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 characterized a G-protein-coupled glutamate receptor in primary cultures of striatal neurons. Glutamate, quisqualate, or trans-1-aminocyclopentane-1,3-dicarboxylate inhibited by 30-40% either forskolin-stimulated cAMP production in intact cells or forskolin plus vasoactive intestinal peptide-activated adenylyl cyclase assayed in neuronal membrane preparations. These inhibitory effects were suppressed after treatment of striatal neurons with Bordetella pertussis toxin, suggesting the involvement of a heterotrimeric guanine nucleotide-binding protein (G protein) of the G(i)/G(o) subtype. The pharmacological profile of this glutamate receptor negatively coupled to adenylyl cyclase was different from that of the metabotropic Qp glutamate receptor coupled to phospholipase C in striatal neurons and from that of the recently cloned "mGluR2" glutamate receptor, which is negatively coupled to adenylyl cyclase when expressed in non-neuronal cells.
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PMID:Characterization of a metabotropic glutamate receptor: direct negative coupling to adenylyl cyclase and involvement of a pertussis toxin-sensitive G protein. 135 3

Glutamate (GLU) mediates its 'fast' excitatory transmitter action in the brain by directly gating cation-selective ion channels ('ionotropic' receptors). However, GLU can also activate another type of receptor, coupled to phospholipase C ('metabotropic' receptor). In hippocampal cells, stimulation of this metabotropic receptor by GLU, or by a racemic mixture of (1S-3R and 1R-3S) 1-aminocyclopentyl-1,3-dicarboxylate (ACPD), induces a slower excitation mediated by inhibition of K+ currents. We have assessed whether this slow form of metabotropic receptor excitation can contribute to the effects of synaptically released GLU in hippocampal slice cultures, by recording the responses of CA3 pyramidal cells to afferent mossy fibre stimulation. When the fast ionotropic response was blocked pharmacologically, mossy fibre stimulation produced a slow depolarizing postsynaptic potential associated with a decrease in membrane conductance, a depression of the slow after-hyperpolarization following a train of action potentials, and reduced accommodation during the action potential train. Under voltage-clamp, mossy fibre stimulation produced a slow voltage-dependent inward current which resembled that produced by application of exogenous ACPD or quisqualate (QUIS), and which was occluded by these metabotropic agonists. We therefore suggest that synaptically released GLU can induce two types of postsynaptic responses: a fast excitation through activation of ionotropic receptors and a slower excitation associated with inhibition of K+ conductances through activation of metabotropic receptors. This is analogous to the dual action of acetylcholine on ionotropic (nicotinic) and metabotropic (muscarinic) receptors.
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PMID:Glutamate mediates a slow synaptic response in hippocampal slice cultures. 167

The potential for cross-talk between the adenyl cyclase and phosphoinositide (PPI) lipid second messenger system was investigated in astrocytes cultured from neonatal rat brain. Glutamate-stimulated PPI turnover, measured by the formation of total inositol phosphates from myo-[3H]inositol-labeled lipids, was inhibited in a concentration-dependent manner by the elevation of intracellular cyclic AMP levels produced either by stimulation of the isoproterenol receptor linked to adenyl cyclase or by its direct activation by forskolin. N6,2'-O-Dibutyryl cyclic AMP, an analogue that can also activate cyclic AMP-dependent kinase, inhibited glutamate-stimulated PPI turnover in a concentration-dependent manner as well, a result suggesting that cyclic AMP-dependent kinase is involved in mediating the inhibition. Inclusion of an inhibitor of cyclic AMP-dependent kinase, 1-(5-isoquinolinesulfonyl)-2 methylpiperazine dihydrochloride or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride, blocked the cyclic AMP-mediated inhibition in a concentration-dependent manner, a finding further supporting this hypothesis. The site of inhibition of the phosphoinositol lipid pathway by cyclic AMP was probed using a digitonin-permeabilized cell system. Guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable analogue of GTP, stimulated PPI turnover and potentiated glutamate-stimulated PPI turnover, and guanosine 5'-O-(3-thiodiphosphate) inhibited glutamate-stimulated PPI turnover in these cells, results providing evidence that glutamate receptors are coupled to phospholipase C by a guanine nucleotide binding protein in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate-stimulated, guanine nucleotide-mediated phosphoinositide turnover in astrocytes is inhibited by cyclic AMP. 197 58

