Metabotropic glutamate receptor 3

Protein GRM3 PDB 2e4u.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesGRM3, GLUR3, GPRC1C, MGLUR3, mGlu3, glutamate metabotropic receptor 3
External IDsOMIM: 601115 MGI: 1351340 HomoloGene: 651 GeneCards: GRM3
Gene location (Human)
Chromosome 7 (human)
Chr.Chromosome 7 (human)[1]
Chromosome 7 (human)
Genomic location for GRM3
Genomic location for GRM3
Band7q21.11-q21.12Start86,643,914 bp[1]
End86,864,884 bp[1]
RNA expression pattern
PBB GE GRM3 205814 at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 7: 86.64 – 86.86 Mbn/a
PubMed search[2][3]
View/Edit HumanView/Edit Mouse

Metabotropic glutamate receptor 3 (mGluR3) is a protein that, in humans, is encoded by the GRM3 gene.[4][5]


In humans, mGluR3 is encoded by the GRM3 gene on chromosome 7. At least five protein-coding isoforms are predicted based on genomic information. The mGluR3 protein is a seven-pass transmembrane protein.


L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.[5]

Clinical significance[edit]

The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with a range of psychiatric disorders, including bipolar affective disorder[6] as well as schizophrenia.[7]

A mutation in the Kozak sequence in the 1st exon of the GRM3 gene was shown to change translation and transcription of cloned GRM3 gene constructs and was significantly associated with bipolar disorder with an odds ratio of 4.4.[6] Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p<10−9.[8] A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism.[9] The mGluR3 receptor encoded by GRM3 is targetable by several drugs that have been used in previous trials of schizophrenia and anxiety disorder. The agonist, antagonist and allosteric modulator drugs of mGluR3 can now be explored as new treatments for mental illness.[6] Other scientific evidence has been published which shows that the well established anti-manic drug lithium carbonate also changes GRM3 gene expression in the mouse brain after treatment with lithium carbonate.[10]


mGluR3 modulators that are significantly selective over the isoform mGluR2 are known since 2013.


  • with a bicyclo[3.1.0]hexane skeleton
  • (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid[17]



Allosteric modulators[edit]

  • D3-ML337: selective NAM, IC50 = 450 nM for mGluR3, IC50 >30μM for mGluR2[21]
  • MNI-137:[22] inhibitor
  • VU-0650786: NAM[23]
  • compound 7p:[24] non-competitive antagonist (presumably allosteric inhibitor)


Metabotropic glutamate receptor 3 has been shown to interact with:

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198822 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (Mar 1997). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q". Genomics. 31 (2): 230–3. doi:10.1006/geno.1996.0036. PMID 8824806.
  5. ^ a b "Entrez Gene: GRM3 glutamate receptor, metabotropic 3".
  6. ^ a b c Kandaswamy R, McQuillin A, Sharp SI, Fiorentino A, Anjorin A, Blizard RA, Curtis D, Gurling HM (2013). "Genetic association, mutation screening, and functional analysis of a Kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder". JAMA Psychiatry. 70 (6): 591–8. doi:10.1001/jamapsychiatry.2013.38. PMID 23575746.
  7. ^ Fromer, Menachem; Pocklington, Andrew J.; Kavanagh, David H.; Williams, Hywel J.; Dwyer, Sarah; Gormley, Padhraig; Georgieva, Lyudmila; Rees, Elliott; Palta, Priit; Ruderfer, Douglas M.; Carrera, Noa (2014-02-13). "De novo mutations in schizophrenia implicate synaptic networks". Nature. 506 (7487): 179–184. doi:10.1038/nature12929. ISSN 1476-4687. PMC 4237002. PMID 24463507.
  8. ^ Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). "Biological insights from 108 schizophrenia-associated genetic loci". Nature. 511 (7510): 421–7. doi:10.1038/nature13595. PMC 4112379. PMID 25056061.
  9. ^ O'Brien NL, Way MJ, Kandaswamy R, Fiorentino A, Sharp SI, Quadri G, Alex J, Anjorin A, Ball D, Cherian R, Dar K, Gormez A, Guerrini I, Heydtmann M, Hillman A, Lankappa S, Lydall G, O'Kane A, Patel S, Quested D, Smith I, Thomson AD, Bass NJ, Morgan MY, Curtis D, McQuillin A (2014). "The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder". Psychiatr. Genet. 24 (6): 277–278. doi:10.1097/YPG.0000000000000050. PMC 4272221. PMID 25046171.
  10. ^ McQuillin A, Rizig M, Gurling HM (2007). "A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder". Pharmacogenet. Genomics. 17 (8): 605–17. doi:10.1097/FPC.0b013e328011b5b2. PMID 17622937.
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  14. ^ Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD (1997). "Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties". Journal of Medicinal Chemistry. 40 (4): 528–37. doi:10.1021/jm9606756. PMID 9046344.
  15. ^ Dominguez C, Prieto L, Valli MJ, Massey SM, Bures M, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD, Monn JA (2005). "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". Journal of Medicinal Chemistry. 48 (10): 3605–12. doi:10.1021/jm040222y. PMID 15887967.
  16. ^ Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, Hao J (March 2018). "Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3Receptor Agonist". J. Med. Chem. 61 (6): 2303–2328. doi:10.1021/acs.jmedchem.7b01481. PMID 29350927.
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  18. ^ Sakagami K, Yasuhara A, Chaki S, Yoshikawa R, Kawakita Y, Saito A, Taguchi T, Nakazato A (2008). "Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist". Bioorg. Med. Chem. 16 (8): 4359–66. doi:10.1016/j.bmc.2008.02.066. PMID 18348906.
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Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.