated animals only the DA content was increased. Inhibition of DA carriers by nomifensine or low temperature prevented the effect of NaF + AlCl3. N-ethylmaleimide (NEM) preincubation did not modify the effect of NaF + AlCl3 on [3H]DA release Neomycin (0.1 mM), a phospholipase C (PLC) inhibitor, significantly decreased the effect of NaF + AlCl3 on [3H]DA and [3H]GABA release. The internal concentration of Ca2+ in synaptosomes was enhanced by NaF + AlCl3 in normal solution. However, [Ca2+]i was not influenced by NaF + AlCl3 in Ca(2+)-free medium. It is concluded that a non-receptor-mediated activation, by NaF + AlCl3, of the alpha-subunit of a G protein, results in a [Ca2+]o-independent release of DA and GABA, but not that of ACh.
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PMID:Transmitter release by non-receptor activation of the alpha-subunit of guanine nucleotide regulatory protein in rat striatal slices. 856 25

Image analysis techniques have been used to demonstrate that progesterone induces a rapid calcium transient in the acrosomal domain of greater than 90% of human spermatozoa (n = 2354). These results are at variance with previous reports, suggesting that progesterone receptors are only expressed on a small subpopulation of these cells, by virtue of their ability to bind fluorescent probes incorporating progesterone 3- (O-carboxymethyl) oxime conjugated to BSA. In the present study, we could confirm that such probes only bound to a small proportion of human spermatozoa (3.01 +/- 0.29%; n = 7557) although 91.79 +/- 1.8% of the same sperm populations exhibited a calcium transient in response to progesterone. These results indicate that the binding of labeled progesterone conjugates to human spermatozoa does not reflect the size of the progesterone responsive population; the response elicited by this steroid is essentially ubiquitous. Progesterone action was shown to involve an influx of extracellular calcium via mechanisms that did not involve voltage sensitive- or second messenger operated-channels, phospholipase C, or G proteins. Despite previous evidence suggesting that progesterone action might involve a GABAA receptor/chloride channel, neither GABA nor the GABA agonist muscimol had any effect on intracellular calcium concentrations in human spermatozoa or influenced their functional competence. The only factor that disrupted the responses of human spermatozoa to progesterone was this steroid itself. Progesterone exposure induced a prolonged period of refractoriness to further stimulation that influenced the capacity of these cells to generate calcium transients, and their ability to exhibit a biological response to changes in intracellular calcium. There are implications in these results for our understanding of the extragenomic action of progesterone on human spermatozoa and the clinical manipulation of this system for the assessment and suppression of human sperm function.
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PMID:The extragenomic action of progesterone on human spermatozoa: evidence for a ubiquitous response that is rapidly down-regulated. 875 77

gamma-Aminobutyric acid (GABA)A receptor-mediated inhibitory synaptic transmission in visual cortex undergoes long-term potentiation (LTP), which is input-specific and associative. The present study, conducted under a blockade of ionotropic glutamate receptors, demonstrates an induction mechanism of LTP considerably different from those of associative LTP at excitatory synapses. Inhibitory responses of layer V cells evoked by layer IV stimulation were studied in developing rat visual cortex slices by using intracellular and whole-cell recording methods. LTP induction was prevented by the application of an antagonist for GABAB receptors but not for GABAA or metabotropic glutamate receptors. Inhibition of postsynaptic G-proteins, phospholipase C, inositol trisphosphate (IP3) receptors, or Ca2+ increase prevented the generation of LTP, as did the blockade of GABAB receptors. In rat cerebral cortex, GABAB receptor activation is not known to affect the IP3 level by itself. However, it facilitates IP3 formation induced by the activation of alpha 1 adrenoceptors, which are believed to be located postsynaptically. Accordingly, I examined the involvement of these and other amine receptors, including histamine H1, muscarinic acetylcholine, and serotonin 5-HT2 receptors, all of which are coupled to IP3 formation. Only the blockade of alpha 1 adrenoceptors or serotonin 5-HT2 receptors prevented LTP induction in most, but not all, of the cells. These results suggest that LTP induction requires the activation of postsynaptic GABAB receptors and that its effect is mediated at least partly by facilitation of the monoamine-induced IP3 formation, which then causes Ca2+ release from the internal stores in postsynaptic cells.
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PMID:GABAB receptors, monoamine receptors, and postsynaptic inositol trisphosphate-induced Ca2+ release are involved in the induction of long-term potentiation at visual cortical inhibitory synapses. 881 13


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