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)

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

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

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

Cannabinoid receptors are molecular targets for marijuana and hashish, the widespread drugs of abuse. These receptors are expressed in areas of the central nervous system that contribute in important ways to the control of memory, cognition, movement and pain perception. Indeed, such functions can be strongly influenced by cannabinoid drugs, with consequences that include euphoria, analgesia, sedation and memory impairment. Although the pharmacology of cannabinoid drugs is now beginning to be understood, we still lack essential information on the endogenous signalling system(s) by which cannabinoid receptors are normally engaged. An endogenous ligand for cannabinoid receptors, anandamide, has been described. Here we report that sn-2 arachidonylglycerol (2-AG), a cannabinoid ligand isolated from intestinal tissue, is present in brain in amounts 170 times greater than anandamide. 2-AG is produced in hippocampal slices by stimulation of the Schaffer collaterals, an excitatory fibre tract that projects from CA3 to CA1 neurons. Formation of 2-AG is calcium dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase. 2-AG activates neuronal cannabinoid receptors as a full agonist, and prevents the induction of long-term potentiation at CA3-CA1 synapses. Our results indicate that 2-AG is a second endogenous cannabinoid ligand in the central nervous system.
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PMID:A second endogenous cannabinoid that modulates long-term potentiation. 928 89

Quisqualate is a potent specific agonist for Group 1 metabotropic glutamate receptors (mGluR's), that activate G protein-coupled phospholipase C (PLC) in a molecular signal-transduction mechanism that raises cytoplasmic Ca2+ and, when excessive, damages hippocampal neurons. Psychosine (beta-galactosylsphingosine), a cationic lysosphingolipid occurring naturally in nervous tissues, dose-dependently inhibited PLC activation induced by metabotropic alpha 1-adrenergic receptor signaling in cultured rat brain astrocytes in vitro. In the present study, we have tested neuroprotective efficacy of psychosine in vivo, in a rat model of glutamate excitotoxicity induced by intracerebroventricular (i.c.v.) administration of quisqualate. A sublethal i.c.v. dose of quisqualate caused episodes of prolonged akinesia and convulsions, and major damage to pyramidal neurons of the hippocampal CA1 and CA3 sector, but not to granule cell neurons of the dentate gyrus. Prior infusion of psychosine greatly attenuated quisqualate-induced behaviors, and fully prevented destruction by quisqualate of vulnerable hippocampal neurons. Psychosine may prove useful in prophylaxis of neurodegenerative disorders that arise from intensive hippocampal Group 1 mGluR stimulation.
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PMID:Psychosine blocks quisqualate-induced glutamate excitotoxicity in hippocampal CA sector neurons. 974 72

Alternative splicing has been shown to occur at the metabotropic glutamate receptor 1 (mGluR1) gene. Three main isoforms that differ in their carboxy-termini have been described so far and named mGluR1alpha, mGluR1beta and mGluR1c. These variants when expressed in recombinant systems all activate phospholipase C, although the [Ca2+] signals generated have different kinetics. Tissue distribution studies of specific mGluR1 splice variants are limited to the mGluR1alpha isoform. In the present work, we examined the localization of mGluR1beta in the adult rat and mouse forebrain by using a specific antipeptide antibody. Furthermore, the mGluR1beta immunostaining was compared with that obtained with antibodies specific for mGluR1alpha or with a pan-mGluR1 antibody which recognizes all isoforms. mGluR1beta-like immunoreactivity (LI) was found confined to the neuropil and neuronal perikarya and appeared discretely distributed in the rodent forebrain. Differential cellular distribution between mGluR1alpha and mGluR1beta was observed. In the hippocampus, mGluR1alpha-LI was restricted to non-principal neurons in all fields, whereas mGluR1beta-LI was strongest in principal cells of the CA3 field and dentate granule cells but absent in CA1. We have also shown that the vast majority of neurons in the striatum express mGluR1. The predominant form appeared to be mGluR1beta, with a distribution pattern reflecting the patch-matrix organization of the striatum. The specificity of the immunoreactivity described for mGluR1 splice variants was confirmed in mGluR1-deficient mice. The observation of a different cellular and regional distribution of mGluR1 splice variants, in particular in the hippocampus, suggests that they may mediate different roles in synaptic transmission.
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PMID:Immunohistochemical localization of the mGluR1beta metabotropic glutamate receptor in the adult rodent forebrain: evidence for a differential distribution of mGluR1 splice variants. 977 43

