Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebellar Purkinje neurons possess AMPA ((RS)-alpha-amino-3-hydroxyl-5- methyl-4-isoxazolepropionic acid)-sensitive ionotropic glutamate receptors (AMPA GluRs) and ACPD ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid)-sensitive metabotropic glutamate receptors (mGluRs). The contributions of these receptors to responses elicited by dual receptor activation in cultured cerebellar Purkinje neurons were delineated by quantitative analysis of agonist-induced single unit activity. Responses to co-activation using Quis or AMPA + ACPD were biphasic, consisting of a dramatic increase in firing rate (excitatory phase) followed by a temporary decrease (inhibitory phase). In half of the cells tested bursting was induced during both the excitatory and inhibitory phases and the duration of each phase was prolonged relative to responses observed in non-bursting cells. Quantitative comparisons of these responses and responses produced by selective activation of AMPA GluRs and mGluRs revealed that: (a) AMPA GluRs mediated the dramatic changes in firing rate, (b) mGluRs mediated the dramatic increases in bursting and the extended duration of each phase and (c) these AMPA GluR and mGluR mediated effects were largely additive when simultaneously activated. Nevertheless, interactions did occur with repeated co-activation of AMPA GluRs and mGluRs, as indicated by selective changes in the mGluR-mediated bursting component of the response. Such modulation may contribute to synaptic regulation of Purkinje neuron excitability, for example, that associated with long term depression.
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PMID:Ionotropic and metabotropic components of electrophysiological response of cerebellar Purkinje neurons to excitatory amino acids. 750 90

We have investigated the effects of administration of exogenous glutamate receptor agonists on the amplitude of field excitatory post-synaptic potentials (fEPSPs) evoked in the CA1 region of the rat hippocampal slice by stimulation of the Schaffer collateral-commissural fibres. L-Glutamate applied by iontophoresis or by bath perfusion (50 microM for 5 min) evoked a slowly rising increase in the amplitude of the fESPS which persisted for over 90 min. L-Glutamate induced potentiation was blocked by either D(-)-2-amino-5-phosphonopentanoic acid (40 microM) or by (RS)-alpha-methyl-4-carboxyphenylglycine (500 microM). In slices in which synaptic long-term potentiation had been saturated, iontophoretically applied L-glutamate did not induce further potentiation, but reset the fEPSP amplitude back to control levels. Iontophoretic administration of N-methyl-D-aspartate (NMDA) evoked a transient potentiation which decayed back to control levels within 90 min whereas bath perfusion of NMDA (50 microM) evoked a persistent depression. Bath perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 50 microM) evoked no persistent effects. Bath administration of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 50 or 100 microM) caused a short term depression of the fEPSP and no significant persistent effects. Perfusion of 100 microM ACPD in medium containing 1 microM picrotoxin caused a much smaller short term depression of the fEPSP and this was followed by a gradually developing and persistent potentiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of synaptic transmission in the rat hippocampal slice by exogenous L-glutamate and selective L-glutamate receptor subtype agonists. 753 Aug 14

1. Unlike long-term potentiation, long-term depression (LTD) in the central nervous system remains poorly understood. The present study was undertaken to investigate the role of GABAA receptors in LTD and synaptic plasticity. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). 3. Muscimol induced a time- and concentration-dependent LTD of the amplitude of orthodromic potentials. Increasing the stimulation frequency from 0.01 Hz to 1 Hz for 10 s reversed the LTD induced by muscimol. Muscimol also induced LTD in the absence of electrical stimulation. 4. Adenosine decreased the spike size in a concentration-dependent manner, but failed to induce LTD. 5. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one at concentrations that did not have any effect themselves on the population spike (0.5 and 1 microM), potentiated the inhibitory effect of muscimol on the population spike size, including concentrations which were not effective by themselves. Both steroids were able to potentiate the ability of muscimol to induce LTD. 6. Bicuculline, 5 microM, reversed the LTD induced by muscimol, 10 microM. 7. The NMDA receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (2-AP5), the NMDA/metabotropic antagonist 2-AP3 and selective metabotropic antagonist L-(+)-2-amino-3-phosphonopropionic acid (L(+)-AP3) failed to modify the LTD. Similarly, quisqualic acid and (1S, 3R)-aminocyclopentane dicarboxylic acid (ACPD) a selective agonist at metabotropic receptors did not induce LTD or short-term depression, whereas kynurenic acid prevented the reversal of the LTD obtained at 1 Hz. 8. It is concluded that LTD can be induced by the selective activation of GABAA receptors. The lack of involvement of glutamate receptors in our protocol confirms the unique nature of the LTD described here. The phenomenon of GABA-induced LTD and its reversal by 1 Hz stimulation may represent a novel type of long-lasting depression by which inhibitory interneurones can modulate pyramidal cell excitability in a frequency-dependent manner.
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PMID:Induction of a novel form of hippocampal long-term depression by muscimol: involvement of GABAA but not glutamate receptors. 758 68

