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Metabotropic Glutamate Receptors (metabotropic + glutamate_receptor)
Kinds of Metabotropic Glutamate Receptors Terms modified by Metabotropic Glutamate Receptors Selected AbstractsNew Allosteric Modulators of Metabotropic Glutamate Receptor 5 (mGluR5) Found by Ligand-Based Virtual ScreeningCHEMBIOCHEM, Issue 4 2005Steffen Renner Ligand-based pharmacophore searching identified new allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), a class III G protein-coupled receptor. This virtual-screening approach can be seen as a working alternative to more demanding structure-based design techniques with the main aim of developing novel lead series. [source] Regulation of Neurotransmitter Release by Metabotropic Glutamate ReceptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2000Jayne Cartmell Abstract: The G protein-coupled metabotropic glutamate (mGlu) receptors are differentially localized at various synapses throughout the brain. Depending on the receptor subtype, they appear to be localized at presynaptic and/or postsynaptic sites, including glial as well as neuronal elements. The heterogeneous distribution of these receptors on glutamate and nonglutamate neurons/cells thus allows modulation of synaptic transmission by a number of different mechanisms. Electrophysiological studies have demonstrated that the activation of mGlu receptors can modulate the activity of Ca2+ or K+ channels, or interfere with release processes downstream of Ca2+ entry, and consequently regulate neuronal synaptic activity. Such changes evoked by mGlu receptors can ultimately regulate transmitter release at both glutamatergic and nonglutamatergic synapses. Increasing neurochemical evidence has emerged, obtained from in vitro and in vivo studies, showing modulation of the release of a variety of transmitters by mGlu receptors. This review addresses the neurochemical evidence for mGlu receptor-mediated regulation of neurotransmitters, such as excitatory and inhibitory amino acids, monoamines, and neuropeptides. [source] Metabotropic Glutamate Receptors: Gatekeepers of HomeostasisJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2010J. B. Kuzmiski The capacity to appropriately respond to physiological challenges or perturbations in homeostasis is a requisite for survival. It is becoming increasingly clear that long-lasting alterations in synaptic efficacy are a fundamental mechanism for modifying neuroendocrine and autonomic output. We review recent advances in our understanding of plasticity at glutamate synapses onto magnocellular neurones (MNCs) in the paraventricular and supraoptic nuclei of the hypothalamus, with a focus on the contributions of metabotropic glutamate receptors (mGluRs) to long-lasting modifications in synaptic efficacy. Special attention is paid to the role of presynaptic mGluRs as gatekeepers for metaplasticity and regulation of body fluid homeostasis. The work highlighted here provides insight into the synaptic mechanisms that couple MNC activity to physiological states. [source] Chronic Ethanol-Induced Subtype- and Subregion-Specific Decrease in the mRNA Expression of Metabotropic Glutamate Receptors in Rat HippocampusALCOHOLISM, Issue 9 2004Agnes Simonyi Background: Chronic ethanol consumption is known to induce adaptive changes in the hippocampal glutamatergic transmission and alter NMDA receptor binding and subunit expression. Metabotropic glutamate (mGlu) receptors have been shown to function as modulators of neuronal excitability and can fine tune glutamatergic transmission. This study was aimed to determine whether chronic ethanol treatment could change the messenger RNA (mRNA) expression of mGlu receptors in the hippocampus. Methods: Male Sprague Dawley® rats were fed a Lieber-DeCarli liquid diet with 5% (w/v) ethanol or isocaloric amount of maltose for 2 months. Quantitative in situ hybridization was carried out using coronal brain sections through the hippocampus. Results: The results revealed decreases in mRNA expression of several mGlu receptors in different subregions of the hippocampus. In the dentate gyrus, mGlu3 and mGlu5 receptor mRNA levels were significantly lower in the ethanol-treated rats than in the control rats. In the CA3 region, the mRNA expression of mGlu1, mGlu5, and mGlu7 receptors showed substantial decreases after ethanol exposure. The mGlu7 receptor mRNA levels were also declined in the CA1 region and the polymorph layer of the dentate gyrus. No changes were found in mRNA expression of mGlu2, mGlu4, and mGlu8 receptors. Conclusions: Considering the involvement of hippocampal mGlu receptors in learning and memory processes as well as in neurotoxicity and seizure production, the reduced expression of these receptors might contribute to ethanol withdrawal-induced seizures and also may play a role in cognitive deficits and brain damage caused by long-term ethanol