Excitatory amino acids stimulated inositol phospholipid hydrolysis in primary cultures of astrocytes, as reflected by an increased formation of [3H]inositol monophosphate [( 3H]InsP) in the presence of 10 mM Li+. Quisqualate was the most potent activator of inositol phospholipid hydrolysis, followed by glutamate and ibotenate. Kainate exhibited low activity, whereas N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) were inactive. The increase in [3H]InsP formation induced by glutamate was potentiated after 12-h exposure to the proliferative agent epidermal growth factor (EGF), suggesting that activation of the mitotic cycle leads to an enhanced coupling of glutamate recognition sites with phospholipase C. To study how glutamate receptors are involved in regulating cell proliferation, we have measured [methyl-3H]thymidine incorporation in cultured astrocytes. Excitatory amino acids reduced thymidine incorporation with a pharmacological profile similar to that observed for the stimulation of inositol phospholipid hydrolysis. Quisqualate acted as a potent antiproliferative agent, both under basal conditions and in cells stimulated to proliferate by addition of EGF or phorbol 12-tetradecanoate 13-acetate. Glutamate and ibotenate reduced [methyl-3H]thymidine incorporation at high concentrations, whereas kainate, AMPA, and NMDA were virtually inactive. The action of quisqualate on both inositol phospholipid hydrolysis and thymidine incorporation was attenuated by 2-amino-4-phosphonobutyrate, which acted as a weak agonist/competitive antagonist. Other excitatory amino acid receptor antagonists were not effective.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory amino acids stimulate inositol phospholipid hydrolysis and reduce proliferation in cultured astrocytes. 240 74

Excitatory amino acids (EAA) are known to induce an increase in the breakdown of polyphosphoinositides (PI) in brain slices and in dispersed cultures of neurons. We have now used astroglia cultured from newborn rat cerebra to demonstrate that glutamate provokes, in [3H]inositol-labeled cells, an accumulation of inositol phosphates in a time- and concentration-dependent manner. The ED50 value for glutamate was 40 microM. Quisqualate, ibotenate, and kainate were also active, with their relative potencies in the order of quisqualate greater than ibotenate much greater than kainate. No effect was detected with N-methyl-D-aspartate and quinolinic acid in the absence of Mg2+. The nonselective glutamate receptor antagonist gamma-D-glutamylglycine fully inhibited glutamate agonist-induced PI breakdown. A brief pretreatment of the astroglial cells with phorbol esters negated these effects of EAA receptor agonists, suggesting a feedback role for protein kinase C in phospholipase C action. Glutamate also elevated cytosolic free Ca2+ in Fura-2-loaded astroglial cells, as assessed by digital fluorescence imaging microscopy. Since a close metabolic partnership is known to exist between neurons and glia, these findings may have important functional consequences for neural cells in vivo.
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PMID:Activation of polyphosphoinositide metabolism as a signal-transducing system coupled to excitatory amino acid receptors in astroglial cells. 256 42

Glutamate evoked pertussis toxin-sensitive currents in Xenopus oocytes expressing metabotropic glutamate receptor subtype 1 (mGluR1) and exogenous Gi1 alpha. The mGluR1-currents were completely blocked by U-73122, a phospholipase C (PLC) inhibitor and by niflumic acid, a chloride channel blocker. In the oocyte further coinjected with poly(A)+ RNA from the guinea pig cerebellum, the mGluR1-currents were inhibited by U-50488H, an opioid kappa-agonist, and this inhibition was blocked by norbinaltorphimine, an opioid kappa-antagonist. These findings suggest that the mRNA encoding a novel subtype of opioid kappa-receptor which inhibits Gi1-PLC-mediated currents is present in guinea pig cerebellar poly(A)+ fractions.
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PMID:Evidence for a metabostatic opioid kappa-receptor inhibiting pertussis toxin-sensitive metabotropic glutamate receptor-currents in Xenopus oocytes. 749 99

