Disease relevance of Grm1

• These findings indicate that status epilepticus affects mGluR expression in a gene- and cell-specific manner, and that these changes vary with the developmental stage [1].
• Using in situ hybridization, we measured the levels of mGluR1-mGluR5 mRNA in regions of the rat brain 24 h after transient global ischemia, a time point when no neuronal damage can yet be observed morphologically [2].
• These findings may be of significance in treatment of cognitive deficits associated with neurodegenerative disorders as a group I mGluR-mediated activation of septohippocampal cholinergic neurons would enhance the release of acetylcholine both in the hippocampus and in the septum [3].
• In the ganglion cell layer, virtually every ganglion cell and displaced amacrine cell was labelled for mGluR1 and mGluR4 [4].
• The metabotropic glutamate receptor (mGluR) antagonist, alpha-methyl-4-carboxyphenylglycine (MCPG) was administered into the left lateral ventricle 5 min prior to fluid percussion traumatic brain injury (TBI) in the rat [5].

Psychiatry related information on Grm1

• This hypothesis was supported by the evidence that mGlu-receptor stimulated PI hydrolysis was amplified in hippocampal slices from rats subjected to a passive avoidance learning paradigm, and that this amplification was greater in slices from corticosterone-nursed rats of both sexes [6].
• These results demonstrate that treatment with agonists to group II and III mGluRs following SCI affects mechanical responses, exploratory behavior, and mGluR2/3 expression without affecting the amount of tissue spared, suggesting that the level of mGluR expression after SCI may modulate nociceptive responses [7].
• Therefore, the central application of group I mGluR antagonists or groups II and III mGluR agonists might be of therapeutic value in treating pain disorder [8].
• The finding that the NMDA receptor-PAF-MAP kinase signaling pathway is attenuated by mGluR activation highlights the exquisite interplay between glutamate receptors in the decision making process between neuronal survival and death [9].
• Furthermore, the critical period during which the high sensitivity to agonist-induced desensitization of mGluR developed coincided with the period when phorbol ester-activated protein kinase C acquired the ability to suppress mGluR activity [10].

High impact information on Grm1

• This transmission involves a G protein-coupled metabotropic glutamate receptor (mGluR) [11].
• Immunocytochemical and immunoelectron microscopic studies indicate that restricted localization of a specific mGluR subtype, mGluR6, at the postsynaptic site of the rat rod bipolar cell [11].
• Here we show that agonists of the metabotropic glutamate receptor (mGluR) activate dendritic terminals of interneurons in the absence of action potentials, thereby inhibiting the postsynaptic relay neuron [12].
• In ventral midbrain dopamine neurons, activation of metabotropic glutamate receptors (mGluR1) mobilized calcium from caffeine/ryanodine-sensitive stores and increased an apamin-sensitive potassium conductance [13].
• The rapid rise and brief duration of synaptically released glutamate in the extracellular space can therefore mediate a rapid excitation through activation of ionotropic receptors, followed by inhibition through the mGluR1 receptor [13].

Chemical compound and disease context of Grm1

• The enhanced stimulation of phosphoinositide hydrolysis showed little sensitivity to pertussis toxin, and appeared to be selective to mGluR agonists, as there was not a similar increase in the ability of norepinephrine or carbachol to stimulate phosphoinositide hydrolysis [14].
• A1 receptor modulation of mGluR-induced Ca2+ elevations is blocked by pertussis toxin and is mimicked by the wasp venom peptide mastoparan, suggesting that potentiation occurs by means of a G(i/o) mechanism [15].
• We conclude that activation of the mGluR4 receptor protects hippocampal neurons from NO toxicity and that the mechanism of NO induced neurodegeneration does not appear to involve inhibition of the mGluR1 receptor subtype activity or the phosphoinositide system [16].
• Activation of the two types of K(+) channel currents by mGluR agonists was attenuated by pertussis toxin and by inhibition of phospholipase C (PLC) or cytochrome P450 arachidonate epoxygenase [17].
• Within the basal ganglia, receptors of group I (mGluR1 and mGluR5) are widely expressed; the present study was thus aimed at blocking these receptors in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease in the rat [18].

Biological context of Grm1

• However, some studies suggest that other mGluR subtypes may also be involved in regulation of excitatory and inhibitory synaptic transmission in area CA1 [19].
• The metabotropic glutamate receptors are coupled to intracellular signal transduction via G-proteins and consist of a family of at least five different subtypes, termed mGluR1-mGluR5 [20].
• Of the eight subtypes cloned to date, mGluR1 and mGluR5 are coupled to phosphoinositide hydrolysis in expression systems, and both are activated by the glutamate analogue 1-aminocyclopentane-1S,3R-dicarboxylic acid [21].
• To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles [22].
• The differential regulation of mGluR subtypes may be part of an adaptive cell program that helps to rescue adult motoneurons from excitotoxic cell death during the stress induced by peripheral denervation [23].

