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)

1. Glutamate suppressed high-voltage-activated barium currents (IBa, HVA) in tiger salamander retinal ganglion cells. Both ionotropic (iGluR) and metabotropic (mGluR) receptors contributed to this calcium channel inhibition. 2. Trans-ACPD (1-aminocyclopentane-trans-1S,3R-dicarboxylic acid), a broad-spectrum metabotropic glutamate receptor agonist, suppressed a dihydropyridine-sensitive barium current. Kainate, an ionotropic glutamate receptor agonist, reduced an omega-conotoxin GVIA-sensitive current. 3. The relative effectiveness of selective agonists indicated that the predominant metabotropic receptor was the L-2-amino-4-phosphonobutyrate (L-AP4)-sensitive, group III receptor. This receptor reversed the action of forskolin, but this was not responsible for calcium channel suppression. l-AP4 raised internal calcium concentration. Antagonists of phospholipase C, inositol trisphosphate (IP3) receptors and ryanodine receptors inhibited the action of metabotropic agonists, indicating that group III receptor transduction was linked to this pathway. 4. The action of kainate was partially suppressed by BAPTA, by calmodulin antagonists and by blockers of calmodulin-dependent phosphatase. Suppression by kainate of the calcium channel current was more rapid when calcium was the charge carrier, instead of barium. The results indicate that calcium influx through kainate-sensitive glutamate receptors can activate calmodulin, which stimulates phosphatases that may directly suppress voltage-sensitive calcium channels. 5. Thus, ionotropic and metabotropic glutamate receptors inhibit distinct calcium channels. They could act synergistically, since both increase internal calcium. These pathways provide negative feedback that can reduce calcium influx when ganglion cells are depolarized.
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PMID:Metabotropic and ionotropic glutamate receptors regulate calcium channel currents in salamander retinal ganglion cells. 966 Aug 96

Metabotropic glutamate receptors (mGluRs) participate in glutamate neural transmission, but their role in the pathophysiology of spinal cord injury (SCI) has not been explored. Accordingly, we examined the role of group I mGluRs, which are linked to phospholipase C, in mediating SCI using an in vitro model. A dorsal column segment was isolated from the spinal cord of adult rats, maintained in vitro, and injured by compression for 15 sec with a clip having a 2 g closing force. Under control conditions after SCI, the compound action potential (CAP) amplitude was reduced to 69.1 +/- 5.4% of baseline. Blockade of group I mGluR receptors with MCPG, 4CPG, or AIDA resulted in improved recovery of CAP amplitude (82.2 +/- 2.0%, 86.2 +/- 3.9%, and 86.0 +/- 2.5% of baseline, respectively). The group I/II agonist trans-ACPD and selective group I agonist DHPG exacerbated the posttraumatic reduction of CAP amplitude. The phospholipase C inhibitor U-73122 improved recovery of CAP amplitude after traumatic spinal cord axonal injury. Western blotting and immunocytochemistry demonstrated the presence of mGluR1alpha-immunopositive astrocytes and the absence of mGluR5 in spinal cord white matter. These studies are consistent with the hypothesis that activation of group I mGluR receptors after SCI exacerbates posttraumatic axonal injury through a phospholipase C dependent mechanism. The presence of mGluR1alpha labeling on astrocytes suggests a role for these cells in the pathophysiology of SCI. Additional studies in vivo, are required to further clarify the role of mGluRs in acute traumatic SCI.
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PMID:Role of group I metabotropic glutamate receptors in traumatic spinal cord white matter injury. 984 Jul 66

