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Darryle D Schoepp - One of the best experts on this subject based on the ideXlab platform.
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The Metabotropic excitatory amino acid Receptor agonist 1S,3R-ACPD selectively potentiates N-methyl-D-aspartate-induced brain injury.
European journal of pharmacology, 1992Co-Authors: John W Mcdonald, Darryle D SchoeppAbstract:Abstract The role of Metabotropic type excitatory amino acid Receptors in brain injury was assessed using the selective Metabotropic Receptor agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). Intrastriatal stereotaxic injection of 1S,3R-ACPD (250 nmol) in PND 7 rats produced little brain injury as assessed by hemispheric weight disparities. However, 1S,3R-ACPD markedly potentiated N-methyl-D-aspartate (NMDA)-, but not α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-, mediated brain injury. This effect was stereoselective since the inactive Metabotropic agonist, 1R,3S-ACPD, did not potentiate NMDA toxicity.
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inhibition of cyclic amp formation by a selective Metabotropic glutamate Receptor agonist
Journal of Neurochemistry, 1992Co-Authors: Darryle D Schoepp, Bryan G Johnson, James A. MonnAbstract:It is well documented that the effects of excitatory amino acid (EAA) agonists on phosphoinositide hydrolysis involve a GTP-binding protein-linked or "Metabotropic" Receptor mechanism. The mechanisms by which EAAs alter cyclic AMP levels in brain slices, however, are not yet clear. In this study, the selective Metabotropic EAA agonist trans-(+-)-1-aminocyclopentane-1,3-dicarboxylic acid and its isomers were examined for effects on basal and forskolin-stimulated cyclic AMP formation in slices of the rat hippocampus. Trans-(+-)-1-Aminocyclopentane-1,3-dicarboxylic acid had little effect on basal cyclic AMP but inhibited forskolin-stimulated cyclic AMP formation in a biphasic manner. The 1S,3R isomer of 1-aminocyclopentane-1,3-dicarboxylic acid produced potent but only partial (approximately 50%) inhibition of forskolin-stimulated cyclic AMP formation. 1R,3S-1-Aminocyclopentane-1,3-dicarboxylic acid fully inhibited forskolin-stimulated cyclic AMP but with lower potency than the 1S,3R isomer. These results show that in addition to the formation of phosphoinositide-derived second messengers, the cellular consequences of selectively activating hippocampal Metabotropic EAA Receptors include an alteration of cellular cyclic AMP levels.
Peter D Suzdak - One of the best experts on this subject based on the ideXlab platform.
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characterization of the Metabotropic glutamate Receptor in mouse cerebellar granule cells lack of effect of 2 3 dihydroxy 6 nitro 7 sulphamoylbenzo f quinoxaline nbqx
European Journal of Pharmacology, 1993Co-Authors: Peter D Suzdak, Malcolm J. Sheardown, Tage HonoréAbstract:Abstract The ability of excitatory amino acids to stimulate phosphoinositide hydrolysis in mouse cerebellar granule cells was characterized. Quisqualic acid (EC50 = 2 μM), ibotenic acid (EC50 = 15 μM), kainic acid (EC50 = 30 μM), glutamate (EC50 = 51 μM) and (1S,3R)-1-amino-cyclo-pentane-1,3-dicarboxylic acid (t-ACPD) (EC50 = 175 μM) dose-dependently stimulated phosphoninositide hydrolysis. The stimulation of phosphoinositide hydrolysis was dose-dependently blocked by 2-amino-3-phosphonopropionic acid (L-AP3) and pertussis toxin, but was unaffected by other excitatory amino acid agonists or antagonists. These data suggest that the pharmacology of excitatory amino acid-stimulated phosphoinositide hydrolysis in the mouse cerebellar granule cells is mediated through the G protein coupled Metabotropic glutamate Receptor. The overall pharmacology of the Metabotropic Receptor present in mouse cerebellar granule cells differs from that of previously reported tissue preparations such as rat cerebellar granule cells. In addition, the effect of the α-amino-3-hydroxyl-5-methyl-1-isoxazole-4-propionic acid (AMPA) Receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxaline (NBQX), on excitatory amino acid-stimulated phosphoinositide hydrolysis was also examined. NBQX was without effect on either basal phosphoinositide hydrolysis or excitatory amino acid-stimulated phosphoinositide hydrolysis, suggesting that the neuroprotective effect of NBQX is not mediated through the Metabotropic glutamate Receptor.