Anatomical context of Grm1

• In the present study we used in situ hybridization to examine possible changes in mGluR expression at the level of the hippocampus after status epilepticus in postnatal day 10 (P10) pup and adult (P40) rats [1].
• Distinct cellular distributions of mGluR expression were also observed within the nucleus accumbens, globus pallidus, ventral pallidum, and substantia nigra pars reticulata [24].
• MGluR1 was the only mGluR message prominently expressed in the dopaminergic neurons of the substantia nigra pars compacta, suggesting the involvement of this receptor in the regulation of dopamine release from nigrostriatal terminals [24].
• In order to elucidate the function of these receptors in the biology of the extrapyramidal motor system, we have used in situ hybridization to examine the regional and cellular expression patterns of mGluR1-mGluR5 in the adult rat basal ganglia [24].
• Thus, postsynaptic mGluR1 and mGluR5 in hippocampal interneurons cooperatively mediate slow feedback inhibition of CA3 pyramidal cells [25].

Associations of Grm1 with chemical compounds

• Site-directed mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators [26].
• In addition, the facilitation of nociceptive responses induced by (1S,3S)-ACPD or (RS)-DHPG was reduced by prior i.t. administration of the mGluR antagonists, (+)-MCPG or (S)-4C3HPG, respectively, as well as by the N-Methyl-D-aspartate (NMDA) receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) [27].
• Bath application of the non-selective mGluR agonist (1 S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1 S,3R-ACPD) or the group-I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) depolarized all cholinergic neurones tested by activation of an inward current at -60 mV [28].
• These results indicate that although mGluRs may play a minor role in formalin-induced nociception, mGluR agonist-related facilitation of formalin scores may reflect an interaction with the NMDA receptor [27].
• Under control conditions, blocking G protein activation using intracellular GDPbetaS with or without N-(2, 6-dimethylphenylcarbamoylmethyl) triethylammonium chloride (QX-314) prevented mGluR-mediated activation of the TRP-like conductance [29].

Physical interactions of Grm1

• [(3)H]Quisqualic acid binding to mGluR1 required the presence of calcium (or magnesium) ions but not sodium or chloride ions while [(3)H]DCG-IV binding to mGluR3 was dependent upon both cations and anions [30].
• We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF) [31].

Regulatory relationships of Grm1

• Finally, we found that the novel mGluR antagonist LY341495 completely blocked the activation of mGluR1 and mGluR5 and blocked the phosphoinositide hydrolysis response to DHPG in rat cortical slices [21].
• Using confocal imaging, Homer-induced mGluR clusters were observed intra-cellularly as well as on the plasma membrane [32].
• Recent evidence has shown that the Galphaq-protein-coupled metabotropic glutamate receptor (mGluR) 5 up-regulates phosphorylation of MAPK/ERK1/2 [33].
• Coactivation of mGluR1/5 and DR1/5 with (S)-3,5-dihydroxyphenylglycine and (+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride enhanced the phosphorylation of ERK2 [34].
• Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms [35].

Other interactions of Grm1

• Status epilepticus did not alter expression of mGluR1, mGluR3, or mGluR5 mRNAs [1].
• Double-labeling with probes for mGluR1 and mGluR7 revealed that individual mitral/tufted neurons in the olfactory bulb expressed both mRNAs [36].
• In recombinant systems, BINA produced a robust and selective potentiation of the response of mGluR2 to glutamate with no effect on the glutamate response of other mGluR subtypes [37].
• Group I metabotropic glutamate receptors (mGluR1 and 5) couple to intracellular calcium pools by a family of proteins, termed Homer, that cross-link the receptor to inositol trisphosphate receptors. mGluRs also couple to membrane ion channels via G-proteins [38].
• High expression of mGluR1 mRNA mainly occurred in midline nuclei such as the centromedial/centrolateral (CM/CL) nuclei, parafascicular and submedius nuclei, and in the ventroposteromedial (VPM) and posterior (Po) nuclei [39].

Analytical, diagnostic and therapeutic context of Grm1

• To functionally characterize this difference, in vivo microdialysis was used to verify differences in mGluR regulation of extracellular glutamate in the PFC [40].
• In the present study, the effect of rearing conditions on the expression of mGluR proteins in the prefrontal cortex (PFC) was assessed by immunoblotting [40].
• Using a reverse transcriptase-polymerase chain reaction technique with primers specifically recognizing each cloned mGluR subtype, we found that rat adult spinal cord specifically expresses high levels of mRNA encoding mGluR1a but not mGluR1b [41].
• The mGluR1 mRNA signal was reduced to 49.6+/-6.9% as compared to the contralateral side 2 weeks after axotomy and 31.2+/-8.3% after 4 weeks [23].
• In order to determine whether such a distribution is uniform amongst postsynaptic mGluRs, their distribution was compared quantitatively by a pre-embedding silver-intensified immunogold technique at electron microscopic level in hippocampal pyramidal cells (mGluR5), cerebellar Purkinje cells (mGluR1 alpha) and Golgi cells (mGluR2) [42].

References