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)

A preparation enriched in junctional complexes, as judged by marker enzymes and electron microscopy, was prepared from rat cerebellum. The junctional complexes were incubated with gamma-amino [14C]butyric acid at 25degreesC for 10 min, using [3H]sucrose as a marker for entrapped space, Total binding was determined in the absence of, and non-specific binding in the presence of, and excess of unlabelled gamma-aminobutyric acid. The difference bewteen the two binding values, i.e. the specific binding, was saturable and reversible, and showed positive cooperativity with a Hill number of about 2. The specific binding was inhibited by N-methylbicuculline, picrotoxinine and imidazole-4-acetic acid, but not by curare, strychnine or L-2,4-diaminobutyric acid. The above compounds had little effect on the non-specipic binding, but addition of ethylenediaminetetraacetic acid decreased non-specific binding by 80%. Trypsin, pronase, phospholipase A2 (EC 3.1.1.4), lysolecithin and sodium dodecyl sulfate decreased binding. Phospholipase C (EC 3.1.4.3) increased the specific binding by 260%. Phospholipids competed with gamma-aminobutyric acid for binding, with phosphatidylethanolamine being more potent than phosphatidylcholine. These results lend support for Watkins' hypothesis that phosphatidylethanolamine competes with gamma-aminobutyric acid for binding to the receptor protein.
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PMID:The effect of phospholipases and proteases on the binding of gamma-aminobutyric acid to junctional complexes of rat cerebellum. 13 18

Binding sites for tritum-labeled gamma-aminobutyric acid (GABA) in cerebellar cortex of Huntington's chorea patients have an increased affinity but unaltered maximum capacity as compared to binding sites in tissue from control patients. A similar binding pattern is produced in control membranes by treatment with Triton X-100, phospholipase C, or glycerophosphoethanolamine. Thus, it is likely that phospholipids or their metabolites regulate the accessibility of the GABA binding site and that this regulation is abnormal in Huntington's chorea.
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PMID:[3H]GABA binding in brains from Huntington's chorea patients: altered regulation by phospholipids? 22 59

In this study we have used fluoride as a tool to investigate the involvement of G protein-coupled effector systems in the regulation of the depolarization-induced release of gamma-aminobutyric acid (GABA) from rat cerebral cortex. To distinguish among the activating effects of NaF on G proteins linked to different effectors, such as adenylate cyclase, polyphosphoinositide phospholipase C, and K+ channels, agents specific to these effectors have been used in parallel. NaF induced a marked dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, with an EC50 of 1.26 mM, increasing release by 103% at 5 mM NaF. No effect on basal release was seen up to 3 mM NaF, and no modulation of [3H]acetylcholine (ACh) release was seen up to 5 mM NaF. Phorbol 12,13-diacetate (PDA) produced a similar dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, potentiating the release of [14C]GABA by 50% at 10 microM PDA. The phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine (IBMX) and theophylline, inhibited the K(+)-evoked release of [14C]GABA, and IBMX reversed the NaF facilitation of GABA release in a dose-dependent manner (pA2 2.57). The K+ channel blocker (IA current) tetrahydroaminoacridine (THA), which markedly inhibits the K(+)-evoked release of [14C]GABA, also reversed the NaF facilitatory effect, but the release of [3H]ACh was less sensitive to the inhibitory effect of THA. On the other hand, the K+ channel blocker, tetraethylammonium, which has no effect on the release of [14C]GABA, caused a significant facilitation of K(+)-evoked release of [3H]ACh. From these studies, it is concluded that GABA release in cerebral cortex is subject to regulation by G protein-linked effector systems that are distinct from those affecting the release of [3H]ACh in cerebral cortex.
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PMID:Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers. 169 Feb 66

