Disease relevance of GRM3

• Using a reporter gene assay, now we describe the functional activity of GRM3 promoter by transient transfection in both human neuroblastoma and astroglioma cell lines [1].
• Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins [2].
• Up-regulation of Metabotropic glutamate receptor 3 (mGluR3) in rat fibrosis and cirrhosis model of persistent hypoxic condition [3].

Psychiatry related information on GRM3

• Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population [4].

High impact information on GRM3

• These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia [5].
• In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate [5].
• Resequencing revealed no missense or splice-site SNPs, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription [5].
• However, phosphorylation of the mGluR3 cytoplasmic tail at Ser-845 inhibits the interaction with PP2C [6].
• Moreover, its pharmacology and transduction mechanisms are surprisingly similar to those of mGluR2 and mGluR3 [7].

Biological context of GRM3

• In a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001) [5].
• The existence of the GRM3Delta4 isoform is relevant in the light of the reported association of non-coding single nucleotide polymorphisms (SNPs) in GRM3 with schizophrenia, and with the potential of GRM3 as a therapeutic target for several neuropsychiatric disorders [8].
• Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q [9].
• In the present study, we sought to identify genetic variation in the metabotropic glutamate receptor 3 (GRM3) gene, which has been mapped to chromosome 7q21.1-q21.2 [Scherer et al., 1996] and might contribute to genetic predisposition to schizophrenia and/or bipolar affective disorder [4].
• Identification and characterization of the promoter region of the GRM3 gene [1].

Anatomical context of GRM3

• In this study, we have mapped GRM3 and GRM8 to human chromosome 7q21.1-q21.2 and 7q31.3-q32.1, respectively, using somatic cell hybrid and fluorescence in situ hybridization analysis [9].
• [3H]-LY341495 bound to membranes expressing human mGlu2 and mGlu3 receptors in a reversible and saturable manner with relatively high affinities (Bmax 20.5 +/- 5.4 and 32.0 +/- 7.0 pmol/mg protein; and K(D) = 1.67 +/- 0.20 and 0.75 +/- 0.43 nM, respectively) [10].
• The mRNAs for mGluR1, 4 and 5 were observed in the spinal gray matter, whereas mGluR2 mRNA was absent in the spinal cord and mGluR3 mRNA was displayed only on glial cells in the white matter [11].
• The newly identified mGluR3 and mGluR5a may be involved in the differentiation of oligodendrocytes, myelination and the development of white matter damage [12].
• The capacity of mGluR3 to modulate the release of IL-6 in the presence of IL-1beta supports the possible involvement of this receptor subtype in the regulation of the inflammatory and immune response under pathological conditions associated with glial cell activation [13].
• Immunohistochemical studies show that the mGluR3 protein is localized to the zona glomerulosa of the human adrenal cortex[14].

Associations of GRM3 with chemical compounds

• Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia [5].
• In functional assays, we previously described LY341495 as a highly potent and selective mGlu2 and mGlu3 receptor antagonist [10].
• 1S,3R-ACPD differs from 3,5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negatively linked to cAMP formation [15].
• LY354740 was six-fold less potent in activating human mGlu3 receptors (EC50 = 24.3 +/- 0.5 nM) [16].
• [(3)H]-1 bound appreciably to recombinant human mGlu2, mGlu3 and mGlu8 receptors and to rat forebrain membranes and was displaced by L-glutamate and L-(+)-2 amino-4-phosphonobutyric acid [17].

Regulatory relationships of GRM3

• Each of these racemic methyl-substituted analogues displaced specific binding of the mGlu2/3 receptor antagonist (3)H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid ((3)H-LY341495) from membranes expressing mGlu2 or mGlu3 receptor subtypes [18].
• Endophilins A1 and A3, as well as mGluR3 activated APP shedding relatively specifically [19].

Other interactions of GRM3

• Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce glutamate release are anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268) [20].
• Thus, mGluR3 and mGluR5 can critically and differentially modulate the expression of glutamate transporters and may represent interesting pharmacological targets to regulate the extracellular levels of glutamate in pathological conditions [2].
• We sequenced between 1865 (mGluR8a) and 3697 (mGluR1) total nucleotides for each macaque gene and obtained complete coding sequences for GluR1-7, mGluR3 and mGluR4 [21].
• Preliminary evidence with potential susceptilibity genes such as COMT, DISC1, and GRM3 support these assumptions [22].
• The mGluR2/3 agonist LY354740 (also known as Eglumegad) has been shown to interfere in the hypothalamus-pituitary-adrenal axis, with chronic oral administration of the drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata), and effect confirmed in human adrenocortical cells in vitro [23] [14].

Analytical, diagnostic and therapeutic context of GRM3

• Our RT-PCR analysis detected mRNAs for mGluR3 and mGluR5 isoforms in OPCs [12].
• LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety, including the elevated plus maze (EPM) test [24].
• A specific probe from the human mGluR3 clone was used to hybridise to Northern blots of mRNA from various human tissues and different brain regions [25].
• Reverse transcription followed by multiplex PCR analysis showed that the GPCs expressed both mGluR3 and mGluR5a mRNAs [26].
• The mouse mGluR3 gene was then mapped by fluorescent in situ hybridization analysis to chromosome 5qA2 [27].

References