1. The pharmacology of the metabotropic glutamate receptor (mGluR) that mediates synaptic depression at corticostriatal synapses was investigated with the use of field potential and whole cell patch-clamp recording from striatal slices and whole cell recordings from isolated striatal neurons. 2. The mGluR2,3-selective agonists (R,S)-4-carboxy-3-hydroxyphenylglycine (CHPG), (2S, 1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV), and (2S, 3S, 4S)-alpha-(carboxycyclopropyl) glycine (L-CCG-I) inhibited the synaptically driven population spike (PS) evoked by afferent stimulation during field potential recording in striatal slices. These agonists also inhibited excitatory postsynaptic potentials (EPSPs) evoked by afferent stimulation during whole cell recordings. The metabotropic receptor antagonist R,S-alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the synaptic depressant actions of DCG-IV and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD). 3. The mGluR4,6,7-selective agonist L-serine-O-phosphate (L-SOP) did not alter corticostriatal synaptic transmission, but both this agonist and the mGluR4,6,7 agonist D,L-2-amino-4-phosphonobutyric acid (AP4) reduced the amplitude of the population EPSP and PS evoked in the dentate gyrus (DG) by stimulation of the lateral perforant path (LPP). These data are consistent with earlier observations that AP4 does not inhibit corticostriatal transmission, but produces presynaptic depression at LPP-DG synapses. 4. Application of mGluR agonists that inhibited transmission did not alter the input resistance or excitability of striatal neurons and did not inhibit responses evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. 760 56

A cDNA encoding the human metabotropic glutamate receptor type 4 (hmGluR4) was isolated from human brain cDNA libraries by cross-hybridization with rat mGluR4 probes. The deduced amino acid sequence of human mGluR4 consists of 912 residues and shows a sequence identity of 96% to the amino acid sequence of rat mGluR4. Northern blot analyses indicate that hmGluR4 is strongly expressed in the cerebellum of the adult human brain but also at low levels in hippocampus, hypothalamus and thalamus. Stimulation of hmGluR4 with L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP), L-glutamate or (1S,3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) in stably transfected Chinese hamster ovary (CHO) cells depressed forskolin-induced cAMP accumulation, whereas quisqualate (0.5 mM) was ineffective. The rank order of agonist potencies is: L-AP4 > L-SOP > L-glutamate > (1S,3R)-ACPD >> quisqualate. (R,S)-alpha-methyl-4-carboxyphenylglycine (1 mM), a reported antagonist at some mGluR subtypes, did not reduce the depression of forskolin-induced cAMP accumulation by L-AP4.
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PMID:Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4. 761 40

A cDNA encoding the human metabotropic glutamate receptor type 2 (hmGluR2) was isolated from human brain cDNA libraries by cross-hybridization with rat mGluR2 probes. The deduced amino acid sequence of the human mGluR2 receptor consists of 872 residues and shows a sequence identity of 97% to the amino acid sequence of rat mGluR2. Northern blot analyses showed that hmGluR2 is widely expressed in different regions of the adult brain as well as in fetal human brain. Genomic Southern blotting localized the mGluR2 gene to human chromosome 3. Chinese hamster ovary (CHO) cells stably transfected with the cloned hmGluR2 cDNA exhibit agonist induced depression of forskolin-stimulated cAMP accumulation. A direct comparison of CHO cells stably expressing human and rat mGluR2 with five agonists revealed the same rank order of potency [(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine >> (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid = L-glutamate >> quisqualate = L-2-amino-4-phosphonobutyric acid] and similar EC50 values for both homologous receptors. (R,S)-alpha-methyl-4-carboxyphenylglycine, a reported antagonist at some mGluR subtypes, reduced the depression of forskolin-induced cAMP accumulation by (1S,3R)-ACPD in both human and rat mGluR2.
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PMID:Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. 762 Jun 13

The possible roles of G-protein coupled metabotropic glutamate receptors in central nervous function are currently the focus of intensive investigation. The complexity of effects produced by agonists at these receptors probably reflects the activity of a range of sub-types. The metabotropic glutamate receptors first described are linked to phospholipase C, mediating phosphoinositide hydrolysis and release of Ca2+ from intracellular stores. A substance generally considered to be a selective agonist for these receptors is (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). This substance not only stimulates phosphoinositide hydrolysis, but also inhibits cyclic AMP formation. A family of metabotropic glutamate receptors, incorporating both phospholipase C- and adenylcyclase-linked sub-types has been cloned. Various effects of metabotropic glutamate receptor agonists on membrane ion fluxes and synaptic events have been reported, including neuronal depolarization and/or excitation, hyperpolarization, inhibition of Ca(2+)-dependent and voltage-gated K+ currents, potentiation of N-methyl-D-aspartate-induced responses, depression of synaptic excitation and either induction or augmentation of long-term potentiation. To clarify the role of metabotropic glutamate receptors in central nervous activity and to aid the characterization of the various receptor types that may be involved, a range of highly selective agonists and antagonists is required. To date, currently available antagonists such as L-2-amino-3-phosphonopropionate and L-aspartic acid-beta-hydroxamate appear to be unselective and insufficiently potent. We report here the actions of three phenylglycine derivatives, the particular agonist and/or antagonist properties of which may help to elucidate the roles of metabotropic glutamate receptors in central nervous activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system. 768 Jul 90