consumption. [source] Metabotropic glutamate receptor 1 activity generates persistent, N -methyl- d -aspartate receptor-dependent depression of hippocampal pyramidal cell excitabilityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2009J. P. Clement Abstract Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)- a -amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of ,-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and ,-aminobutyric acidA receptors, DHPG-LDE was blocked by antagonists of N -methyl- d -aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K+ increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases. [source] Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2004Takeshi Aoki Abstract The aim of the present study was to clarify the role of the metabotropic glutamate 5 (mGlu5) receptor subtype in the development of rewarding effect induced by a prototypical µ-opioid receptor agonist morphine in the mouse. In the conditioned place preference paradigm, intracerebroventricular (i.c.v.) administration of a selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), attenuated the morphine-induced rewarding effects. Using immunoblot analysis, we confirmed that the increased level of protein kinase C, (PKC,) isoform was observed in the limbic forebrain of ICR mice conditioned with morphine. Here we found for the first time that the treatment with MPEP significantly inhibited the up-regulation of PKC, isoform in the limbic forebrain of mice showing the significant place preference. Furthermore, it should be mentioned that the protein level of mGlu5 was significantly increased in membrane preparations of the limbic forebrain obtained from morphine-conditioned mice compared to those from saline-conditioned mice. As well as the result from the immunoblot analysis, we demonstrated using the receptor binding assay that the number of mGlu5 receptors in the mouse limbic forebrain was significantly increased by morphine conditioning. The present data provide direct evidence that the activation of mGlu5 receptor linked to the increased PKC, isoform in the mouse limbic forebrain is implicated in the development of rewarding effect of morphine. [source] Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2003Itsunari Minami Abstract Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity-dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell-surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)-293 cells. Depolarization-induced Homer1a expression in Purkinje neurons was blocked by a mitogen-activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1-mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1. [source] Metabotropic glutamate receptor 1 activity generates persistent, N -methyl- d -aspartate receptor-dependent depression of hippocampal pyramidal cell excitabilityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2009J. P. Clement Abstract Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)- a -amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of ,-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and ,-aminobutyric acidA receptors, DHPG-LDE was blocked by antagonists of N -methyl- d -aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K+ increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases. [source] Group I metabotropic glutamate receptors regulate the frequency,response function of hippocampal CA1 synapses for the induction of LTP and LTDEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2004Els J. M. Van Dam Abstract Synaptically released glutamate binds to ionotropic or metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and can be divided into three subclasses (Group I,III) depending on their pharmacology and coupling to signal transduction cascades. Group I mGluRs are coupled to phospholipase C and are implicated in several important physiological processes, including activity-dependent synaptic plasticity, but their exact role in synaptic plasticity remains unclear. Synaptic plasticity can manifest itself as an increase or decrease of synaptic efficacy, referred to as long-term potentiation (LTP) and long-term depression (LTD). The likelihood, degree and direction of the change in synaptic efficacy depends on the history of the synapse and is referred to as ,metaplasticity'. We provide direct experimental evidence for an involvement of group I mGluRs in metaplasticity in CA1 hippocampal synapses. Bath application of a low concentration of the specific group I agonist 3,5-dihydroxyphenylglycine (DHPG), which does not affect basal synaptic transmission, resulted in a leftward shift of the frequency,response function for the induction of LTD and LTP in naïve synapses. DHPG resulted in the induction of LTP at frequencies which induced LTD in control slices. These alterations in the induction of LTD and LTP resemble the metaplastic changes observed in previously depressed synapses. In addition, in the