The present report describes the effect of mGluR agonists and antagonists administration on phospholipase C activation by measuring accumulation of [3H] inositol monophosphates (IP) in rats pre-labeled with [3H]myo-inositol (i.c.v. 24 h pre-treatment). The levels of accumulated [3H]IP were then determined from clarified tissue homogenates using ion-exchange chromotography. Following lithium chloride treatment (10 mg/kg, s.c.), (R/S)-3, 5-dihydroxyphenylglycine (DHPG), a selective group I mGluR agonist was found to dose-dependently cause a maximal increase in the levels of [3H]IP at 0.3 to 3 micromol/8 microliter i.c.v. with lower doses resulting in less efficacious or no responses. This effect was temporal-dependent reaching a plateau at 2 h. The DHPG-induced increases in [3H]IP were most pronounced in the hippocampus where a 3- to 5-fold increase above vehicle was consistently found, but significant approximately 2-fold increases were also seen in the cerebellum, striatum and frontal cortex. The mixed group I and II agonist, (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (1S, 3R-t-ACPD), similarly resulted in dose-dependent increases in [3H]IP levels with doses of 1 to 3 micromol i.c.v. Furthermore, this effect was enantiomer specific since the less active 1R,3S-t-ACPD failed to alter phosphoinositol hydrolysis. Administration of the selective mGluR5 agonist (R/S)-2-chloro-5-hydroxyphenyl-glycine (CHPG) resulted in a dose-dependent increase in hippocampal but not cerebellar levels of [3H]IP, consistent with the receptor distribution of the two group I mGluRs. The Group II agonist LY354740 (1S,2S,5R,6S-2-aminobicycl[3.1.0]hexane-2,6-dicarboxylate monohydrate) and the group III agonist L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid) failed to alter the levels of [3H]IP. LY341495 (2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid) is a nM potent Group II antagonist. However, LY341495 has also been found to have microM potency in inhibiting mGluR1 and 5. The stimulation of [3H]PI hydrolysis by 1 micromol DHPG was dose-dependently blocked by co-administration of the mGluR antagonists, LY341495 at doses that are constant with an interaction at Group I mGluR's. Taken together these results suggest that stimulation of group I mGluRs results in measurable increases in PI hydrolysis in vivo. This method could be quite useful in determining the doses and routes of administration of agonists and antagonists that are required to interact with group I mGluRs.
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PMID:Phosphoinositide hydrolysis in vivo with group I metabotropic glutamate receptor agonists. 1006 44

In a previous study we showed that phosphorylation of the astrocytic marker glial fibrillary acidic protein (GFAP) in hippocampal slices from immature rats (P12-P16) is regulated by a metabotropic glutamate receptor (mGluR). The subtypes of these receptors are divided into three groups and exhibit two distinct transduction signals: activation of phospholipase C and liberation of internal calcium (group I) or modulation of cAMP synthesis (groups II and III). Here we investigated the subtype of mGluR involved. Phosphorylation was strongly stimulated by the selective group II agonists DCG IV, L-CCG-I and 1S,3S-ACPD, whereas the group I agonist 3,5-DHPG and the group III agonist L-AP4 had no effect. These results show that the receptor regulating GFAP phosphorylation in the immature hippocampus has some of the properties of a group II mGluR.
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PMID:The mGluR stimulating GFAP phosphorylation in immature hippocampal slices has some properties of a group II receptor. 1042 85