In this study the role of membrane-associated molecules involved in entorhinohippocampal pathfinding was examined. First outgrowth preferences of entorhinal neurites were analyzed on membrane carpets obtained from their proper target area, the hippocampus, and compared to preferences on control membranes from brain regions which do not receive afferent connections from the entorhinal cortex. On a substrate consisting of alternating lanes of hippocampal and control membranes, entorhinal neurites exhibited a strong tendency to grow on lanes of hippocampal membrane. These tissue-specific outgrowth preferences were maintained even on membrane preparations from adult brain tissue devoid of myelin. To determine the possible maturation dependence of these membranes, we examined guidance preferences of entorhinal neurites on hippocampal membranes of different developmental stages ranging from embryonic to postnatal and adult. Given a choice between alternating lanes of embryonic (E15-E16) and neonatal (P0-P1) hippocampal membranes, entorhinal neurites preferred to extend on neonatal membranes. No outgrowth preferences were observed on membranes obtained between E19 and P10. From P10 onward there was a reoccurrence of a preference for postnatal membrane lanes when neurites were presented with a choice between P15, P30, and adult membranes (>P60). This choice behavior of entorhinal neurites temporally correlates with the ingrowth of the perforant path into the hippocampus and with the stabilization of this brain area in vivo. Experiments in which postnatal and adult hippocampal membranes were heat inactivated or treated to remove molecules sensitive to phosphatidylinositol-specific phospholipase C demonstrated that entorhinal fiber preferences were controlled in this assay by attractive guidance cues and were independent of phosphatidylinositol-sensitive linked molecules. Moreover, entorhinal neurites displayed a positive discrimination for membrane-associated guidance cues of their target field, thus preferring to grow on membranes from the molecular layer of the dentate gyrus compared with CA3 or hilus membranes. Heat-inactivation experiments indicated that preferential growth of entorhinal axons is due to a specific attractivity of the molecular layer substrate. The data presented demonstrate that outgrowth of entorhinal fibers on hippocampal membranes is target and maturation dependent.
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PMID:Target- and maturation-specific membrane-associated molecules determine the ingrowth of entorhinal fibers into the hippocampus. 1039 88

Activation of metabotropic glutamate receptors (mGluRs) produces multiple effects in cortical neurons, resulting in the emergence of network activities including epileptiform discharges. The cellular mechanisms underlying such network responses are largely unknown. We examined the properties of group I mGluR-mediated cellular responses in CA3 neurons and attempted to determine their role in the generation of the network activities. Group I mGluR stimulation causes depolarization of hippocampal neurons. This depolarization is primarily mediated by two sets of conductance change: the opening of a voltage-dependent cationic conductance (mediating I(mGluR(V))) and the closing of a voltage-independent (background) K(+) conductance. I(mGluR(V)) was no longer elicited by group I mGluR agonists in the presence of U73122, a phospholipase C (PLC) blocker. Also, the current could not be activated in hippocampal CA3 neurons from PLCbeta1 knock-out mice. In contrast, suppression of PLC signaling did not affect the group I mGluR-mediated suppression of background K(+) conductance. Thus, the suppression of the background K(+) conductance occurred upstream to PLC activation, whereas the generation of I(mGluR(V)) occurred downstream to PLC activation. Group I mGluR agonists normally elicited rhythmic single cell and population burst responses in the CA3 neurons. In the absence of an I(mGluR(V)) response, CA3 neurons in slices prepared from PLCbeta1-/- mutant mice could no longer generate these responses. The results suggest that I(mGluR(V)) expression in CA3 hippocampal neuron is PLCbeta1-dependent and that I(mGluR(V)) plays a necessary role in the generation of rhythmic single cell bursts and synchronized epileptiform discharges in the CA3 region of the hippocampus.
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PMID:Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLCbeta1 signaling. 1148 62