presence of DHPG additional potentiation could be induced after LTP had apparently been saturated. These findings provide strong evidence for an involvement of group I mGluRs in the regulation of metaplasticity in the CA1 field of the hippocampus. [source] Global physicochemical properties as activity discriminants for the mGluR1 subtype of metabotropic glutamate receptorsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2001Marta Filizola Abstract Metabotropic glutamate receptors (mGluRs) are important as candidate therapeutic targets for many neurological disorders. In the present work, the focus has been on the mGluR1 subtype, where agonists have a proconvulsant profile while antagonists exert anticonvulsant activity. Identification of molecular determinants for the inhibition of mGluR1 provides a new avenue for the discovery and development of novel anticonvulsant drugs. Spatial configuration of key groups alone cannot explain activation selectivity at this specific receptor subtype. In fact, all known agonists and antagonists acting at mGluR1 can accommodate the same critical moieties in a similar geometric arrangement that corresponds to the extended conformation of glutamate. Therefore, other factors must account for the differences in activation. This study presents the results of an analysis of a large suite of steric, topological, electrostatic, and thermodynamic molecular properties calculated for a representative set of potent mGluR1 agonists and antagonists. Global steric parameters and the total nonpolar area provide discrimination between the mGluR1 agonists and antagonists considered in the present work. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 2018,2027, 2001 [source] Site-specific unglycosylation to improve crystallization of the metabotropic glutamate receptor 3 extracellular domainACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2009Takanori Muto Metabotropic glutamate receptors (mGluRs) are involved in the regulation of many physiological and pathological processes in the central nervous system. The extracellular domain (ECD) of mGluR subtype 3 (mGluR3) was produced using the baculovirus expression system and purified from the culture medium. However, the recombinant protein showed heterogeneity in molecular weight on SDS,PAGE analysis. It was found that the unglycosylation of Asn414 significantly reduced the heterogeneity. Consequently, three site-specifically unglycosylated mutant proteins of mGluR3 ECD, replacing Asn414 only or replacing Asn414 in combination with other glycosylation sites, were successfully crystallized in the presence of l -glutamate. Among them, crystals of the N414/439Q mutant diffracted X-rays to 2.35,Å resolution using synchrotron radiation. The crystal belonged to the monoclinic space group P21, with unit-cell parameters a = 84.0, b = 97.5, c = 108.1,Å, , = 93.0°. Assuming the presence of two protomers per crystallographic asymmetric unit, the Matthews coefficient VM was calculated to be 3.5,Å3,Da,1 and the solvent content was 65%. [source] Functions of glutamate transporters in cerebellar Purkinje cell synapsesACTA PHYSIOLOGICA, Issue 1 2009Y. Takayasu Abstract Glutamate transporters play a critical role in the maintenance of low extracellular concentrations of glutamate, which prevents the overactivation of post-synaptic glutamate receptors. Four distinct glutamate transporters, GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3 and EAAT4, are distributed in the molecular layer of the cerebellum, especially near glutamatergic synapses in Purkinje cells (PCs). This review summarizes the current knowledge about the differential roles of these transporters at excitatory synapses of PCs. Data come predominantly from electrophysiological experiments in mutant mice that are deficient in each of these transporter genes. GLAST expressed in Bergmann glia contributes to the clearing of the majority of glutamate that floods out of the synaptic cleft immediately after transmitter release from the climbing fibre (CF) and parallel fibre (PF) terminals. It is indispensable to maintain a one-to-one relationship in synaptic transmission at the CF synapses by preventing transcellular glutamate spillover. GLT-1 plays a similar but minor role in the uptake of glutamate as GLAST. Although the loss of neither GLAST nor GLT-1 affects cerebellar morphology, the deletion of both GLAST and GLT-1 genes causes the death of the mutant animal and hinders the folium formation of the cerebellum. EAAT4 removes the low concentrations of glutamate that escape from uptake by glial transporters, preventing the transmitter from spilling over into neighbouring synapses. It also regulates the activation of metabotropic glutamate receptor 1 (mGluR1) in perisynaptic regions at PF synapses, which in turn affects mGluR1-mediated events including slow EPSCs and long-term depression. No change in synaptic function is detected