Metabotropic glutamate receptor 3

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Glutamate receptor, metabotropic 3
Protein GRM3 PDB 2e4u.png
PDB rendering based on 2e4u.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols GRM3 ; GLUR3; GPRC1C; MGLUR3; mGlu3
External IDs OMIM601115 MGI1351340 HomoloGene651 IUPHAR: mGlu3 ChEMBL: 2888 GeneCards: GRM3 Gene
RNA expression pattern
PBB GE GRM3 205814 at tn.png
More reference expression data
Species Human Mouse
Entrez 2913 108069
Ensembl ENSG00000198822 ENSMUSG00000003974
UniProt Q14832 Q9QYS2
RefSeq (mRNA) NM_000840 NM_181850
RefSeq (protein) NP_000831 NP_862898
Location (UCSC) Chr 7:
86.27 – 86.49 Mb
Chr 5:
9.49 – 9.73 Mb
PubMed search [1] [2]

Metabotropic glutamate receptor 3 is a protein that in humans is encoded by the GRM3 gene.[1][2]

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.[2] The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with bipolar affective disorder.[3] 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.[4] The GRM3 gene is a likely cause of genetic susceptibility to a genetic sub type of bipolar affective disorder. Because 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 of mania and depression. This might become the first example of personalised medicine based on genetics for psychiatric disorders ( 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 [5]


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[11]


Allosteric modulators[edit]

  • ML337: selective NAM, IC50 = 593 nM for mGluR3, IC50 >30μM for mGluR2[15]
  • MNI-137:[16] inhibitior
  • compound 7p:[17] non-competitive antagonist (presumably allosteric inhibitor)


Metabotropic glutamate receptor 3 has been shown to interact with GRIP1,[18] PICK1[18] and PPM1A.[19]

See also[edit]


  1. ^ 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. 
  2. ^ a b "Entrez Gene: GRM3 glutamate receptor, metabotropic 3". 
  3. ^ Kandaswamy, R. et al. Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder. JAMA psychiatry, 1-8, doi:10.1001/jamapsychiatry.2013.38 (2013).
  4. ^ 1 Kandaswamy, R. et al. Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder. JAMA psychiatry, 1-8, doi:10.1001/jamapsychiatry.2013.38 (2013).
  5. ^ 1 McQuillin, A., Rizig, M. & Gurling, H. M. 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. Pharmacogenetics and genomics 17, 605-617, doi:10.1097/FPC.0b013e328011b5b2 (2007).
  6. ^ Nakazato A, Kumagai T, Sakagami K, et al. (2000). "Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists". Journal of Medicinal Chemistry 43 (25): 4893–909. doi:10.1021/jm000346k. PMID 11123999. 
  7. ^ Monn JA, Massey SM, Valli MJ, et al. (2007). "Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors". Journal of Medicinal Chemistry 50 (2): 233–40. doi:10.1021/jm060917u. PMID 17228865. 
  8. ^ Monn JA, Valli MJ, Massey SM, et al. (1999). "Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors". Journal of Medicinal Chemistry 42 (6): 1027–40. doi:10.1021/jm980616n. PMID 10090786. 
  9. ^ Monn JA, Valli MJ, Massey SM, et al. (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. 
  10. ^ Dominguez C, Prieto L, Valli MJ, et al. (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. 
  11. ^ Clausen RP, Bräuner-Osborne H, Greenwood JR, et al. (2002). "Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid". Journal of Medicinal Chemistry 45 (19): 4240–5. doi:10.1021/jm020122x. PMID 12213064. 
  12. ^ Sakagami K, Yasuhara A, Chaki S, et al. (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. 
  13. ^ a) Nakazato A, Sakagami K, Yasuhara A, et al. (2004). "Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists". Journal of Medicinal Chemistry 47 (18): 4570–87. doi:10.1021/jm0400294. PMID 15317467. ,
    b) Yasuhara A, Nakamura M, Sakagami K, et al. (2006). "Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential". Bioorg. Med. Chem. 14 (12): 4193–207. doi:10.1016/j.bmc.2006.01.060. PMID 16487713. ,
    c) Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A (2006). "Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists". Bioorg. Med. Chem. 14 (10): 3405–20. doi:10.1016/j.bmc.2005.12.061. PMID 16431115. 
  14. ^ Woltering TJ, Adam G, Huguenin P, et al. (2008). "Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA". ChemMedChem 3 (2): 323–35. doi:10.1002/cmdc.200700226. PMID 18058780. 
  15. ^ Wenthur CJ, Morrison R, Felts AS, et al. (2013). "Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)". J. Med. Chem. 56 (12): 5208–12. doi:10.1021/jm400439t. PMID 23718281. 
  16. ^ Hemstapat K, Da Costa H, Nong Y, et al. (2007). "A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors". J. Pharmacol. Exp. Ther. 322 (1): 254–64. doi:10.1124/jpet.106.117093. PMID 17416742. 
  17. ^ Woltering TJ, Wichmann J, Goetschi E, et al. (2008). "Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists". Bioorg. Med. Chem. Lett. 18 (8): 2725–9. doi:10.1016/j.bmcl.2008.02.076. PMID 18374569. 
  18. ^ a b Hirbec, Hélène; Perestenko Olga; Nishimune Atsushi; Meyer Guido; Nakanishi Shigetada; Henley Jeremy M; Dev Kumlesh K (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". J. Biol. Chem. (United States) 277 (18): 15221–4. doi:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216. 
  19. ^ Flajolet, Marc; Rakhilin Sergey; Wang Hong; Starkova Natalia; Nuangchamnong Nina; Nairn Angus C; Greengard Paul (Dec 2003). "Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (26): 16006–11. doi:10.1073/pnas.2136600100. ISSN 0027-8424. PMC 307683. PMID 14663150. 

External links[edit]

Further reading[edit]

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