L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropicglutamate 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.
A possible connection has been suggested between mGluRs and neuromodulators, as mGluR1 antagonists block adrenergic receptor activation in neurons.
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.
In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allostericbinding sites exist on the mGluR1. 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).
^Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, Bordi F et al. (November 1994). "Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1". Nature372 (6503): 237–43. doi:10.1038/372237a0. PMID7969468.
^Ortiz P, Vanaclocha F, López-Bran E, Esquivias JI, López-Estebaranz JL, Martín-González M et al. (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. PMID17609672.
^ abHemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D 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. PMID16645124.
^Kohara A, Takahashi M, Yatsugi S, Tamura S, Shitaka Y, Hayashibe 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. PMID18164695.
^Kohara A, Nagakura Y, Kiso T, Toya T, Watabiki T, Tamura S 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. PMID17597604.
^Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y 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. PMID15976016.
^Suzuki G, Kimura T, Satow A, Kaneko N, Fukuda J, Hikichi H 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. PMID17360958.
Desai MA, Burnett JP, Mayne NG, Schoepp DD (1995). "Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter.". Mol. Pharmacol.48 (4): 648–57. PMID7476890.
Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (1997). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.". Genomics31 (2): 230–3. doi:10.1006/geno.1996.0036. PMID8824806.
Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL et al. (1997). "Homer: a protein that selectively binds metabotropic glutamate receptors.". Nature386 (6622): 284–8. doi:10.1038/386284a0. PMID9069287.
Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM (1997). "Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants.". Neuropharmacology35 (12): 1649–60. doi:10.1016/S0028-3908(96)00108-6. PMID9076744.
Francesconi A, Duvoisin RM (1998). "Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation.". J. Biol. Chem.273 (10): 5615–24. doi:10.1074/jbc.273.10.5615. PMID9488690.
Okamoto T, Sekiyama N, Otsu M, Shimada Y, Sato A, Nakanishi S et al. (1998). "Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1.". J. Biol. Chem.273 (21): 13089–96. doi:10.1074/jbc.273.21.13089. PMID9582347.
Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA et al. (1998). "GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain.". J. Biol. Chem.273 (28): 17749–55. doi:10.1074/jbc.273.28.17749. PMID9651375.
Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD et al. (1998). "Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.". Neuron21 (4): 707–16. doi:10.1016/S0896-6273(00)80588-7. PMID9808458.
Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M et al. (1998). "Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors.". Neuron21 (4): 717–26. doi:10.1016/S0896-6273(00)80589-9. PMID9808459.
Ciruela F, Robbins MJ, Willis AC, McIlhinney RA (1999). "Interactions of the C terminus of metabotropic glutamate receptor type 1alpha with rat brain proteins: evidence for a direct interaction with tubulin.". J. Neurochem.72 (1): 346–54. doi:10.1046/j.1471-4159.1999.0720346.x. PMID9886087.
Robbins MJ, Ciruela F, Rhodes A, McIlhinney RA (1999). "Characterization of the dimerization of metabotropic glutamate receptors using an N-terminal truncation of mGluR1alpha.". J. Neurochem.72 (6): 2539–47. doi:10.1046/j.1471-4159.1999.0722539.x. PMID10349865.
Mody N, Hermans E, Nahorski SR, Challiss RA (1999). "Inhibition of N-linked glycosylation of the human type 1alpha metabotropic glutamate receptor by tunicamycin: effects on cell-surface receptor expression and function.". Neuropharmacology38 (10): 1485–92. doi:10.1016/S0028-3908(99)00099-4. PMID10530810.
Ganesh S, Amano K, Yamakawa K (2000). "Assignment of the gene GRM1 coding for metabotropic glutamate receptor 1 to human chromosome band 6q24 by in situ hybridization.". Cytogenet. Cell Genet.88 (3–4): 314–5. doi:10.1159/000015517. PMID10828618.