The effects of phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), on high-affinity Na(+)-dependent gamma-aminobutyric acid (GABA) uptake were investigated in primary cultures of neurons and glial cells from rat brain cortex. Incubation of glial cells with PMA led to concentration- and time-dependent decreases in the GABA transport in glial cells. This effect could be completely suppressed by addition of the PKC inhibitor H7. The PMA effects could be mimicked by oleoylacetylglycerol, the diacylglycerol kinase inhibitor R59022 and exogenous phospholipase C. Treatment with PMA did not affect GABA transport in neuronal cells.
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PMID:Inhibition of high-affinity gamma-aminobutyric acid uptake in primary astrocyte cultures by phorbol esters and phospholipase C. 190 65

The effects of a novel glutamate analogue, (trans)-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD), have been tested in striatal neurons in primary culture and in Xenopus oocytes injected with rat brain RNA. Both systems have been previously shown to contain well characterized metabotropic receptors coupled to phospholipase C (Qp), as well as ionotropic glutamate receptors. In striatal neurons, ACPD stimulated inositol phosphate (InsP) accumulation (EC50 = 9.7 +/- 2.5 microM; maximal effect, 184.7 +/- 11.6% of basal accumulation). This effect of ACPD was likely to be mediated by Qp receptors, because maximal ACPD and quisqualate-induced InsP formation were not additive. In contrast, the effects of ACPD and norepinephrine on InsP formation were additive. ACPD-induced InsP formation was not antagonised by antagonists of muscarinic and alpha 1-adrenergic receptors (1 microM atropine and 0.1 microM prazosin, respectively). In Xenopus oocytes, ACPD and quisqualate induced an oscillatory increase of a Ca2(+)-dependent chloride conductance, which is characteristic of the activation of phospholipase C-coupled receptors in this model. The specificity of ACPD on Qp receptors was demonstrated by testing the effect of this drug on quisqualate/kainate as well as on N-methyl-D-aspartate ionotropic receptors. In striatal neurons, the activation of quisqualate/kainate and N-methyl-D-aspartate receptors was tested by measurement of [3H]-gamma-aminobutyric acid release and by electrophysiological recordings using the patch-clamp technique. At concentrations as high as 1 mM, ACPD was inactive on these inotropic receptors, either as agonist or as antagonist. In conclusion, ACPD appeared to be a highly specific agonist of Qp receptors, with no activity on ionotropic glutamate receptors. It will be a useful drug to study the physiological properties of Qp receptors in vertebrate brains.
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PMID:(trans)-1-amino-cyclopentyl-1,3-dicarboxylate stimulates quisqualate phosphoinositide-coupled receptors but not ionotropic glutamate receptors in striatal neurons and Xenopus oocytes. 216 27

Experiments were undertaken to define the role of two calcium-associated enzyme systems in modulating transmitter-stimulated production of cyclic nucleotides in rat brain. Cyclic AMP (cAMP) accumulation was examined in cerebral cortical slices using a prelabeling technique. The enhancement of isoproterenol-stimulated cAMP production by alpha-adrenergic and gamma-aminobutyric acid-B (GABAB) agonists was reduced by exposing the tissue to EGTA, a chelator of divalent cations, or quinacrine, a nonselective inhibitor of phospholipase A2. Likewise, chronic (2 weeks) administration of corticosterone decreased the alpha-adrenergic and GABAB receptor modulation of second messenger production. Neither cyclooxygenase nor lipoxygenase inhibitors selectively influenced the facilitating response of alpha-adrenergic and GABAB agonists. Other experiments revealed that although norepinephrine and 6-fluoronorepinephrine stimulated inositol phosphate (IP) production in cerebral cortical slices with potencies equal to those displayed in the cyclic nucleotide assay, selective alpha 1-adrenergic agonists were less efficacious on IP formation and were without effect in the cAMP assay. Conversely, a selective alpha 2-adrenergic receptor agonist facilitated the cAMP response to a beta-adrenergic agonist without affecting IP formation. The rank orders of potency of a series of alpha-adrenergic antagonists suggest that IP accumulation is mediated solely by alpha 1-adrenergic receptors, whereas the augmentation of cAMP accumulation is regulated by a mixed population of alpha-adrenergic sites. The results suggest that the alpha-adrenergic and GABAB receptor-mediated enhancement of isoproterenol-stimulated cAMP formation appears to be more closely associated with phospholipase A2 than phospholipase C and may be mediated by arachidonate or some other fatty acid.
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PMID:An examination of the involvement of phospholipases A2 and C in the alpha-adrenergic and gamma-aminobutyric acid receptor modulation of cyclic AMP accumulation in rat brain slices. 287 92