in mice that are deficient in EAAC1. [source] Activation of class I metabotropic glutamate receptors limits dendritic growth of Purkinje cells in organotypic slice culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Alexandra Sirzen-Zelenskaya Abstract The development of the dendritic tree of a neuron is a complex process which is thought to be regulated strongly by signals from afferent fibers. We showed previously that the blockade of glutamatergic excitatory neurotransmission has little effect on Purkinje cell dendritic development. We have now studied the effects of glutamate receptor agonists on the development of Purkinje cell dendrites in mouse organotypic slice cultures. The activation of N -methyl- d -aspartate receptors had no major effect on Purkinje cell dendrites and the activation of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptors was strongly excitotoxic so that no analysis of its effects on dendritic development was possible. The activation of metabotropic glutamate receptors led to a very strong inhibition of dendritic growth, resulting in Purkinje cells with very small stubby dendrites. This effect was specific for the activation of class I metabotropic glutamate receptors and could not be reduced by blocking synaptic transmission in the cultures, indicating that it was mediated by receptors present on Purkinje cells. Pharmacological experiments suggest that the signaling pathway involved does not require activation of phospholipase C or protein kinase C. The inhibition of dendritic growth by activation of class I metabotropic glutamate receptor could be a useful negative feedback mechanism for limiting the size of the dendritic tree of Purkinje cells after the establishment of a sufficient number of parallel fiber contacts. This developmental mechanism could protect Purkinje cells from excitotoxic death through excessive release of glutamate from an overload of parallel fiber contacts. [source] The KCl cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2001A. I. Gulyás Abstract Immunocytochemical visualization of the neuron-specific K+/Cl, cotransporter, KCC2, at the cellular and subcellular level revealed an area- and layer-specific diffuse labelling, and a discrete staining outlining the somata and dendrites of some interneurons in all areas of the rat hippocampus. KCC2 was highly expressed in parvalbumin-containing interneurons, as well as in subsets of calbindin, calretinin and metabotropic glutamate receptor 1a-immunoreactive interneurons. During the first 2 postnatal weeks, an increase of KCC2 staining was observed in the molecular layer of the dentate gyrus, correlating temporally with the arrival of entorhinal cortical inputs. Subcellular localization demonstrated KCC2 in the plasma membranes. Immunoreactivity in principal cells was responsible for the diffuse staining found in the neuropil. In these cells, KCC2 was detected primarily in dendritic spine heads, at the origin of spines and, at a much lower level on the somata and dendritic shafts. KCC2 expression was considerably higher in the somata and dendrites of interneurons, most notably of parvalbumin-containing cells, as well as in the thorny excrescences of CA3 pyramidal cells and in the spines of spiny hilar and stratum lucidum interneurons. The data indicate that KCC2 is highly expressed in the vicinity of excitatory inputs in the hippocampus, perhaps in close association with extrasynaptic GABAA receptors. A high level of excitation is known to lead to a simultaneous net influx of Na+ and Cl,, as evidenced by dendritic swelling. KCC2 located in the same microenvironment may provide a Cl, extrusion mechanism to deal with both ion and water homeostasis in addition to its role in setting the driving force of Cl, currents involved in fast postsynaptic inhibition. [source] Heterogeneous distribution of AMPA glutamate receptor subunits at the photoreceptor synapses of rodent retinaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2001Iris Hack Abstract In the retina the segregation of different aspects of visual information starts at the first synapse in signal transfer from the photoreceptors to the second-order neurons, via the neurotransmitter glutamate. We examined the distribution of the four AMPA glutamate receptor subunits GluR1,GluR4 at the photoreceptor synapses in mouse and rat retinae by light and immunoelectron microscopy and serial section reconstructions. On the dendrites of OFF-cone bipolar cells, which make flat, noninvaginating contacts postsynaptic at cone synaptic terminals, the subunits GluR1 and GluR2 were predominantly found. Horizontal cell processes postsynaptic at both rod and cone synaptic terminals preferentially expressed the subunits GluR2, GluR2/3 and GluR4. An intriguing finding was the presence of GluR2/3 and GluR4 subunits on dendrites of putative rod bipolar cells, which are thought to signal through the sign-inverting