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)

Dopamine, by activating dopamine D1-type receptors, and adenosine, by activating adenosine A(2A) receptors, stimulate phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000) at Thr-34. In this study, we investigated the effect of metabotropic glutamate (mGlu) receptors on DARPP-32 phosphorylation at Thr-34 in neostriatal slices. A broad-spectrum mGlu receptor agonist, trans-ACPD, and a group I mGlu receptor agonist, DHPG, stimulated DARPP-32 phosphorylation at Thr-34. Studies with mGlu receptor antagonists revealed that the effects of trans-ACPD and DHPG were mediated through activation of mGlu5 receptors. The action of mGlu5 receptors required activation of adenosine A(2A) receptors by endogenous adenosine. Conversely, the action of adenosine A(2A) receptors required activation of mGlu5 receptors by endogenous glutamate. Coactivation of mGlu5 and adenosine A(2A) receptors by exogenous agonists synergistically increased DARPP-32 phosphorylation. mGlu5 receptors did not require activation of dopamine D1-type receptors by endogenous dopamine, nor did dopamine D1-type receptors require activation of mGlu5 receptors by endogenous glutamate. DHPG potentiated the effect of forskolin, but not that of 8-bromo-cAMP, and stimulated DARPP-32 phosphorylation in the presence of the phosphodiesterase inhibitor IBMX, suggesting that mGlu5 receptors stimulate the rate of cAMP formation coupled to adenosine A(2A) receptors. The action of mGlu5 receptors was attenuated by inhibitors of extracellular signal-regulated kinase, but not by inhibitors of phospholipase C, p38, casein kinase 1, or Cdk5. The results demonstrate that mGlu5 receptors potentiate adenosine A(2A)DARPP-32 signaling by stimulating the adenosine A(2A) receptor-mediated formation of cAMP in an extracellular signal-regulated kinase-dependent manner.
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PMID:Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. 1253 71

Group I metabotropic glutamate receptors (mGluRs) are important for hippocampal interneuron function. We used whole-cell recording and confocal imaging to characterize group I mGluR actions in CA1 oriens/alveus interneurons in slices. In tetrodotoxin and ionotropic glutamate receptor antagonists, the group I mGluR specific agonist DHPG increased intradendritic Ca(2+) levels and depolarized interneurons, whereas the group II mGluR specific agonist DCG-IV and the group III mGluR specific agonist L-AP4 did not. DHPG-induced depolarizing and Ca(2+) responses were antagonized by the group I mGluR antagonist 4CPG, but only Ca(2+) responses were significantly inhibited by the mGluR1 antagonist CPCCOEt. DHPG-induced depolarizing responses were not blocked by the inositol-1,4,5-trisphosphate (IP(3)) receptor inhibitor heparin, the protein kinase C (PKC) antagonists GF-109203X, or the inhibitor of phospholipase C (PLC) U73122. Thus, these responses to DHPG may not be transduced by the PLC-->IP(3)/diacylglycerol (DAG) pathway classically linked to group I mGluRs. DHPG-induced depolarizations were not blocked by intracellular GDP beta S or bath-application of N-ethylmaleimide (NEM), suggesting the involvement of a G protein-independent pathway. Our findings indicate that group I mGluRs induce a depolarization of oriens/alveus interneurons via a G protein-independent mechanism different from their classic signalling pathway. Since depolarizations are associated with intracellular Ca(2+) rises, these actions may be important for their synaptic plasticity and vulnerability to excitotoxicity.
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PMID:Group I metabotropic glutamate receptor actions in oriens/alveus interneurons of rat hippocampal CA1 region. 1505 57