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l 2 amino 4 phosphonobutyrate l ap4 is an agonist at the type iv Metabotropic glutamate Receptor which is negatively coupled to adenylate cyclase
European Journal of Pharmacology, 1992Co-Authors: Christian Thomsen, Peter Lommer Kristensen, Eileen R Mulvihill, Betty A Haldeman, Peter D SuzdakAbstract:Abstract Glutamate and L-AP4 inhibited forskolin-stimulated cyclic AMP (cAMP) production in baby hamster kidney (BHK) cells transfected with the type IV Metabotropic Receptor (mGluR4). In situ hybridization revealed a high level of mRNA for the mGluR4 in the entorhinal cortex, but not in the dentate gyrus. These data demonstrate that mGluR4 Receptors arc negatively coupled to the cAMP cascade, and suggest that the mGluR4 Receptor may be the previously described presynaptic L-AP4 Receptor.
Shigetada Nakanishi - One of the best experts on this subject based on the ideXlab platform.
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molecular characterization of a new Metabotropic glutamate Receptor mglur7 coupled to inhibitory cyclic amp signal transduction
Journal of Biological Chemistry, 1994Co-Authors: Naoyuki Okamoto, Seiji Hori, Yasunori Hayashi, Noboru Mizuno, Ryuichi Shigemoto, Chihiro Akazawa, Shigetada NakanishiAbstract:Abstract A cDNA clone for a new rat Metabotropic glutamate Receptor termed mGluR7 was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the Metabotropic Receptor (mGluR) family and by the subsequent screening of a rat forebrain cDNA library. The cloned mGluR7 subtype consists of 915 amino acid residues and exhibits a structural architecture common to the mGluR family with a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR7 shows the highest sequence similarity to mGluR4 and mGluR6 among the members of the mGluR family. Similar to mGluR4 and mGluR6, mGluR7 inhibits forskolin-stimulated cyclic AMP accumulation in response to agonist interaction and potently reacts with L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate in Chinese hamster ovary cells transfected with the cloned cDNA. RNA blot and in situ hybridization analyses of mGluR7 mRNA indicated that it is widely expressed in many neuronal cells of the central nervous system and is thus different from the more limitedly expressed mGluR4 or mGluR6 mRNA. mGluR7 together with mGluR4 thus corresponds to the putative L-2-amino-4-phosphonobutyrate Receptor which plays an important role in modulation of glutamate transmission in the central nervous system.
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molecular characterization of a novel retinal Metabotropic glutamate Receptor mglur6 with a high agonist selectivity for l 2 amino 4 phosphonobutyrate
Journal of Biological Chemistry, 1993Co-Authors: Yoshiaki Nakajima, Hideki Iwakabe, Hiroyuki Nawa, Noboru Mizuno, Ryuichi Shigemoto, Chihiro Akazawa, Shigetada NakanishiAbstract:A cDNA clone for a new Metabotropic glutamate Receptor, termed mGluR6, was isolated from a rat retinal cDNA library by cross-hybridization with the previously isolated cDNA clone for a Metabotropic glutamate Receptor. The cloned mGluR6 subtype consists of 871 amino acid residues and exhibits a structural architecture common to the Metabotropic Receptor family, possessing a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR6 shows the highest sequence similarity to mGluR4 among the Metabotropic Receptor subtypes and inhibits the forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary cells transfected with the cloned cDNA. mGluR6 potently reacts with L-2-amino-4-phosphonobutyrate (L-AP4) and L-serine-O-phosphate, and the potencies of these compounds are one order of magnitude greater than that of L-glutamate. Blot and in situ hybridization analyses indicated that mGluR6 mRNA is restrictedly expressed in the inner nuclear layer of the retina where ON-bipolar cells are distributed. The Metabotropic Receptor that responds strongly to L-AP4 and L-serine-O-phosphate in ON-bipolar cells is known to mediate glutamate synaptic transmission between photoReceptor cells and ON-bipolar cells. On the basis of the agonist selectivity of mGluR6 and its specific expression in retinal cells, the physiological role of this Receptor subtype in the visual system is discussed.