Rat cerebellar granule cells in primary culture possess muscarinic, metabotropic glutamatergic, histaminergic and alpha-adrenergic receptors which couple to phosphoinositide-specific phospholipase C. We have determined the ability of these receptors to elevate inositol(1,4,5)trisphosphate and to release intracellular calcium, in order to establish the correlation between these two responses. In resting cerebellar granule cells, only the muscarinic agonist carbachol evoked significant increases in both inositol(1,4, 5)trisphosphate and cytoplasmic free Ca2+. Mild depolarization (20 mM KCl) enhanced inositol(1,4,5)trisphosphate elevation by carbachol and histamine, but not by noradrenaline or the metabotropic glutamate agonist 1S,3R ACPD. In contrast, Ca2+-release responses were modified differently by 20 mM KCl-depolarization: the responses to carbachol, histamine and 1S,3R ACPD, but not the responses to noradrenaline, were markedly enhanced. The contribution of ryanodine-sensitive Ca2+-release channels (ryanodine receptors) to the calcium release signal in depolarized cells was determined. Ryanodine (10 microM) inhibited most effectively the cytoplasmic Ca2+ elevation evoked by 1S,3R ACPD (> 90%), while Ca2+ release upon stimulation by carbachol and histamine was only inhibited by approximately 60% and remained larger than in the absence of KCl. Our data are consistent with a specific coupling between metabotropic glutamate receptors and ryanodine-sensitive Ca2+-release channels which may not require generation of inositol(1, 4,5)trisphosphate.
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PMID:Differential coupling of G-protein-linked receptors to Ca2+ mobilization through inositol(1,4,5)trisphosphate or ryanodine receptors in cerebellar granule cells in primary culture. 1051 Jan 66

Osteoblasts and osteoclasts express functional N-methyl-d-aspartate (NMDA) receptors, which participate in regulation of bone matrix. In rat femoral osteoblasts held in whole cell clamp there is a robust NMDA current but little if any response to l-glutamate. We have investigated expression of metabotropic glutamate receptors (mGluRs) in these cells. By reverse transcription polymerase chain reaction, we have detected expression of mGluR1b (but not mGluR1a, 2, 3, 4, 5, or 6). Blockade of mGluRs with (+/-)-alpha-methyl-carboxyphenyl-glycine resulted in an enlarged l-glutamate-induced current that resembled the response to NMDA. Conversely, prior stimulation of mGluRs with trans-(+/-)-1-amino-1, 3-cyclopentanedicarboxylic acid (1S,3R-ACPD; mGluR agonist) reduced the NMDA-induced current by 77%. Monitoring of [Ca(2+)](i) showed that NMDA induced a sustained elevation of [Ca(2+)](i), which was dependent upon [Ca(2+)](o). Treatment with 1S,3R-ACPD generated an initial transient that was independent of [Ca(2+)](o), followed by a sustained, [Ca(2+)](o)-dependent phase, a response consistent with phospholipase C-mediated mobilization of stored Ca(2+). Investigations of the interaction between the two receptors confirmed inhibitory modulation of the NMDA receptor-induced rise in [Ca(2+)](i) by mGluRs. Parathyroid hormone, which also activates phospholipase C in osteoblasts, had a similar inhibitory effect on the NMDA receptor-induced [Ca(2+)](i) response. Elevation of [Ca(2+)](i) mediated by mGluR activation was reduced by subsequent stimulation of NMDA receptors. This is the first description of mGluRs in bone and shows that complex glutamatergic signaling can occur in this tissue.
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PMID:Expression of functional metabotropic glutamate receptors in primary cultured rat osteoblasts. Cross-talk with N-methyl-D-aspartate receptors. 1095 Sep 53

Low-frequency stimulation of primary afferent Adelta-fibers can induce long-term depression of synaptic transmission in rat superficial spinal dorsal horn. Here, we have identified another form of long-term depression in superficial spinal dorsal horn neurons that is induced by specific group I but not group II metabotropic glutamate receptor (mGluR) agonists. Synaptic strength between Adelta-fibers and dorsal horn neurons was examined by intracellular recordings in a spinal cord-dorsal root slice preparation from young rat. In the presence of bicuculline and strychnine, bath application of (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) or the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) but not the specific group II mGluR agonist (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) for 20 min produced an acute and a long-term depression of synaptic strength. Bath application of the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid did not affect these depressions by (1S,3R)-ACPD. After pre-incubation of slices with pertussis toxin, a G-protein inhibitor, (1S,3R)-ACPD still induced acute and long-term depressions. The phospholipase C inhibitor U73122 stereoselectively blocked the induction of long-term depression without affecting acute synaptic inhibition. This study demonstrates that, in the spinal cord, direct activation of group I mGluRs that are coupled to phospholipase C through pertussis toxin-insensitive G-proteins induces a long-term depression of synaptic strength. This may be relevant to the processing of sensory information in the spinal cord, including nociception.
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PMID:Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn. 1097 7