We investigated the molecular mechanism underlying the neuroprotective effect of theanine, a green tea component, using primary cultured rat cortical neurons, focusing on group I metabotropic glutamate receptors (mGluRs). Theanine and a group I mGluR agonist, DHPG, inhibited the delayed death of neurons caused by brief exposure to glutamate, and this effect of theanine was abolished by group I mGluR antagonists. Although the administration of glutamate alone decreased the neuronal expression of phospholipase C (PLC)-beta1 and -gamma1, which are linked to group I mGluRs, their expression was equal to the control levels on cotreatment with theanine. Treatment with theanine or DHPG alone for 5-7 days resulted in increased expression of PLC-beta1 and -gamma1, and the action of theanine was completely abolished by group I mGluR antagonists. These findings indicate that group I mGluRs might be involved in neuroprotective effect of theanine by increasing the expression levels of PLC-beta1 and -gamma1.
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PMID:Possible involvement of group I mGluRs in neuroprotective effect of theanine. 1520 10

It is well known that metabotropic glutamate receptors (mGluRs) have multiple actions on neuronal excitability mediated by G-protein-coupled receptors, although the exact mechanisms by which these actions occur are not understood. This study examines the effects of mGluRs agonists on voltage-dependent Ca2+ channels (VDCCs) currents (ICa) in the nucleus tractus solitarius (NTS) of rats using patch-clamp recording methods. An application of (RS)-3,5-dihydroxyphenylglycine (DHPG, Group I mGluR agonist) caused both facilitation and inhibition of L-type and N/P/Q-types ICa, respectively. Neither (2S, 2'R, 3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG, Group II mGluRs agonist) nor L-(+)-2-amino-4-phosphonobutyric acid (AP-4, Group III mGluRs agonist) nor (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, mGluR5 agonist) modulated ICa. Intracellular dialysis of the Gq/11-protein antibody and Gi-protein antibody attenuated the DHPG-induced facilitation and inhibition, respectively. The phospholipase C (PLC) inhibitor, as well as inhibition of either the protein kinase C (PKC) or inositol-1,4,5-trisphosphate (IP3) attenuated the DHPG-induced facilitation of ICa but not a DHPG-induced inhibition. Application of a strong depolarizing voltage prepulse attenuated the DHPG-induced inhibition of ICa. These results indicate that mGluR1 facilitates L-type VDCCs via Gq/11-protein involving PKC including IP3 formation. On the other hand, mGluR1 inhibits N- and P/Q-types VDCCs via Gi-protein betagamma subunits.
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PMID:Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. 1545 84

Chronic glutamate treatment during gestational period caused a significant decrease in total metabotropic glutamate receptors (mGluR) number. Similar results were observed on the steady-state level of mGlu(1) receptor detected by immunoblotting assays, suggesting that this is the main receptor subtype modulated by agonist exposure. Furthermore, no variations on mRNA coding mGlu(1) receptor were found, suggesting post-transcriptional modulation as a possible mechanism of the lost of receptor detected at the membrane surface. On the other hand, western-blotting to determine level of G(q/11) protein and phospholipase C beta(1) revealed a significant decrease of both proteins in mothers brain. This decrease was associated with significant variation in glutamate and DHPG-stimulated phospholipase C activity. No significant differences on mGluR transduction pathway components were observed in fetuses brain. These results suggest that glutamate intake during pregnancy causes a down-regulation of different proteins involved in glutamate response mediated by mGluR only in mothers brain without significantly affecting fetuses brain.
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PMID:Effect of chronic glutamate administration to pregnant rats during gestation on metabotropic glutamate receptors from mothers and full-term fetuses brain. 1571 58

Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA ("neuroprotective effect") and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196-205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 microM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 microM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.
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PMID:Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis. 1602 52

Group I metabotropic glutamate (mGlu) receptors (i.e. mGlu1 and mGlu5) coupled to phospholipase C have been widely investigated for their possible role in excitotoxic and post-ischemic neuronal death. Recently, phospholipase C has been shown to directly stimulate the activity of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair that has been proposed to play a key role in necrotic cell death. In this study, we investigated whether the stimulation of group I mGlu receptors leads to an increase in PARP activity, as detected by flow cytometry, immunodot blot and immunocytochemistry, both in baby hamster kidney cells transfected with mGlu1a or mGlu5a receptors and in cultured cortical cells. Our results show that the group I mGlu receptor agonist DHPG elicited a significant increase in PARP activity that was completely abolished by the administration of the mGlu1 antagonist 3-MATIDA and partially prevented, in cortical neurons, by the mGlu5 antagonist MPEP. To evaluate whether this pathway is involved in post-ischemic neuronal death, we used a sublethal model of oxygen-glucose deprivation in mixed cortical cell cultures. DHPG exacerbated neuronal death, and this effect was significantly prevented by the application of the PARP inhibitor DPQ. This novel pathway may contribute to the effects of mGlu1 receptors in the mechanisms leading to post-ischemic neuronal death.
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PMID:Group I metabotropic glutamate receptors stimulate the activity of poly(ADP-ribose) polymerase in mammalian mGlu1-transfected cells and in cortical cell cultures. 1602 54

