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 member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.
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PMID:Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. 1295 75

Activation of group I metabotropic glutamate receptors (mGluRs) alters the firing patterns of individual CA3 pyramidal cells in guinea pig hippocampal slices. Following addition of the selective group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) to the bathing solution, pyramidal cells initially firing regular, single action potentials switched to firing in brief bursts. This change in firing pattern resulted from modulation by mGluRs of three afterpotentials. The medium and slow afterhyperpolarizations (m and sAHPs) were blocked by mGluR activation. In addition, a voltage-dependent after depolarization (ADP) was induced. Recordings from mutant mice lacking phospholipase C(beta1) (PLC(beta1)) showed that mGluR block of the mAHP, as well as induction of the ADP, depended on the phosphoinositide hydrolysis pathway. Block of the sAHP, however, was partly spared in the absence of PLC(beta1). Optical recordings of post spike intracellular Ca(2+) rises showed that mGluR block of the AHP was not mediated by alterations of action potential-associated Ca(2+) increases (Ca(2+) transients). The mGluR induction of an ADP was also independent of any changes in the Ca(2+) transient. The mGluR-induced change in the firing pattern of hippocampal pyramidal cells is thus the result of multiple mechanisms, including suppression of both m and sAHPs and activation of an ADP, that act together to produce a specific excitatory effect, namely an increased likelihood that a single action potential will lead immediately to one or more following action potentials.
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PMID:Modulation of afterpotentials and firing pattern in guinea pig CA3 neurones by group I metabotropic glutamate receptors. 1457 86

Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis. The induction of these persistent ictaform bursts is prevented by l-cysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)-coupled mGluRs. Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR-mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 microM picrotoxin, a gamma-aminobutyric acid type A antagonist, 250- to 500-ms synchronized bursts were elicited. (S)-3,5-Dihydroxyphenylglycine (DHPG, 50 microM), an agonist at group I mGluRs, increased the burst length to 1-3 s in duration, a change that persisted after agonist washout. This persistent change in burst length was elicited in the presence of 10 microM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, although PLD activation with CSA (100 microM) was highly effective at suppressing group I mGluR-mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR-induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect by PLD-driven activation of PKC, which may desensitize the phospholipase C-linked group I mGluRs and thereby prevent group I mGluR-induced epileptogenesis.
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PMID:Contrasting roles of protein kinase C in induction versus suppression of group I mGluR-mediated epileptogenesis in vitro. 1604 42

Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine (NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M(1) or adrenergic alpha1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD (NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common Galphaq-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M(1) and alpha1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signal-regulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M(1) and alpha1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M(1) and alpha1 receptors could function to induce long-term changes in synaptic function important for cognition.
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PMID:Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus. 1848 Feb 91

Activation of group I metabotropic glutamate receptors (mGluRs) produces a long-lasting change in hippocampal excitability that persists in the absence of an agonist. Exposure to the group I mGluR agonist dihydroxyphenylglycine (DHPG) results in the induction of spontaneously occurring epileptiform activity in the CA3 region of rat hippocampal slices that includes both brief interictal discharges and longer synchronous activity that resembles seizure or ictal activity (>2s duration oscillating at a frequency greater than 2 Hz). We evaluated activity-dependent mechanisms for the induction and maintenance of epileptiform activity. Both the induction and maintenance of epileptiform activity was blocked by inhibiting action potential generation with tetrodotoxin or substitution of sodium with choline or by blocking AMPA/KA ionotropic glutamate receptors. The ictal epileptiform activity induced by DHPG was composed of synchronous synaptic activity. Antagonists of group I mGluRs, either mGluR1 or mGluR5, suppressed the induction of ictal activity but had minimal effects on the maintenance of epileptiform activity. Group I mGluRs activate phospholipase C and inhibition of phospholipase C suppressed the induction but not the maintenance of epileptiform activity. Taken together, these results point to a use dependent change in CA3 neuronal network function produced by group I mGluR activation. Furthermore, activation of both mGluR1 and 5 is required to induce ictal discharges. The induction of epileptiform activity by DHPG is an in vitro model of epileptogenesis, and the development of epileptiform activity in this model depends on neuronal activity and synaptic transmission.
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PMID:Activity-dependent induction and maintenance of epileptiform activity produced by group I metabotropic glutamate receptors in the rat hippocampal slice. 1849 30

