Metabotropic glutamate receptor 1

Glutamate receptor, metabotropic 1

PDB rendering based on 1ewk.
Symbols GRM1; GPRC1A; GRM1A; MGLUR1; MGLUR1A; mGlu1
External IDs OMIM604473 MGI1351338 HomoloGene649 GeneCards: GRM1 Gene
RNA expression pattern
PBB GE GRM1 207299 s at tn.png
PBB GE GRM1 210939 s at tn.png
PBB GE GRM1 210940 s at tn.png
More reference expression data
Species Human Mouse
Entrez 2911 14816
Ensembl ENSG00000152822 ENSMUSG00000019828
UniProt Q13255 Q3V0U2
RefSeq (mRNA) NM_000838.3 XM_976537
RefSeq (protein) NP_000829.2 XP_981631
Location (UCSC) Chr 6:
146.35 – 146.76 Mb
Chr 10:
10.41 – 10.8 Mb
PubMed search [1] [2]

The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein.[1][2][3]



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. Alternative splice variants of the GRM1 gene have been described but their full-length nature has not been determined.[1]

Studies with knockout mice

Mice lacking functional glutamate receptor 1 were reported in 1994. By homologous recombination mediated gene targeting those mice became deficient in mGlu receptor 1 protein. The mice did not show any basic anatomical changes in the brain but had impaired cerebellar long-term depression and hippocampal long-term potentiation. In addition they had impaired motor functions, characterized by impaired balance. In the Morris watermaze test, an assay for learning abilities, those mice needed significantly more time to successfully complete the task.[4]

Clinical significance

Mutations in the GRM1 gene may contribute to melanoma susceptibility.[5]


In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allosteric binding sites exist on the mGluR1.[6] A respectable number of potent and specific allosteric ligands – predominantly antagonists/inhibitors – has been developed in recent years, although no orthosteric subtype-selective ligands have yet been discovered (2008).[7]

  • JNJ-16259685: highly potent, selective non-competitive antagonist[8]
  • R-214,127 and [3H]-analog: high-affinity, selective allosteric inhibitor[9]
  • YM-202,074: high-affinity, selective allosteric antagonist[10]
  • YM-230,888: high-affinity, selective allosteric antagonist[11]
  • YM-298,198 and [3H]-analog: selective non-competitive antagonist[12]
  • FTIDC: highly potent and selective allosteric antagonist/inverse agonist[13]
  • A-841,720: potent non-competitive antagonist; minor hmGluR5 binding[14]
  • VU-71: potentiator[6]
  • Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides: orally available PAMs[15]
Chemical structures of mGluR1 selective ligands.

See also


  1. ^ a b "Entrez Gene: GRM1 glutamate receptor, metabotropic 1". 
  2. ^ Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM (1996). "Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants". Neuropharmacology 35 (12): 1649–60. doi:10.1016/S0028-3908(96)00108-6. PMID 9076744. 
  3. ^ Makoff AJ, Phillips T, Pilling C, Emson P (September 1997). "Expression of a novel splice variant of human mGluR1 in the cerebellum". Neuroreport 8 (13): 2943–7. doi:10.1097/00001756-199709080-00027. PMID 9376535. 
  4. ^ Conquet F, Bashir ZI, Davies CH, et al. (November 1994). "Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1". Nature 372 (6503): 237–43. doi:10.1038/372237a0. PMID 7969468. 
  5. ^ Ortiz P, Vanaclocha F, López-Bran E, Esquivias JI, López-Estebaranz JL, Martín-González M, Arrue I, García-Romero D, Ochoa C, González-Perez A, Ruiz A, Real LM (November 2007). "Genetic analysis of the GRM1 gene in human melanoma susceptibility". Eur. J. Hum. Genet. 15 (11): 1176–82. doi:10.1038/sj.ejhg.5201887. PMID 17609672. 
  6. ^ a b Hemstapat K, de Paulis T, Chen Y, et al. (2006). "A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators". Mol. Pharmacol. 70 (2): 616–26. doi:10.1124/mol.105.021857. PMID 16645124. 
  7. ^ based on a plain pubmed review
  8. ^ Lavreysen H, Wouters R, Bischoff F, et al. (2004). "JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist". Neuropharmacology 47 (7): 961–72. doi:10.1016/j.neuropharm.2004.08.007. PMID 15555631. 
  9. ^ Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). "[3HR214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists"]. Mol. Pharmacol. 63 (5): 1082–93. doi:10.1124/mol.63.5.1082. PMID 12695537. 
  10. ^ Kohara A, Takahashi M, Yatsugi S, et al. (2008). "Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models". Brain Res. 1191: 168–79. doi:10.1016/j.brainres.2007.11.035. PMID 18164695. 
  11. ^ Kohara A, Nagakura Y, Kiso T, et al. (2007). "Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models". Eur. J. Pharmacol. 571 (1): 8–16. doi:10.1016/j.ejphar.2007.05.030. PMID 17597604. 
  12. ^ Kohara A, Toya T, Tamura S, et al. (2005). "Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and noncompetitive antagonist of metabotropic glutamate receptor type 1". J. Pharmacol. Exp. Ther. 315 (1): 163–9. doi:10.1124/jpet.105.087171. PMID 15976016. 
  13. ^ Suzuki G, Kimura T, Satow A, et al. (2007). "Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)". J. Pharmacol. Exp. Ther. 321 (3): 1144–53. doi:10.1124/jpet.106.116574. PMID 17360958. 
  14. ^ El-Kouhen O, Lehto SG, Pan JB, et al. (2006). "Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist". Br. J. Pharmacol. 149 (6): 761–74. doi:10.1038/sj.bjp.0706877. PMC 2014656. PMID 17016515. 
  15. ^ Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (2009). "Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers". Bioorg. Med. Chem. Lett. 19 (6): 1666–9. doi:10.1016/j.bmcl.2009.01.108. PMID 19233648. 

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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