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)

The possibility that activation of class I (phospholipase C-coupled) metabotropic glutamate receptors (mGluRs) can facilitate the induction of long-term potentiation (LTP) was investigated in the dentate gyrus of rat hippocampal slices. In the presence of picrotoxin, a weak tetanus led to a short-term potentiation (STP) lasting 10-15 min. Application of the class I mGluR agonists trans-azetidine-2,4-dicarboxylic acid (tADA, 100 microM) or 3,5-dihydroxyphenylglycine (DHPG, 100 microM) for 15 or 30 min before the weak tetanus did not affect baseline synaptic transmission or the magnitude of the subsequent potentiation. DHPG (70 microM) did, however, reduce accommodation of neuronal firing in response to depolarizing current injection. These results suggest that at the medial perforant path-granule cell synapse, class I mGluR activation by exogenous agonist application does not facilitate the induction of LTP.
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PMID:Class I metabotropic glutamate receptor agonists do not facilitate the induction of long-term potentiation in the dentate gyrus of the rat in vitro. 878 34

We previously found that carnitine prevents glutamate neurotoxicity and that this effect is mediated by activation of metabotropic glutamate receptors. We show now that carnitine inhibits the hydrolysis of inositol phospholipids induced by different agonists of metabotropic glutamate receptors (tACPD; (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid; DHPG, (R,S)-3,5-dyhydroxyphenylglycine or S4C3HPG, (S)-4-carboxy-3-hydroxyphenylglycine). The EC50 was ca. 170 microM and the inhibition was complete at 1 mM carnitine. Carnitine also inhibits completely hydrolysis of inositol phospholipids induced by arterenol (agonist of adrenoceptors) and only partially (ca. 50%) that induced by carbachol (agonist of muscarinic receptors). Carnitine did not inhibit phospholipase C activity but inhibits partially (43%) the hydrolysis of inositol phospholipids induced by direct activation of G proteins with AIF4-. The results reported indicate that carnitine inhibits the hydrolysis of inositol phospholipids induced by activation of metabotropic receptors likely by interfering the function of some types of G proteins.
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PMID:Carnitine inhibits hydrolysis of inositol phospholipids induced by activation of metabotropic receptors. 982 Nov 58

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

Metabotropic glutamate (mGlu) receptors coupled to phospholipase D (PLD) appear to be distinct from any known mGlu receptor subtype linked to phospholipase C or adenylyl cyclase. The availability of antagonists is necessary for understanding the role of these receptors in the central nervous system, but selective ligands have not yet been identified. In a previous report, we observed that 3, 5-dihydroxyphenylglycine (3,5-DHPG) inhibits the PLD response induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in adult rat hippocampal slices. We now show that the antagonist action of 3, 5-DHPG (IC50 = 70 microM) was noncompetitive in nature and nonselective, because the drug was also able to reduce PLD activation elicited by 100 microM norepinephrine and 1 mM histamine. In the search for a selective and more potent antagonist, we examined the effects of sixteen stereoisomers of 2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG) on the PLD-specific transphosphatidylation reaction resulting in the formation of [3H]phosphatidylethanol. The (2R,1'S,2'R,3'S)-PCCG stereoisomer (PCCG-13) antagonized the formation of [3H]phosphatidylethanol induced by 100 microM (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylate in a dose-dependent manner and with a much lower IC50 value (25 nM) compared with 3,5-DHPG. In addition, increasing concentrations of PCCG-13 were able to shift to the right the agonist dose-response curve but had no effect when tested on other receptors coupled to PLD. The potent, selective, and competitive antagonist PCCG-13 may represent an important tool for elucidating the role of PLD-coupled mGlu receptors in adult hippocampus.
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PMID:Antagonist pharmacology of metabotropic glutamate receptors coupled to phospholipase D activation in adult rat hippocampus: focus on (2R,1'S,2'R,3'S)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine versus 3, 5-dihydroxyphenylglycine. 1010 Oct 28

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

Previously, we have found that activation of mGlu receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-DHPG, can induce long-term depression (LTD) in the CA1 region of the hippocampus and that, once established, this synaptic depression can be reversed by application of the mGlu receptor antagonist, (S)-MCPG [Palmer et al., 1997. Neuropharmacology 36, 1517-1532]. We have started to investigate the signal transduction mechanisms involved in these effects. Group I mGlu receptors couple to phospholipase C and therefore can activate protein kinase C and mobilise Ca2+ from intracellular stores. However, neither protein kinase C inhibitors (chelerythrine or Ro 31-8220) nor agents which deplete intracellular Ca2+ stores (thapsigargin or cyclopiazonic acid) were able to prevent DHPG-induced LTD. Furthermore, the ability of MCPG to reverse DHPG-induced LTD was not prevented by these compounds. These results suggest that it is unlikely that DHPG-induced LTD, or its reversal by MCPG, is produced via activation of either protein kinase C or by release of Ca2+ from intracellular stores.
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PMID:An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus. 1053 Aug 20