Gq-protein-coupled Group I metabotropic glutamate receptors (mGluR) reportedly activate phospholipase C (PLC), leading to Ca(2+) release from intracellular stores and the formation of diacylglycerol (DAG). We electrophysiologically examined the involvement of the Group I mGluR in tetraethylammonium (TEA)-induced long-term potentiation (LTP) at mossy fiber (MF)-CA3 synapses in the rat hippocampus. TEA-induced LTP was almost completely blocked under the selective blockade of either mGluR1 or mGluR5, both of which are Group I mGluR. This result was supported by the blockade of TEA-induced LTP even in the absence of these blockers under low temperature conditions, in which the activation of Group I mGluR is thought not to be fully effective. In addition, the blockade of mGluR1 resulted in lower short-term potentiation (STP) during TEA application compared with the blockade of mGluR5. These results demonstrate the crucial roles of Group I mGluR in the TEA-induced LTP at MF-CA3 synapses and the different contributions of mGluR1 and mGluR5 to the initial component of plasticity.
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PMID:Group I metabotropic glutamate receptors are involved in TEA-induced long-term potentiation at mossy fiber-CA3 synapses in the rat hippocampus. 1996 34

Presynaptic kainate receptors regulate synaptic transmission in several brain areas but are not known to have this action at immature mossy fiber (MF) terminals, which during the first week of postnatal life release GABA, which exerts into targeted cells a depolarizing and excitatory action. Here, we report that, during the first week of postnatal life, endogenous activation of GluK1 receptors by glutamate present in the extracellular space severely depresses MF-mediated GABAergic currents [GABA(A)-mediated postsynaptic currents (GPSCs)]. Activation of GluK1 receptors was prevented by treating the slices with enzymatic glutamate scavengers that enhanced the clearance of glutamate from the extracellular space. The depressant effect of GluK1 on MF-GPSCs was mediated by a metabotropic process sensitive to pertussis toxin. In the presence of U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a selective inhibitor of phospholipase C, along the transduction pathway downstream to G-protein, GluK1 activation increased the probability of GABA release, thus unveiling the ionotropic action of this receptor. In line with this type of action, we found that GluK1 enhanced MF excitability by directly depolarizing MF terminals via calcium-permeable cation channels. Furthermore, GluK1 dynamically regulated the direction of spike time-dependent plasticity occurring by pairing MF stimulation with postsynaptic spiking and switched spike time-dependent potentiation into depression. The GluK1-induced depression of MF-GPSCs would prevent excessive activation of the CA3 associative network by the excitatory action of GABA and the emergence of seizures in the immature brain.
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PMID:In the developing rat hippocampus, endogenous activation of presynaptic kainate receptors reduces GABA release from mossy fiber terminals. 2013 Jan 84

Cholecystokinin (CCK), a neuropeptide originally discovered in the gastrointestinal tract, is abundantly distributed in the mammalian brains including the hippocampus. Whereas CCK has been shown to increase glutamate concentration in the perfusate of hippocampal slices and in purified rat hippocampal synaptosomes, the cellular and molecular mechanisms whereby CCK modulates glutamatergic function remain unexplored. Here, we examined the effects of CCK on glutamatergic transmission in the hippocampus using whole-cell recordings from hippocampal slices. Application of CCK increased AMPA receptor-mediated EPSCs at perforant path-dentate gyrus granule cell, CA3-CA3 and Schaffer collateral-CA1 synapses without effects at mossy fiber-CA3 synapses. CCK-induced increases in AMPA EPSCs were mediated by CCK-2 receptors and were not modulated developmentally and transcriptionally. CCK reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that CCK facilitates presynaptic glutamate release. CCK increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle depletion. CCK-mediated increases in glutamate release required the functions of phospholipase C, intracellular Ca(2+) release and protein kinase Cgamma. CCK released endogenously from hippocampal interneurons facilitated glutamatergic transmission. Our results provide a cellular and molecular mechanism to explain the roles of CCK in the brain.
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PMID:Cholecystokinin facilitates glutamate release by increasing the number of readily releasable vesicles and releasing probability. 2039 36