metabotropic glutamate receptor 6, mGluR6. Furthermore, at the rod terminals, horizontal cell processes and rod bipolar cell dendrites showed labelling for the AMPA receptor subunits at the ribbon synaptic site or perisynaptically at their site of invagination into the rod terminal. The wide distribution of AMPA receptor subunits at the photoreceptor synapses suggests that AMPA receptors play an important role in visual signal transfer from the photoreceptors to their postsynaptic partners. [source] Association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set shifting in healthy individualsGENES, BRAIN AND BEHAVIOR, Issue 5 2010B. T. Baune Set-shifting and maintenance are complex cognitive processes, which are often impaired in schizophrenia. The genetic basis of these processes is poorly understood. We aimed to investigate the association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set-shifting in healthy individuals. The relationship between 14 selected single nucleotide polymorphisms (SNPs) of the GRM3 gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 ± 0.19). Results show that SNP rs17676277 is related to the performance on the MCST. Subjects with the TT genotype showed significantly less perseverative errors as compared with the AA (P = 0.025) and AT (P = 0.0005) and combined AA/AT genotypes (P = 0.0005). Haplotype analyses suggest the involvement of various SNPs of the GRM3 gene in perseverative error processing in a dominant model of inheritance. The findings strongly suggest that the genetic variation (rs17676277 and three haplotypes) in the metabotropic GRM3 is related to cognitive set-shifting in healthy individuals independent of working memory. However, because of a relatively small sample size for a genetic association study, the present results are tentative and require replication. [source] Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged ratsAGING CELL, Issue 5 2010Brigitte Potier Summary This study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT-1 and reduced glutamate uptake occur in the aged (24,27 months) Sprague,Dawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3,5 months) and aged rats are depressed by DL-TBOA, an inhibitor of glutamate transporter activity, in an N -Methyl- d- Aspartate (NMDA)-receptor-dependent manner. In aged but not in young rats, part of the depressing effect of DL-TBOA also involves metabotropic glutamate receptor (mGluRs) activation as it is significantly reduced by the specific mGluR antagonist d-methyl-4-carboxy-phenylglycine (MCPG). The paired-pulse facilitation ratio, a functional index of glutamate release, is reduced by MCPG in aged slices to a level comparable to that in young rats both under control conditions and after being enhanced by DL-TBOA. These results suggest that the age-associated glutamate uptake deficiency favors presynaptic mGluR activation that lowers glutamate release. In parallel, 2 Hz-induced long-term depression is significantly decreased in aged animals and is fully restored by MCPG. All these data indicate a facilitated activation of extrasynaptic NMDAR and mGluRs in aged rats, possibly because of an altered distribution of glutamate in the extrasynaptic space. This in turn affects synaptic transmission and plasticity within the aged hippocampal CA1 network. [source] Commonalities in the neurobiology between autism and fragile XJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008R. Hagerman There is a close association between autism and fragile X syndrome (FXS) with 30% of males with FXS having autism and 2 to 7% of children with autism having the fragile X mutation. The protein that is missing or deficient in FXS, FMRP, is an RNA binding and transport protein which regulates the translation of many messages important for synaptic plasticity. Typically FMRP inhibits the translation of these messages, such that protein production increases when FMRP is absent. Some of these proteins are known to also cause autism when they are mutated including neuroligin 3 and 4 and the SHANK protein. Therefore, when FMRP is missing there is dysregulation of other proteins that are known to cause autism. FMRP is an important inhibitor of protein production in the metabotropic glutamate receptor 5 pathway (mGluR5) which leads to long term depression (LTD) or the weakening of synaptic connections. Therefore, when FMRP is missing there is enhanced mGluR5 activity leading to enhanced LTD and weak or immature synaptic connections. The use of mGluR5 antagonists to reverse the LTD in the animal models of FXS has led to reversal of the learning, behaviour and dendritic spine abnormalities in these animals. There are now initial studies taking place in humans regarding the use of mGluR5 antagonists to improve behaviour and cognition in FXS. It is likely that these mGluR5 antagonists will also be helpful in a subgroup of patients with non fragile X autism who have similar