The pharmacological profile of metabotropic glutamate receptor (mGluR) activation of phospholipase D (PLD), and the associated signalling pathways, were examined in rat cerebrocortical synaptosomes. The assay was conducted using a transphosphatidylation reaction in synaptosomes which were pre-labelled with either [(3)H]-arachidonic acid or [(32)P]-orthophosphate. The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD) and (RS)-3,5-dihydroxyphenylglycine (DHPG), both activated PLD, while phorbol 12,13-dibutyrate (PDBu) treatment caused receptor-independent activation of PLD and had an additive effect on 1S,3R-ACPD induced PLD activity. A protein kinase C (PKC) inhibitor, GF109203X, failed to antagonize mGluR receptor-coupled PLD activity. We could not detect any increase in the products of PI (phosphoinositide)-specific phospholipase C (PI-PLC), inositol(1,4, 5)trisphosphate or diacylglycerol, by 1S, 3R-ACPD at 15 s. However, diacylglycerol increased monophasically in response to mGluR agonists and remained elevated for at least 15 min. Phosphatidic acid phosphohydrolase (PAP) activity, which converts PA to DAG, was present in the synaptosomes. These data suggest that, in rat cerebrocortical synaptosomes, the 1S,3R-ACPD-sensitive mGluR is coupled to PLD through a mechanism that is independent of both PKC and PI-PLC.
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PMID:Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes. 1105 24

C6 glioma cells were treated for hours with 100 microM L-glutamate, quisqualate or trans-ACPD. In all cases, phospholipase C-coupled metabotropic glutamate receptors (mGluRs) present in these cells are down-regulated after this agonist treatment. Cell surface metabotropic glutamate receptor density was minimum at 6 h of agonist treatment and reached near control values after 30 h of treatment. This recovery was associated with a progressive increase in mGluR1 and mGluR1a mRNA level between 6 and 24 h and was not due to agonist removal. Specific L-[3H]glutamate or [3H](+/-)trans-ACPD binding decrease detected in C6 cells after 6 h of 100 microM L-glutamate treatment was associated with a remarkable increase of specific L-[3H]glutamate binding detected in clathrin-coated vesicles isolated from these treated cells. Moreover, this decrease was blocked in the presence of 0.5 M sucrose or 1 microM phenylarsine oxide, suggesting that desensitization and down-regulation of mGluR can be due to an endocytosis process through clathrin-coated pits and vesicles.
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PMID:Internalization of metabotropic glutamate receptor in C6 cells through clathrin-coated vesicles. 1186 9

Chronic R-N(6)-phenylisopropiladenosine (R-PIA) subcutaneous injection for 6 days significantly increased total glutamate receptor number (180% of control) in rat brain synaptic plasma membranes (SPM), without affecting receptor affinity. A higher increase in metabotropic glutamate (mGlu) receptor number (258% of control) was also detected, indicating that mGlu is the main type of glutamate receptor affected by this treatment. On the other hand, the observed increase in basal and calcium- and Gpp(NH)p-stimulated phospholipase C (PLC) activity after treatment was associated with a significant increase in PLC beta(1) isoform, detected in SPM by immunoblotting assays. Moreover, an increase in PLC activity stimulation with trans-ACPD, in the absence and in the presence of Gpp(NH)p, was detected after R-PIA treatment. These results show that mGlu receptors and its effector system, PLC activity, are up-regulated by chronic exposure to an adenosine A(1) receptor agonist and suggest the existence of a cross-talk mechanism between both signal transduction pathways in rat brain.
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PMID:Adenosine A1 receptor agonist treatment up-regulates rat brain metabotropic glutamate receptors. 1243 85


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