Kimberly M Huber - One of the best experts on this subject based on the ideXlab platform.
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altered neocortical rhythmic activity states in fmr1 ko mice are due to enhanced mglur5 signaling and involve changes in excitatory circuitry
The Journal of Neuroscience, 2011Co-Authors: Seth A Hays, Kimberly M Huber, Jay R GibsonAbstract:Despite the pronounced neurological deficits associated with mental retardation and autism, the degree to which neocortical circuit function is altered remains unknown. Here, we study changes in neocortical network function in the form of persistent activity states in the mouse model of fragile X syndrome—the Fmr1 knock-out (KO). Persistent activity states, or UP states, in the neocortex underlie the slow oscillation which occurs predominantly during slow-wave sleep, but may also play a role during awake states. We show that spontaneously occurring UP states in the primary somatosensory cortex are 38–67% longer in Fmr1 KO slices. In vivo , UP states reoccur with a clear rhythmic component consistent with that of the slow oscillation and are similarly longer in the Fmr1 KO. Changes in neocortical excitatory circuitry likely play the major role in this alteration as supported by three findings: (1) longer UP states occur in slices of isolated neocortex, (2) pharmacologically isolated excitatory circuits in Fmr1 KO neocortical slices display prolonged bursting states, and (3) selective deletion of Fmr1 in cortical excitatory neurons is sufficient to cause prolonged UP states whereas deletion in inhibitory neurons has no effect. Excess signaling mediated by the group 1 glutamate Metabotropic Receptor, mGluR5, contributes to the longer UP states. Genetic reduction or pharmacological blockade of mGluR5 rescues the prolonged UP state phenotype. Our results reveal an alteration in network function in a mouse model of intellectual disability and autism which may impact both slow-wave sleep and information processing during waking states.
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Metabotropic Receptor dependent long term depression persists in the absence of protein synthesis in the mouse model of fragile x syndrome
Journal of Neurophysiology, 2006Co-Authors: Elena Nosyreva, Kimberly M HuberAbstract:Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental ...
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Metabotropic Receptor dependent long term depression persists in the absence of protein synthesis in the mouse model of fragile x syndrome
Journal of Neurophysiology, 2006Co-Authors: Elena Nosyreva, Kimberly M HuberAbstract:Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate Receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA Receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.
David M Lovinger - One of the best experts on this subject based on the ideXlab platform.
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functional coupling of rat group ii Metabotropic glutamate Receptors to an omega conotoxin gvia sensitive calcium channel in human embryonic kidney 293 cells
Molecular Pharmacology, 1996Co-Authors: Benjamin A. Mccool, Paul Brust, Michael M Harpold, David M LovingerAbstract:Metabotropic glutamate Receptors are G protein-coupled Receptors that perform a variety of modulatory roles in the central and peripheral nervous systems. The development of Receptor subtype-specific agonists/antagonists has lagged far behind the isolation and characterization of Receptor cDNAs. Further more, the coupling of specific Metabotropic Receptors to the various neuronal-specific effector molecules, such as voltage gated Ca2+ channels, has not been well studied. It was recently demonstrated that a rat group II Metabotropic Receptor (rm-GluR2) is capable of coupling to endogenous N-type Ca2+ channels when heterologously expressed in adult rat sympathetic ganglia neurons. To eventually understand the molecular aspects of Metabotropic Receptor modulation of the N-type Ca2+ channel, we have transiently expressed both group II Receptors in a human embryonic kidney 293 cell line (G1A1) that stably expresses the human alpha 1B-1, alpha 2b, and beta 1-3 Ca2+ channel subunits. rmGluR2 and rmGluR3 modulate the omega-conotoxin GVIA-sensitive Ba2+ currents in G1A1 cells using a voltage-dependent mechanism via an endogenous pertussis toxin-sensitive G protein. Cell-attached "macropatch" recordings demonstrate that modulation by rmGluR2 and rmGluR3 is membrane delimited. This is the first report of Ca2+ channel modulation mediated by rmGluR3. In addition, an extensive pharmacological comparison between rmGluR2 and rmGluR3 reveals that these group II Receptors interact with agonists and antagonists in unique ways.
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Metabotropic glutamate Receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3
Journal of neurophysiology, 1995Co-Authors: David M Lovinger, Brian A. MccoolAbstract: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)