Metabotropic glutamate receptor 1

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RefSeq (mRNA)



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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]

A possible connection has been suggested between mGluRs and neuromodulators, as mGluR1 antagonists block adrenergic receptor activation in neurons.[4]

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.[5]

Clinical significance

Mutations in the GRM1 gene may contribute to melanoma susceptibility.[6]


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.[7] 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).[8]

  • JNJ-16259685: highly potent, selective non-competitive antagonist[9]
  • R-214,127 and [3H]-analog: high-affinity, selective allosteric inhibitor[10]
  • YM-202,074: high-affinity, selective allosteric antagonist[11]
  • YM-230,888: high-affinity, selective allosteric antagonist[12]
  • YM-298,198 and [3H]-analog: selective non-competitive antagonist[13]
  • FTIDC: highly potent and selective allosteric antagonist/inverse agonist[14]
  • A-841,720: potent non-competitive antagonist; minor hmGluR5 binding[15]
  • VU-71: potentiator[7]
  • Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides: orally available PAMs[16]
  • Cyclothiazide: non-selective non-competitive antagonist[17]
File:Selective mGluR1 ligands.png
Chemical structures of mGluR1 selective ligands.

See also


  1. 1.0 1.1 "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. Smith RS, Weitz CJ, Araneda RC (Aug 2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology. 102 (2): 1103–14. doi:10.1152/jn.91093.2008. PMC 2724365. PMID 19474170.
  5. Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, Bordi F, Franz-Bacon K, Reggiani A, Matarese V, Condé F (November 1994). "Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1". Nature. 372 (6503): 237–43. doi:10.1038/372237a0. PMID 7969468.
  6. 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.
  7. 7.0 7.1 Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D, Tamagnan GD, Conn PJ (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.
  8. based on a plain pubmed review
  9. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, Lesage AS (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.
  10. Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (2003). "[3H]R214127: 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.
  11. Kohara A, Takahashi M, Yatsugi S, Tamura S, Shitaka Y, Hayashibe S, Kawabata S, Okada M (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.
  12. Kohara A, Nagakura Y, Kiso T, Toya T, Watabiki T, Tamura S, Shitaka Y, Itahana H, Okada M (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.
  13. Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y, Hayashibe S, Kawabata S, Okada M (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.
  14. Suzuki G, Kimura T, Satow A, Kaneko N, Fukuda J, Hikichi H, Sakai N, Maehara S, Kawagoe-Takaki H, Hata M, Azuma T, Ito S, Kawamoto H, Ohta H (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.
  15. El-Kouhen O, Lehto SG, Pan JB, Chang R, Baker SJ, Zhong C, Hollingsworth PR, Mikusa JP, Cronin EA, Chu KL, McGaraughty SP, Uchic ME, Miller LN, Rodell NM, Patel M, Bhatia P, Mezler M, Kolasa T, Zheng GZ, Fox GB, Stewart AO, Decker MW, Moreland RB, Brioni JD, Honore P (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.
  16. 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.
  17. Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology. 52 (3): 744–54. doi:10.1016/j.neuropharm.2006.09.018. PMC 1876747. PMID 17095021.

Further reading

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

External links