problems with hyperactivity, hyperarousal and anxiety to those seen in FXS. A second cause of autism is the fragile X premutation but this mechanism of involvement is related to RNA toxicity which perhaps stimulates neuroimmune problems and may mimic other causes of autism. Neurons with the premutation are more vulnerable to environmental toxicity and oxidative stress leading to early cell death. [source] The PDZ domain protein CAL interacts with mGluR5a and modulates receptor expressionJOURNAL OF NEUROCHEMISTRY, Issue 3 2010Shan Cheng J. Neurochem. (2010) 112, 588,598. Abstract In this study, we investigated the association of metabotropic glutamate receptor subtype-5a (mGluR5a) with cystic fibrosis transmembrane conductance regulator-associated ligand (CAL). Using glutathione- S -transferase pull-down techniques, we found that mGluR5a directly interacted with CAL, with the C-terminus of the receptor binding to the PSD95/Discslarge/ZO-1 homology domain of CAL. The last four amino acids (S-S-S-L) of the C-terminus of the receptor were essential determinants for the interaction. Co-immunoprecipitation experiments and immunofluorescence assays revealed that full-length mGluR5a also associated with intact CAL in vivo, an observation consistent with the results from studies on fragment interactions in vitro. Functionally, upon co-expression with mGluR5a, CAL profoundly inhibited the ubiquitination of mGluR5a and enhanced receptor expression at the protein level but not at the mRNA level. These findings reveal that mGluR5a protein expression is physiologically regulated via its interaction with CAL. These results also suggest a molecular mechanism by which mGluR5a protein expression may be regulated at the post-translational level by the CAL protein, possibly by blocking ubiquitination-dependent receptor degradation. [source] NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the ratJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Chunlong Zhong Abstract Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N -acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI. [source] Loss of metabotropic glutamate receptor-mediated regulation of glutamate transport in chemically activated astrocytes in a rat model of amyotrophic lateral sclerosisJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Céline Vermeiren Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurones accompanied by intense gliosis in lesioned areas of the brain and spinal cord. Glutamate-mediated excitotoxicity resulting from impaired astroglial uptake constitutes one of the current pathophysiological hypotheses explaining the progression of the disease. In this study, we examined the regulation of glutamate transporters by type 5 metabotropic glutamate receptor (mGluR5) in activated astrocytes derived from transgenic rats carrying an ALS-related mutated human superoxide dismutase 1 (hSOD1G93A) transgene. Cells from transgenic animals and wild-type littermates showed similar expression of glutamate,aspartate transporter and glutamate transporter 1 (GLT-1) after in vitro activation, whereas cells carrying the hSOD1 mutation showed a three-fold higher expression of functional mGluR5, as observed in the spinal cord of end-stage animals. In cells from wild-type animals, (S)-3,5-dihydroxyphenylglycine (DHPG) caused an immediate protein kinase C (PKC)-dependent up-regulation of aspartate uptake that reflected the activation of GLT-1. Although this effect was mimicked in both cultures by direct activation of PKC using phorbol myristate acetate, DHPG failed to up-regulate aspartate uptake in cells derived from the transgenic rats. The failure of activated mGluR5 to increase glutamate uptake in astrocytes derived from this animal model of ALS supports the theory of glutamate excitotoxicity in the pathogenesis of the disease. [source] AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1)PIGMENT CELL & MELANOMA RESEARCH, Issue 1 2010Seung-Shick Shin Summary We reported earlier on the oncogenic properties of Grm1 by demonstrating that stable Grm1 -mouse-melanocytic clones proliferate in the absence of growth supplement and anchorage in vitro. In addition, these clones also exhibit aggressive tumorigenic phenotypes in vivo with short latency in tumor formation in both immunodeficient and syngeneic mice. We also detected strong activation of AKT in allograft tumors specifically AKT2 as the predominant isoform involved. In parallel, we assessed several human melanoma biopsy samples and found again that AKT2 was the predominantly activated AKT in these human melanoma biopsies. In cultured stable Grm1 -mouse-melanocytic clones, as well as an metabotropic glutamate receptor 1 (Grm1) expressing human melanoma cell line, C8161, stimulation of Grm1 by its agonist led to the activation of AKT, while preincubation with Grm1-antagonist abolished Grm1-agonist-induced AKT activation. In addition, a reduction in