Metabotropic glutamate receptor 3

Metabotropic glutamate receptor 3
Glutamate receptor, metabotropic 3

PDB rendering based on 2e4u.
Identifiers
Symbols GRM3; GLUR3; GPRC1C; MGLUR3; mGlu3
External IDs OMIM: 601115 MGI: 1351340 HomoloGene: 651 GeneCards: GRM3 Gene
RNA expression pattern
PBB GE GRM3 205814 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2913 108069
Ensembl ENSG00000198822 ENSMUSG00000003974
UniProt Q14832 Q14DJ9
RefSeq (mRNA) NM_000840 NM_181850.2
RefSeq (protein) NP_000831 NP_862898.1
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]

Contents

Ligands

Though truly mGluR3 selective agents still await their discovery, mixed mGluR2/3 (group-II) ligands with selectivity over other mGluR-subtypes are known (2008). Low oral bioavailability is observed in some of them, but it can be met by applying a prodrug strategy.[3]

Agonists

  • with a bicyclo[3.1.0]hexane skeleton
    • MGS-0028[4]
    • LY404040[5]
    • LY379268[6]
    • LY354740[7]; its (+)-C4α-methyl analog is a GluR2 agonist / GluR3 antagonist[8]
  • (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid[9]

Antagonists

  • CECXG - 38x selectivity for mGlu3 over mGlu2
  • LY-341,495 and its 1-fluoro analog[10]: potent orthosteric antagonists
  • MGS-0039[11], HYDIA[12] (both with bicyclo[3.1.0]hexane skeleton)

Allosteric modulators

  • MNI-137[13]: inhibitior
  • compound 7p[14]: non-competitive antagonist (presumably allosteric inhibitor)

Interactions

Metabotropic glutamate receptor 3 has been shown to interact with GRIP1,[15] PICK1[15] and PPM1A.[16]

See also

References

  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". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2913. 
  3. ^ Rorick-Kehn LM, Perkins EJ, Knitowski KM, et al. (2006). "Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344". J. Pharmacol. Exp. Ther. 316 (2): 905–13. doi:10.1124/jpet.105.091926. PMID 16223873. 
  4. ^ 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". J. Med. Chem. 43 (25): 4893–909. doi:10.1021/jm000346k. PMID 11123999. 
  5. ^ 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". J. Med. Chem. 50 (2): 233–40. doi:10.1021/jm060917u. PMID 17228865. 
  6. ^ 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". J. Med. Chem. 42 (6): 1027–40. doi:10.1021/jm980616n. PMID 10090786. 
  7. ^ 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". J. Med. Chem. 40 (4): 528–37. doi:10.1021/jm9606756. PMID 9046344. 
  8. ^ 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". J. Med. Chem. 48 (10): 3605–12. doi:10.1021/jm040222y. PMID 15887967. 
  9. ^ 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". J. Med. Chem. 45 (19): 4240–5. doi:10.1021/jm020122x. PMID 12213064. 
  10. ^ 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. 
  11. ^ 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". J. Med. Chem. 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=307683. 

External links

Further reading

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


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