We have studied the effect of gamma-aminobutyric acid (GABA) and other GABA-receptor agonists (3-aminopropanesulphonic acid and muscimol) on the noradrenaline-induced stimulation of polyphosphoinositide metabolism in rat hippocampal slices. Formation of water-soluble inositol phosphates, and polyphosphoinositide metabolism were studied in hippocampal slices prelabelled with [3H]myoinositol. Noradrenaline induced formation of inositol mono-, bis- and trisphosphate during 10 min incubation in the presence of lithium; activation of phospholipase C by noradrenaline was also reflected by the hydrolysis of polyphosphoinositides and by the increased metabolism of phosphatidylinositol. GABA-receptor agonists were unable to activate per se phospholipase C; however, when added together with a low concentration of noradrenaline, they greatly potentiated the noradrenaline-stimulated polyphosphoinositide metabolism. We conclude that GABA-receptor agonists potentiate the effect of noradrenaline on polyphosphoinositide turnover and we discuss the role of this neurotransmitter interaction in the physiology of the hippocampus.
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PMID:Phospholipase C activation induced by noradrenaline in rat hippocampal slices is potentiated by GABA-receptor stimulation. 303 26

The effects of alpha-toxins from Bungarus multicinctus (alpha BuTX) and Naja naja siamensis (alpha NTX) were studied on synaptic responses and on extrasynaptic responses to focally applied acetylcholine (ACh), histamine (Hm), gamma-aminobutyric acid (GABA), and glutamate (glu) in neurons of the marine mollusc, Aplysia californica. Binding of 125I-alpha BuTX to Aplysia ganglia homogenates was pharmacologically characterized and compared with the pharmacological sensitivity of 125I-alpha BuTX binding to rat brain membrane preparations. Both alpha BuTX and alpha NTX at 10(-5) M reversibly inhibited the ACh-induced increase in Cl- conductance (GCl) without affecting ACh responses mediated by an increase in Na+ conductance (GNa) or an increase in K+ conductance (GK). In addition, both alpha-toxin reversibly inhibited the GCl responses induced by Hm and, in some cases, glu. GABA-induced GCl responses were not affected by either toxin even at concentrations as high as 10(-3) M. Both toxins also inhibited synaptic cholinergic GCl responses as well as the GCl component of postsynaptic potentials mediated by noncholinergic presynaptic neurons. Studies of 125I-alpha BuTX binding to Aplysia ganglia homogenates demonstrated the presence of a single saturable, high affinity site with a dissociation constant (KD) of 3.6 X 10(-9) M. The pharmacological profile of agents which inhibit 125I-alpha BuTx binding to Aplysia ganglia was similar to the profile of vertebrate ganglionic and brain preparations; d-tubocurarine, nicotine, and carbamylcholine effectively and competitively inhibit binding, whereas hexamethonium and decamethonium are less effective and noncompetitive. Strychnine and bicuculline, agents known to block responses to a variety of agonists in Aplysia, were effective competitive inhibitors of toxin binding in Aplysia and in rat brain. Strychnine is not as potent in inhibiting toxin binding to electric organ preparations. Chloride channel blockers, such as penicillin and picrotoxin, and noncholinergic agonists, such as Hm and glu, had no effect on toxin binding. The alpha-toxins appear to inhibit noncholinergic GCl responses through a cholinergic receptor associated with the Cl- conductance mechanism for the noncholinergic agonist.
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PMID:Snake alpha-toxin effects on cholinergic and noncholinergic responses of Aplysia californica neurons. 611 95

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

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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