tumor volume of Grm1 -mouse-melanocytic-allografts was detected in the presence of small interfering AKT2 RNA (siAKT2). Taken together, these results showed that, in addition to the MAPK pathway previously reported being a downstream target of stimulated Grm1, AKT2 is another downstream target in Grm1 mediated melanocyte transformation. [source] Comparisons of structural and functional abnormalities in mouse b-wave mutantsTHE JOURNAL OF PHYSIOLOGY, Issue 18 2008Maureen A. McCall In the most simplistic view, the retinal circuit can be divided into vertical excitatory pathways that use glutamate as their neurotransmitter and lateral inhibitory pathways in the outer and inner synaptic layers that modulate excitation via glycine and GABA. Within the vertical excitatory pathways, the visual signal is initiated in the rod, cone or both photoreceptors, depending on the adaptation state of the retina. This signal is transmitted to the rest of the retina through the bipolar cells, which can be subdivided based on: the photoreceptor that provides their input, their dendritic and axonal morphology, and the polarity of their response evoked by a luminance increment, e.g. depolarizing or hyperpolarizing responses. The polarity of this response is controlled by the type of glutamatergic postsynaptic receptor that is expressed on their dendritic terminals. Hyperpolarizing bipolar cells express AMPA/kainate receptors, whereas depolarizing bipolar cells (DBCs) express the metabotropic glutamate receptor 6 (Grm6). The electroretinogram (ERG) is a non-invasive method used to assess overall retinal function. The initiation of the visual signal in the photoreceptors is reflected in the ERG a-wave and the ensuing depolarization of DBCs in the b-wave. When there is failure of signal transmission from photoreceptors to DBCs or signalling within DBCs, the ERG a-wave is present, while the b-wave is absent or significantly reduced. This ERG phenotype has been found in the human population and is referred to as congenital stationary night blindness. Until recently, it had been assumed that the absence of a b-wave was indicative of a lack of signalling through the On pathway, leaving the Off pathway unaffected. Here we review recent findings that demonstrate that many mouse mutants share a no b-wave ERG phenotype but their retinal morphology and RGC responses differ significantly, suggesting very different effects of the underlying mutations on output from the DBCs to the rest of the retinal circuit. [source] Developmental shift from long-term depression to long-term potentiation in the rat medial vestibular nuclei: role of group I metabotropic glutamate receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2003Julien Puyal The effects of high frequency stimulation (HFS) of the primary vestibular afferents on synaptic transmission in the ventral part of the medial vestibular nuclei (vMVN) were studied during postnatal development and compared with the changes in the expression of the group I metabotropic glutamate receptor (mGluR) subtypes, mGluR1 and mGluR5. During the first stages of development, HFS always induced a mGluR5- and GABAA -dependent long-term depression (LTD) which did not require NMDA receptor and mGluR1 activation. The probability of inducing LTD decreased progressively throughout the development and it was zero at about the end of the second postnatal week. Conversely, long-term potentiation (LTP) appeared at the beginning of the second week and its occurrence increased to reach the adult value at the end of the third week. Of interest, the sudden change in the LTP frequency occurred at the time of eye opening, about the end of the second postnatal week. LTP depended on NMDA receptor and mGluR1 activation. In parallel with the modifications in synaptic plasticity, we observed that the expression patterns and localizations of mGluR5 and mGluR1 in the medial vestibular nuclei (MVN) changed during postnatal development. At the earlier stages the mGluR1 expression was minimal, then increased progressively. In contrast, mGluR5 expression was initially high, then decreased. While mGluR1 was exclusively localized in neuronal compartments and concentrated at the postsynaptic sites at all stages observed, mGluR5 was found mainly in neuronal compartments at immature stages, then preferentially in glial compartments at mature stages. These results provide the first evidence for a progressive change from LTD to LTP accompanied by a distinct maturation expression of mGluR1 and mGluR5 during the development of the MVN. [source] Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents,ANNALS OF NEUROLOGY, Issue 1 2009Kimberly R. Byrnes PhD Objective Activation of metabotropic glutamate receptor 5 (mGluR5) has neuroprotective properties in vitro and has been reported to limit postischemic lesion volume in vivo. Previously, mGluR5 has been identified on microglia in vitro, but the