Glutamate is the principal transmitter of retinal projections to the rodent suprachiasmatic nucleus, a circadian clock synchronized with the light-dark cycle through the activation of glutamate receptors of the ionotropic type. In vitro, an intracellular mobilization of calcium can be induced by glutamate within cells of the suprachiasmatic nucleus maintained in a calcium-free medium, suggesting a participation of metabotropic glutamate receptors coupled to phospholipase C. Using in situ hybridization histochemistry, we examined the expression of messenger RNAs encoding the mGluR1 and mGluR5 subtypes of metabotropic glutamate receptors in the suprachiasmatic nucleus of the adult rat and during postnatal development. In the adult, mGluR1 was expressed in a small subset of neurons segregated caudally within the ventrolateral subdivision of the nucleus, while mGluR5 was mainly expressed in ventrolateral neurons within the middle third of the nucleus. Both subtypes were expressed in morphologically similar small cells, but mGluR5 was also solely expressed in a small population of larger neurons located at the dorsalmost aspect of the ventrolateral subdivision. In addition, with mGluR1 probe silver grain clusters exhibiting a grain density close but below the significant level were observed throughout the ventrolateral subdivision of the nucleus. At birth, mGluR1 and mGluR5 were similarly expressed throughout the caudal half of the nucleus. The expression of mGluR1 increased during early postnatal development and exhibited an adult pattern at postnatal day 21. The expression of mGluR5 increased from postnatal day 7 and reached the adult pattern at postnatal day 45. These observations suggest that each subtype of metabotropic glutamate receptor coupled to phospholipase C underlies specific roles within the rat suprachiasmatic nucleus during postnatal development and in the adult. In the adult, ionotropic and metabotropic receptors likely co-expressed within neuronal subsets located in the retinal terminal field may have interactive and/or additive effects on intracellular calcium concentration. Metabotropic receptors may thus participate in the mediation of photic information conveyed to a subset of neurons. During postnatal development, metabotropic receptors may play a role in the maturation of glutamatergic synapses associated with the retinal input.
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PMID:The messenger RNAs encoding metabotropic glutamate receptor subtypes are expressed in different neuronal subpopulations of the rat suprachiasmatic nucleus. 763 67

Acetylcholine (ACh) is a powerful excitotoxic neurotransmitter in the brain. By stimulating Ca(2+)-mobilizing receptors, ACh, through G-protein(s), stimulates phospholipase C and causes the hydrolysis of a membrane phospholipid, phosphatidylinositol-4,5-bisphosphate to two second messengers, inositol-1,4,5-trisphosphate (ins-(1,4,5)-P3), and diacylglycerol. Ins-(1,4,5)-P3 is important in cholinergic neuronal stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions which may be either transient or persistent. Even short-term cholinergic convulsions may be associated with neuronal injury, especially in the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain Ca2+ which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity. Even if cholinergic-induced brain phosphoinositide signalling is likely to trigger cholinergic excitotoxicity, several other processes may be involved in the ensuing neuronal injury. Once initiated, cholinergic convulsions cannot be stopped with cholinergic antagonists such as atropine even though they are effective when given prior to a cholinergic agonist. However, glutaminergic antagonists, and GABAergic agonists, are effective in the attenuation of ongoing cholinergic status epilepticus. Cholinergic brain stimulation may be, in fact, under a partial control of brain GABAergic tonus, but also cause the release of glutamate. Glutamate stimulates inositol lipid signalling in several neuronal cells and, therefore, underlines the significance of inositol lipid signalling in cholinergic-induced excitotoxicity. Moreover, the anatomical distribution of cholinergic brain damage correlates well with that of glutaminergic neurons. Furthermore, glutamate increases neuronal oxidative stress, i.e. it increases the levels of free intracellular calcium, the production of reactive oxygen species, and causes the depletion of neuronal glutathione. The role of excitatory amino acids as common mediators of cholinergic excitotoxicity may offer new insights into the neurotoxic consequences of cholinergic neuronal stimulation.
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PMID:Phosphoinositide second messengers in cholinergic excitotoxicity. 785 83

A plasma membrane rich fraction was prepared from olfactory rosettes of Atlantic salmon and used to study binding of L-glutamic acid and activation of phospholipase C (PLC). Glutamate binding was saturable, high affinity, and inhibited by aspartic acid and taurocholate but not by alanine and lysine. Binding of glutamate was potently inhibited by various ligands for rat brain metabotropic glutamate receptors (mGluR) and also by kainate and N-methyl-D-aspartate. Glutamate stimulated phosphatidylinositol 4,5-bisphosphate breakdown consistent with G protein-dependent activation of PLC. Northern blot analyses demonstrated the presence of olfactory rosette RNA that hybridizes with cDNA probes for mGluR1 and mGluR4 under low stringency conditions. The results indicate the salmon olfactory system includes a subtype of the metabotropic glutamate receptor family.
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PMID:A subtype of the metabotropic glutamate receptor family in the olfactory system of Atlantic salmon. 795 44

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


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