1. Whole-cell patch-clamp recordings were made from sympathetic preganglionic neurons (SPNs) in transverse thoracolumbar spinal cord slices of 10- to 16-day-old rats, and the effects of L-glutamate (L-Glu) and analogues on excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents evoked by stimulation of lateral funiculus were studied. 2. L-Glu (10-300 microM), quisqualate (QA, 0.1-3 microM), kainate (KA, 0.3-10 microM), ibotenate (10-25 microM), and L-2-amino-4-phosphonobutyrate (L-AP4, 25-300 microM) depressed the EPSCs and IPSCs in a concentration-dependent manner, the rank order being QA > KA > ibotenate > L-AP4 > or = L-Glu. The metabotropic glutamate receptor agonist trans-1-amino-1,3-cyclopentane-dicarboxylic acid (trans-ACPD, 25-100 microM) reduced the synaptic currents as well. A similar effect was not observed with N-methyl-D-aspartate (NMDA). 3. The excitatory amino acid uptake inhibitor L-aspartic acid-beta-hydroxamate (AAH, 100 microM), although having little or no direct effect on EPSCs, unmasked the inhibitory effect of low (< or = 1 microM) concentrations of L-Glu. 4. The synaptic depression was not accompanied by a detectable change in holding currents or EPSC reversal potentials and decay constants in the majority of SPNs studied. At higher concentrations, L-Glu and analogues, but not L-AP4, induced an inward current in some SPNs. 5. Although strongly depressing the EPSCs, L-AP4 and trans-ACPD had no significant effect on the amplitude of inward current induced by exogenous L-Glu.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory amino acids depress synaptic currents in neonate rat sympathetic preganglionic neurons. 768 99

In slices from the rat visual cortex, application of the metabotropic glutamate receptor (mGluR) agonist trans-1-aminocyclo-pentane-1,3-dicarboxylic acid (tACPD), whether combined with tetanization or not, produced only a reversible depression but not long-term depression (LTD) of synaptic transmission. In the presence of both tACPD and the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoate, tetanization induced LTD. These findings suggest requirement of tACPD-sensitive mGluR subtypes for inducing a form of LTD in the visual cortex.
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PMID:Long-term depression requiring tACPD-receptor activation and NMDA-receptor blockade. 788 11

This study was aimed at clarifying the role of metabotropic glutamate receptors (mGluRs) in the regulation of intracellular Ca2+ concentration ([Ca2+]i in postnatal mouse retinal ganglion neurons (RGNs). RGNs were maintained for 1-2 weeks in vitro by adding brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) to the culture medium. In order to select these cells for electrophysiological measurements, RGNs were vitally labelled with an antibody against Thy-1.2. Voltage-activated Ca2+ currents [ICa(V)] were recorded with patch electrodes in the whole-cell configuration. It was found that racemic +/--1-amino-cyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) or its active enantiomer 1S,3R-ACPD rapidly and reversibly either enhanced or depressed ICa(V). Quisqualate (QA), L-2-amino-4-phosphonobutyrate (L-AP4) and the endogenous transmitter glutamate induced similar effects when ionotropic glutamate receptors were blocked with D-2-amino-5-phosphonovalerate (D-APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). omega-Conotoxin GVIA (omega-CgTx GVIA), but not nifedipine prevented modulation of ICa(V) by mGluR agonists. The depression of ICa(V) by t-ACPD was irreversible when cells were dialysed with guanosine-5'-O-(3-thiotriphosphate) (GTP[gamma-S]). Ratio measurements of fura-2 fluorescence in Thy-1+ cells showed that neither t-ACPD, QA nor L-AP4 affected [Ca2+]i by liberation of Ca2+ from intracellular stores. Our results suggest that cultured RGNs express mGluRs. These receptors cannot induce Ca2+ release from intracellular stores but regulate [Ca2+]i by a fast and reversible, G-protein-mediated action on a subpopulation of voltage-activated Ca2+ channels.
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PMID:Potentiating and depressant effects of metabotropic glutamate receptor agonists on high-voltage-activated calcium currents in cultured retinal ganglion neurons from postnatal mice. 790 28


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