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

Activation of metabotropic glutamate receptors (mGluRs) modulates synaptic transmission, whereas the roles of mGluRs in GABAergic transmission in the entorhinal cortex (EC) are elusive. Here, we examined the effects of mGluRs on GABAergic transmission onto the principal neurons in the superficial layers of the EC. Bath application of DHPG, a selective Group I mGluR agonist, increased the frequency and amplitude of spontaneous IPSCs (sIPSCs) whereas application of DCG-IV, an agonist for Group II mGluRs or L-AP4, an agonist for Group III mGluRs failed to change significantly sIPSC frequency and amplitude. Bath application of DHPG failed to change significantly the frequency and amplitude of miniature IPSCs (mIPSCs) recorded in the presence of tetradotoxin but significantly reduced the amplitude of IPSCs evoked by extracellular field stimulation or in synaptically connected interneuron-pyramidal neuron pairs in layer III of the EC. DHPG increased the frequency but reduced the amplitude of APs recorded from entorhinal interneurons. Bath application of DHPG generated membrane depolarization and increased the input resistance of GABAergic interneurons. DHPG-mediated depolarization of GABAergic interneurons was mediated by inhibition of background K(+) channels which are insensitive to extracellular Cs(+), TEA, 4-AP, and Ba(2+). DHPG-induced facilitation of sIPSCs was mediated by mGluR(5) and required the function of Galphaq but was independent of phospholipase C activity. Elevation of synaptic glutamate concentration by bath application of glutamate transporter inhibitors significantly increased sIPSC frequency and amplitude demonstrating a physiological role of mGluRs in GABAergic transmission. Our results provide a cellular and molecular mechanism to explain the physiological and pathological roles of mGluRs in the EC.
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PMID:Distinct modes of modulation of GABAergic transmission by Group I metabotropic glutamate receptors in rat entorhinal cortex. 1973 46

Phosphorylation of ionotropic glutamate receptors in the brain plays a crucial role in the regulation of synaptic plasticity. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor phosphorylation by the stimulation of group I metabotropic glutamate receptors (mGluRs) in the dorsal striatum in vivo. The results showed that intrastriatal infusion of the group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG, 250 nmol), enhanced the sensitivity of GluR2 subunit in its phosphorylation at serine 880 (S880) in the dorsal striatum. This enhancement of the sensitivity of GluR2-S880 phosphorylation was reduced by blocking group I mGluRs and N-methyl-D-aspartate (NMDA) receptors. Similar reduction of the enhancement was also induced by inhibiting phospholipase C (PLC), calcium/calmodulin-dependent protein kinase (CaMK), c-Jun N-terminal kinase (JNK), and protein kinase C (PKC). Inhibition of protein phosphatase (PP) 1/2A and calcineurin (PP2B) alone enhanced GluR2-S880 phosphorylation in the dorsal striatum, whereas inhibition of these phosphatases did not further enhance the S880 phosphorylation by DHPG stimulation. In addition, inhibition of PP1/2A or PP2B also enhanced the phosphorylation of CaMKII, JNK and PKC. These data suggest that the phosphorylation of AMPA receptor GluR2 subunit at S880 is subject to the upregulation by the stimulation of group I mGluRs. Interactions among glutamate receptors, protein kinases, and PPs participate in this upregulation.
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PMID:Alterations in GluR2 AMPA receptor phosphorylation at serine 880 following group I metabotropic glutamate receptor stimulation in the rat dorsal striatum. 1990 85


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