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

Metabotropic glutamate receptors (mGluRs) modulate neuronal function via different transduction mechanisms that are either dependent or independent on G-protein function. Here we investigated, using whole cell patch-clamp recordings in combination with fluorimetric measurements of intracellular calcium concentration ([Ca(2+)](i)), the metabolic pathways involved in the responses induced by group I mGluRs in dopamine neurons of the rat midbrain. The inward current and the [Ca(2+)](i) increase caused by the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 100 microM) were permanently activated and subsequently abolished in cells loaded with the nonhydrolizable GTP-analogue GTP-gamma-S (600 microM). In addition, when GDP-beta-S (600 microM) was dialyzed into the cells to produce the blockade of the G proteins, the DHPG-dependent responses were reduced. When the tissue was bathed with the phospholipase C inhibitor 1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]exyl]-1H-pyrrole-2,5-dione (10 microM), the DHPG-induced calcium transients slightly diminished but the associated inward currents were not affected. Interestingly, a substantial depression of the DHPG-induced inward current and transient increase of [Ca(2+)](i) was caused by the protein tyrosine kinase inhibitors tyrphostin B52 (40 microM) and 4',5,7-trihydroxyisoflavone (genistein; 40 microM), whereas genistein's inactive analogue 4',5,7-trihydroxyisoflavone-7-glucoside (40 microM) was ineffective. The blockade of the Src family of tyrosine kinase by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (20 microM), mitogen-activated protein kinase by 2'-amino-3' methoxyflavone (50 microM), and protein kinase C by staurosporine (1 microM) had no effect on the cellular responses caused by DHPG. The mGluR5-selective antagonist 2-methyl-6-(phenylethynyl)-pyridine (10--100 microM) did not affect the actions of DHPG. Thus our results indicate that the responses, mainly mediated by mGluRs1 in dopamine neurons, are activated by intracellular mechanisms coupled to G proteins and regulated by tyrosine kinases.
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PMID:Group I mGluRs coupled to G proteins are regulated by tyrosine kinase in dopamine neurons of the rat midbrain. 1138 95

Signal transduction mechanisms of group II metabotropic glutamate receptors (mGlu(2/3)) remains a matter of some controversy, therefore we sought to gain new insights into its regulation by studying cAMP production in cultured neurons and astrocytes, and by examining inter-relationships of mGlu(2/3)-induced signalling with cellular calcium and various signalling cascades. mGlu(2/3) agonists 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited 10 microM forskolin-stimulated production of cAMP in murine cortical neurons, striatal neurons and forebrain astrocytes in the absence of extracellular Ca(2+). These agonists potentiated cAMP production in the presence of 1.8 mM Ca(2+) in astrocytes only. This potentiation was dependent on the extracellular Ca(2+) concentration (0.001-10 mM) and inhibited by the mGlu(2/3) antagonist LY341495 (1 microM), adenosine deaminase (1 U/ml) and the adenosine A(2A) receptor antagonist ZM241385 (1 microM). Pre-incubation with the phospholipase C (PLC) inhibitor U73122 (10 microM), L-type Ca(2+)-channel blockers nifedipine (1 microM) and nimodipine (1 microM), the calmodulin kinase II (CaMKII) inhibitor KN-62 (10 microM) or pertussis toxin (100 ng/ml) inhibited this potentiation. In the absence of 1.8 mM Ca(2+), thapsigargin (1 microM) facilitated the potentiation of cAMP production. Measurement of the Ca(2+)-binding dye Fluo-3/AM showed that, compared to Ca(2+)-free conditions, thapsigargin and 1.8 mM Ca(2+) elevated [Ca(2+)](i) in astrocytes; the latter effect being prevented by L-type Ca(2+)-channel blockers. Potentiation of cAMP production was also demonstrated when astrocytes were stimulated with the beta-adrenoceptor agonist isoprenaline (10 microM) in the presence of 1.8 mM Ca(2+), but not with the adenosine agonist NECA (10 microM) or the group I mGlu receptor agonist DHPG (100 microM). BaCl(2) (1.8 mM) in place of Ca(2+) did not facilitate forskolin-stimulated mGlu(2/3)-potentiation of cAMP. In short, this study in astrocytes demonstrates that under physiological Ca(2+) and adenylate cyclase stimulation an elevation of cAMP production is achieved that is mediated by PLC/IP(3)- and CaMKII-dependent pathways and results in the release of endogenous adenosine which acts at G(s) protein-coupled A(2A) receptors. These findings provide new insights into mGlu(2/3) signalling in astrocytes versus neurons, and which could determine the functional phenotypy of astrocytes under physiological and pathological conditions.
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PMID:Astrocyte mGlu(2/3)-mediated cAMP potentiation is calcium sensitive: studies in murine neuronal and astrocyte cultures. 1221 73

The response of the semicircular canal (SCC) to the group I mGluR-selective agonist dihydroxyphenylglycine (DHPG; 300 microM) - facilitation of afferent discharge rate - was dose-dependently reduced by the phospholipase C inhibitor U-73122 (1-100 microM; IC(50): 22 microM), the smooth endoplasmic reticulum Ca(++) ATPase inhibitor thapsigargin (100 nM-3 microM; IC(50): 500 nM), and xestospongin C (100 pM-1 microM; IC(50): 11 nM), an inositol trisphosphate receptor (IP(3)R) antagonist. Ryanodine, a modulator of Ca(++)-induced Ca(++) release, biphasically facilitated, then suppressed this response (1 nM-1 mM; approximate IC(50): 50 microM). 5 mM caffeine increased the amplitude (34.6+/-13.4%) and duration (453+/-169.8%; n=4) of the response of the SCC to DHPG, while 50 mM caffeine eliminated this response (n=2). The protein kinase C inhibitor bisindolylmaleimide I-HCl (10-100 microM; n=3) and the cyclic-ADP ribose antagonist 8-Br-cyclic-ADP ribose (1-10 microM; n=3) had no effect on the response of the SCC to DHPG. These data suggest that the increase in transmitter release following activation of group I mGluRs on vestibular hair cells is associated with intracellular Ca(++) release from both IP(3)-sensitive and ryanodine/caffeine-sensitive intracellular Ca(++) stores. Such positive feedback on transmitter release may serve to enhance the contrast between the spontaneous and stimulus-evoked modes of hair cell transmitter release, thereby optimizing signal discrimination at the synapse between hair cells and vestibular afferent fibers.
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PMID:Transmitter release from Rana pipiens vestibular hair cells via mGluRs: a role for intracellular Ca(++) release. 1236 72


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