Confocal Ca2+ imaging of rat hippocampal slices shows a paradoxical effect of acute reductions of the [Ca2+]o. Upon slice perfusion with low-Ca2+ media, a prompt intracellular Ca2+ rise selectively occurs in neurones. This response is observed only in slices challenged with agonists of group I metabotropic glutamate or M1 muscarinic receptors. In contrast, the intracellular Ca2+ level of non-stimulated neurones is insensitive to reductions of [Ca2+]o. The phenomenon is observed in 20-25 % of cultured cortical neurones. Evidence is provided demonstrating that: (1) this paradoxical response is not due to a non-specific decrease in divalent cation concentration but it is selectively activated by a reduction in [Ca2+]o, being maximal with [Ca2+]o between 0.25 and 0.5 mM; (2) upon maximal stimulation, 70-90 % of CA1-CA3 pyramidal neurones sense a reduction in [Ca2+]o; a weaker response is observed in neurones from the neocortex, whereas neurones from the dentate gyrus and granule cells from the cerebellum fail to respond; (3) conditions that elicit paradoxical Ca2+ responses cause depolarisation and increase the firing rate of hippocampal neurones; (4) paradoxical Ca2+ rises depend, primarily, on Ca2+ influx through L-type voltage-operated Ca2+ channels and to a lesser extent on release from intracellular Ca2+ stores. Inhibition of phospholipase C or protein kinase C failed to suppress the neuronal response, whereas a selective inhibitor of the Src-family of tyrosine kinases abolishes the paradoxical neuronal Ca2+ rise. A model is presented to explain how this response is elicited by contemporaneous reduction of the [Ca2+]o and metabotropic receptor stimulation; implications for the pathophysiology of the CNS are also discussed.
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PMID:Paradoxical Ca2+ rises induced by low external Ca2+ in rat hippocampal neurones. 1269 81

Alpha-latrotoxin (LTX) stimulates vesicular exocytosis by at least two mechanisms that include (1) receptor binding-stimulation and (2) membrane pore formation. Here, we use the toxin mutant LTX(N4C) to selectively study the receptor-mediated actions of LTX. LTX(N4C) binds to both LTX receptors (latrophilin and neurexin) and greatly enhances the frequency of spontaneous and miniature EPSCs recorded from CA3 pyramidal neurons in hippocampal slice cultures. The effect of LTX(N4C) is reversible and is not attenuated by La3+ that is known to block LTX pores. On the other hand, LTX(N4C) action, which requires extracellular Ca2+, is inhibited by thapsigargin, a drug depleting intracellular Ca2+ stores, by 2-aminoethoxydiphenyl borate, a blocker of inositol(1,4,5)-trisphosphate-induced Ca2+ release, and by U73122, a phospholipase C inhibitor. Furthermore, measurements using a fluorescent Ca2+ indicator directly demonstrate that LTX(N4C) increases presynaptic, but not dendritic, free Ca2+ concentration; this Ca2+ rise is blocked by thapsigargin, suggesting, together with electrophysiological data, that the receptor-mediated action of LTX(N4C) involves mobilization of Ca2+ from intracellular stores. Finally, in contrast to wild-type LTX, which inhibits evoked synaptic transmission probably attributable to pore formation, LTX(N4C) actually potentiates synaptic currents elicited by electrical stimulation of afferent fibers. We suggest that the mutant LTX(N4C), lacking the ionophore-like activity of wild-type LTX, activates a presynaptic receptor and stimulates Ca2+ release from intracellular stores, leading to the enhancement of synaptic vesicle exocytosis.
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PMID:The alpha-latrotoxin mutant LTXN4C enhances spontaneous and evoked transmitter release in CA3 pyramidal neurons. 1276 91


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