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Gene Review

GRM3  -  glutamate receptor, metabotropic 3

Homo sapiens

Synonyms: GLUR3, GPRC1C, MGLUR3, Metabotropic glutamate receptor 3, mGlu3, ...
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Disease relevance of GRM3


Psychiatry related information on GRM3


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


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


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


  1. Identification and characterization of the promoter region of the GRM3 gene. Corti, C., Xuereb, J.H., Corsi, M., Ferraguti, F. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  2. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Aronica, E., Gorter, J.A., Ijlst-Keizers, H., Rozemuller, A.J., Yankaya, B., Leenstra, S., Troost, D. Eur. J. Neurosci. (2003) [Pubmed]
  3. Up-regulation of Metabotropic glutamate receptor 3 (mGluR3) in rat fibrosis and cirrhosis model of persistent hypoxic condition. Do, S.H., Yun, H.S., Jeong, W.I., Jeong, D.H., Ki, M.R., Chung, J.Y., Park, S.J., Kim, S.B., Jeong, K.S. Mol. Cell. Biochem. (2007) [Pubmed]
  4. Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Martí, S.B., Cichon, S., Propping, P., Nöthen, M. Am. J. Med. Genet. (2002) [Pubmed]
  5. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Egan, M.F., Straub, R.E., Goldberg, T.E., Yakub, I., Callicott, J.H., Hariri, A.R., Mattay, V.S., Bertolino, A., Hyde, T.M., Shannon-Weickert, C., Akil, M., Crook, J., Vakkalanka, R.K., Balkissoon, R., Gibbs, R.A., Kleinman, J.E., Weinberger, D.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3. Flajolet, M., Rakhilin, S., Wang, H., Starkova, N., Nuangchamnong, N., Nairn, A.C., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Cloning and functional expression of a Drosophila metabotropic glutamate receptor expressed in the embryonic CNS. Parmentier, M.L., Pin, J.P., Bockaert, J., Grau, Y. J. Neurosci. (1996) [Pubmed]
  8. Alternative splicing of human metabotropic glutamate receptor 3. Sartorius, L.J., Nagappan, G., Lipska, B.K., Lu, B., Sei, Y., Ren-Patterson, R., Li, Z., Weinberger, D.R., Harrison, P.J. J. Neurochem. (2006) [Pubmed]
  9. Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q. Scherer, S.W., Duvoisin, R.M., Kuhn, R., Heng, H.H., Belloni, E., Tsui, L.C. Genomics (1996) [Pubmed]
  10. [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Johnson, B.G., Wright, R.A., Arnold, M.B., Wheeler, W.J., Ornstein, P.L., Schoepp, D.D. Neuropharmacology (1999) [Pubmed]
  11. Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis. Tomiyama, M., Kimura, T., Maeda, T., Tanaka, H., Furusawa, K., Kurahashi, K., Matsunaga, M. J. Neurol. Sci. (2001) [Pubmed]
  12. Functional metabotropic glutamate receptors are expressed in oligodendrocyte progenitor cells. Luyt, K., Varadi, A., Molnar, E. J. Neurochem. (2003) [Pubmed]
  13. Activation of metabotropic glutamate receptor 3 enhances interleukin (IL)-1beta-stimulated release of IL-6 in cultured human astrocytes. Aronica, E., Gorter, J.A., Rozemuller, A.J., Yankaya, B., Troost, D. Neuroscience (2005) [Pubmed]
  14. Glutamate receptors and the regulation of steroidogenesis in the human adrenal gland: the metabotropic pathway. Felizola, S.J., Nakamura, Y., Satoh, F., Morimoto, R., Kikuchi, K., Nakamura, T., Hozawa, A., Wang, L., Onodera, Y., Ise, K., McNamara, K.M., Midorikawa, S., Suzuki, S., Sasano, H. Mol. Cell. Endocrinol. (2014) [Pubmed]
  15. The novel metabotropic glutamate receptor agonist 2R,4R-APDC potentiates stimulation of phosphoinositide hydrolysis in the rat hippocampus by 3,5-dihydroxyphenylglycine: evidence for a synergistic interaction between group 1 and group 2 receptors. Schoepp, D.D., Salhoff, C.R., Wright, R.A., Johnson, B.G., Burnett, J.P., Mayne, N.G., Belagaje, R., Wu, S., Monn, J.A. Neuropharmacology (1996) [Pubmed]
  16. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Schoepp, D.D., Johnson, B.G., Wright, R.A., Salhoff, C.R., Mayne, N.G., Wu, S., Cockerman, S.L., Burnett, J.P., Belegaje, R., Bleakman, D., Monn, J.A. Neuropharmacology (1997) [Pubmed]
  17. (2S,1'S,2'R,3'R)-2(2'-Carboxy-3'-hydroxymethylcyclopropyl)glycine-[3H], a potent and selective radioligand for labeling group 2 and 3 metabotropic glutamate receptors. Wheeler, W.J., Clodfelter, D.K., Collado, I., Kulanthaivel, P., Pedregal, C., Stoddard, E.A., Wright, R.A., Schoepp, D.D. Bioorg. Med. Chem. Lett. (2005) [Pubmed]
  18. Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist. Dominguez, C., Prieto, L., Valli, M.J., Massey, S.M., Bures, M., Wright, R.A., Johnson, B.G., Andis, S.L., Kingston, A., Schoepp, D.D., Monn, J.A. J. Med. Chem. (2005) [Pubmed]
  19. Expression cloning screen for modifiers of amyloid precursor protein shedding. Schöbel, S., Neumann, S., Seed, B., Lichtenthaler, S.F. Int. J. Dev. Neurosci. (2006) [Pubmed]
  20. Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Moldrich, R.X., Chapman, A.G., De Sarro, G., Meldrum, B.S. Eur. J. Pharmacol. (2003) [Pubmed]
  21. Expression and sequences of genes encoding glutamate receptors and transporters in primate retina determined using 3'-end amplification polymerase chain reaction. Hanna, M.C., Calkins, D.J. Mol. Vis. (2006) [Pubmed]
  22. Imaging genomics and response to treatment with antipsychotics in schizophrenia. Blasi, G., Bertolino, A. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics. (2006) [Pubmed]
  23. Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function. Coplan, J.D., Mathew, S.J., Smith, E.L., Trost, R.C., Scharf, B.A., Martinez, J., Gorman, J.M., Monn, J.A., Schoepp, D.D., Rosenblum, L.A. CNS. Spectr. (2001) [Pubmed]
  24. Anxiolytic activity of the MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions. Linden, A.M., Greene, S.J., Bergeron, M., Schoepp, D.D. Neuropsychopharmacology (2004) [Pubmed]
  25. Molecular characterization and localization of human metabotropic glutamate receptor type 3. Makoff, A., Volpe, F., Lelchuk, R., Harrington, K., Emson, P. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  26. Metabotropic glutamate receptors are expressed in adult human glial progenitor cells. Luyt, K., Varadi, A., Halfpenny, C.A., Scolding, N.J., Molnar, E. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  27. Genomic organization of the human metabotropic glutamate receptor subtype 3. Corti, C., Sala, C.F., Yang, F., Corsi, M., Xuereb, J.H., Ferraguti, F. J. Neurogenet. (2000) [Pubmed]
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