effects of mGluR5 activation on inflammation in vivo or on recovery after spinal cord injury is unknown. Methods Rats received intrathecal infusion of the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) for 7 days after moderate impact spinal cord injury at T9. Complementary studies examined CHPG effects on activated spinal microglia cultures. Results Functional motor recovery was significantly increased by CHPG treatment up to 28 days after injury, with improvements in weight bearing, step taking, and coordination of stepping behavior. CHPG treatment significantly reduced lesion volume and increased white matter sparing at 28 days after injury. Administration of CHPG attenuated microglial-associated inflammatory responses in a dose-dependent fashion, including expression of ED1, Iba-1, Galectin-3, NADPH oxidase components, tumor necrosis factor-,, and inducible nitric oxide synthase. Because mGluR5 is expressed by microglial cells in the rat spinal cord, such effects may be mediated by direct action on microglial cells. mGluR5 stimulation also reduced microglial activation and decreased microglial-induced neurotoxicity in spinal cord microglia cultures; the latter effects were blocked by the selective mGluR5 antagonist MTEP. Interpretation These data demonstrate that mGluR5 activation can reduce microglial-associated inflammation, suggesting that the protective effects of mGluR5 agonists may reflect this action. Ann Neurol 2009;66:63,74 [source] TRPM1: The endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cellsBIOESSAYS, Issue 7 2010Catherine W. Morgans Abstract For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders. [source] Site-specific unglycosylation to improve crystallization of the metabotropic glutamate receptor 3 extracellular domainACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2009Takanori Muto Metabotropic glutamate receptors (mGluRs) are involved in the regulation of many physiological and pathological processes in the central nervous system. The extracellular domain (ECD) of mGluR subtype 3 (mGluR3) was produced using the baculovirus expression system and purified from the culture medium. However, the recombinant protein showed heterogeneity in molecular weight on SDS,PAGE analysis. It was found that the unglycosylation of Asn414 significantly reduced the heterogeneity. Consequently, three site-specifically unglycosylated mutant proteins of mGluR3 ECD, replacing Asn414 only or replacing Asn414 in combination with other glycosylation sites, were successfully crystallized in the presence of l -glutamate. Among them, crystals of the N414/439Q mutant diffracted X-rays to 2.35,Å resolution using synchrotron radiation. The crystal belonged to the monoclinic space group P21, with unit-cell parameters a = 84.0, b = 97.5, c = 108.1,Å, , = 93.0°. Assuming the presence of two protomers per crystallographic asymmetric unit, the Matthews coefficient VM was calculated to be 3.5,Å3,Da,1 and the solvent content was 65%. [source] Expression, purification, crystallization and preliminary X-ray analysis of the ligand-binding domain of metabotropic glutamate receptor 7ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2007Takanori Muto Glutamate is the major excitatory neurotransmitter and its metabotropic glutamate receptor (mGluR) plays an important role in the central nervous system. The ligand-binding domain (LBD) of mGluR subtype 7 (mGluR7) was produced using the baculovirus expression system and purified from the culture medium. The purified protein was characterized by gel-filtration chromatography, SDS,PAGE and a ligand-binding assay. Crystals of mGluR7 LBD were grown at 293,K by the hanging-drop vapour-diffusion method. The crystals diffracted X-rays to 3.30,Å resolution using synchrotron radiation and belong to the trigonal space group P3121, with unit-cell parameters a = b = 92.4, c = 114.3,Å. Assuming the presence of one protomer per crystallographic asymmetric unit, the Matthews coefficient VM was calculated to be 2.5,Å3,Da,1 and the solvent content was 51%. [source] Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomesBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2000T Shinomura 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 [3H]-arachidonic acid or [32P]-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. British Journal of Pharmacology (2000) 131, 1011,1018; doi:10.1038/sj.bjp.0703651 [source] New Allosteric Modulators of Metabotropic Glutamate Receptor 5 (mGluR5) Found by Ligand-Based Virtual ScreeningCHEMBIOCHEM, Issue 4 2005Steffen Renner Ligand-based pharmacophore searching identified new allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), a class III G protein-coupled receptor. This virtual-screening approach can be seen as a working alternative to more demanding structure-based design techniques with the main aim of developing novel lead series. [source] | ||||||||||||||||||||||||||||