Kainate receptors (KARs) are glutamate-gated ion channels assembled from various combinations of GluK1-GluK5 subunits with different physiological and pharmacological properties. In the hippocampus, KARs expressed at postsynaptic sites mediate a small component of excitatory postsynaptic currents while at presynaptic sites they exert a powerful control on transmitter release at both excitatory and inhibitory connections. KARs are developmentally regulated and play a key role in several developmental processes including neuronal migration, differentiation and synapse formation. Interestingly, they can signal through a canonical ionotropic pathway but also through a noncanonical modality involving pertussis toxin-sensitive G proteins and downstream signaling molecules.In this Chapter some of our recent data concerning the functional role of presynaptic KARs in regulation of transmitter release from immature mossy fiber terminals and in synaptic plasticity processes will be reviewed. Early in postnatal development, MFs release into their targeted neurons mainly GABA which is depolarizing and excitatory. Endogenous activation of GluK1 KARs localized on MF terminals by glutamate present in the extracellular space down regulates GABA release, leading sometimes to synapse silencing. The depressant effect of GluK1 on MF responses is mediated by a metabotropic process, sensitive to pertussis toxin and phospholipase C (PLC) along the transduction pathway downstream to G protein activation. Blocking PLC with the selective antagonist U73122, unmasks the potentiating effect of GluK1 on MF-evoked GABAergic currents, which probably depend on the ionotropic type of action of these receptors.In addition, GluK1 KARs dynamically regulate the direction of spike-time dependent plasticity, a particular form of Hebbian type of learning which consists in bidirectional modifications in synaptic strength according to the temporal order of pre and postsynaptic spiking. At immature MF-CA3 synapses pairing MF stimulation with postsynaptic spiking and vice versa induces long term depression of MF-evoked GABAergic currents. In the case of positive pairing synaptic depression can be switched into spike-time dependent potentiation by blocking GluK1 KARs with UBP 302. The depressant action exerted by GluK1 KARs on MF responses would prevent the excessive activation of the CA3 associative network by the excitatory action of GABA early in postnatal development.
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PMID:In the developing hippocampus kainate receptors control the release of GABA from mossy fiber terminals via a metabotropic type of action. 2171 63

Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of -70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors. The slow inward current was blocked in the absence of extracellular calcium, suggesting that this was a synaptic response. The slow excitatory postsynaptic current (EPSC) reversed near 0mV, reflecting an increase in a non-selective cationic conductance. The slow EPSC is mediated by group I mGluRs, as it was blocked by AP3, a group I mGluR antagonist. Neither a calcium chelator BAPTA nor a phospholipase C (PLC) inhibitor U73122 affected the slow EPSC. La(3+), a general TRP channel blocker or capsazepine, a selective TRPV1 channel antagonist significantly suppressed the slow EPSC. DHPG, a selective group I mGluRs agonist induced an inward current, which was suppressed by capsazepine. These results indicate that in the interneurons of the hippocampal CA3 stratum radiatum group I mGluRs activate TRPV1 channels independently of PLC and intracellular Ca(2+), resulting in the slow EPSC in the interneurons.
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PMID:Slow synaptic transmission mediated by TRPV1 channels in CA3 interneurons of the hippocampus. 2683 39


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