Metabotropic glutamate receptor 1 explained

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]}

Function

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, which includes GRM1 alongside GRM5, 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] Antibodies against mGluR1 receptors cause cerebellar ataxia and impair long-term depression (LTDpathies) in the cerebellum.^[7]

Ligands

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.^[8] 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).^[9]

• JNJ-16259685: highly potent, selective non-competitive antagonist^[10]
• R-214,127 and [³H]-analog: high-affinity, selective allosteric inhibitor^[11]
• YM-202,074: high-affinity, selective allosteric antagonist^[12]
• YM-230,888: high-affinity, selective allosteric antagonist^[13]
• YM-298,198 and [³H]-analog: selective non-competitive antagonist^[14]
• FTIDC: highly potent and selective allosteric antagonist/inverse agonist^[15]
• A-841,720: potent non-competitive antagonist; minor hmGluR5 binding^[16]
• VU-71: potentiator^[8]
• Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides: orally available PAMs^[17]
• Cyclothiazide: selective non-competitive antagonist of the mGluR1^[18] (also AMPA potentiator and minor mGluR5 potentiator but not antagonist^[19])
• Riluzole : selective non-competitive antagonist^[20]
• Theanine : possible indirect inhibitor^[21]

See also

• Metabotropic glutamate receptor

Further reading

• Bockaert J, Pin JP . Molecular tinkering of G protein-coupled receptors: an evolutionary success . The EMBO Journal . 18 . 7 . 1723–1729 . April 1999 . 10202136 . 1171258 . 10.1093/emboj/18.7.1723 .
• King JE, Eugenin EA, Buckner CM, Berman JW . HIV tat and neurotoxicity . Microbes and Infection . 8 . 5 . 1347–1357 . April 2006 . 16697675 . 10.1016/j.micinf.2005.11.014 . free .
• Desai MA, Burnett JP, Mayne NG, Schoepp DD . Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter . Molecular Pharmacology . 48 . 4 . 648–657 . October 1995 . 7476890 .
• Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC . Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q . Genomics . 31 . 2 . 230–233 . January 1996 . 8824806 . 10.1006/geno.1996.0036 . free .
• Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL, Worley PF . Homer: a protein that selectively binds metabotropic glutamate receptors . Nature . 386 . 6622 . 284–288 . March 1997 . 9069287 . 10.1038/386284a0 . 4346579 . 1997Natur.386..284B .
• Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM . Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants . Neuropharmacology . 35 . 12 . 1649–1660 . 1997 . 9076744 . 10.1016/S0028-3908(96)00108-6 . 37222391 .
• Makoff AJ, Phillips T, Pilling C, Emson P . Expression of a novel splice variant of human mGluR1 in the cerebellum . NeuroReport . 8 . 13 . 2943–2947 . September 1997 . 9376535 . 10.1097/00001756-199709080-00027 . 28116484 .
• Francesconi A, Duvoisin RM . Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation . The Journal of Biological Chemistry . 273 . 10 . 5615–5624 . March 1998 . 9488690 . 10.1074/jbc.273.10.5615 . free .
• Okamoto T, Sekiyama N, Otsu M, Shimada Y, Sato A, Nakanishi S, Jingami H . Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1 . The Journal of Biological Chemistry . 273 . 21 . 13089–13096 . May 1998 . 9582347 . 10.1074/jbc.273.21.13089 . free .
• Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ, Siderovski DP . 6 . GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain . The Journal of Biological Chemistry . 273 . 28 . 17749–17755 . July 1998 . 9651375 . 10.1074/jbc.273.28.17749 . free .
• Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ, Worley PF . 6 . Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins . Neuron . 21 . 4 . 707–716 . October 1998 . 9808458 . 10.1016/S0896-6273(00)80588-7 . 16431031 . free .
• Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ, Worley PF . 6 . Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors . Neuron . 21 . 4 . 717–726 . October 1998 . 9808459 . 10.1016/S0896-6273(00)80589-9 . 2851554 . free .
• Ciruela F, Robbins MJ, Willis AC, McIlhinney RA . Interactions of the C terminus of metabotropic glutamate receptor type 1alpha with rat brain proteins: evidence for a direct interaction with tubulin . Journal of Neurochemistry . 72 . 1 . 346–354 . January 1999 . 9886087 . 10.1046/j.1471-4159.1999.0720346.x . 3923065 . free .
• Robbins MJ, Ciruela F, Rhodes A, McIlhinney RA . Characterization of the dimerization of metabotropic glutamate receptors using an N-terminal truncation of mGluR1alpha . Journal of Neurochemistry . 72 . 6 . 2539–2547 . June 1999 . 10349865 . 10.1046/j.1471-4159.1999.0722539.x . 43073802 . free .
• Mody N, Hermans E, Nahorski SR, Challiss RA . Inhibition of N-linked glycosylation of the human type 1alpha metabotropic glutamate receptor by tunicamycin: effects on cell-surface receptor expression and function . Neuropharmacology . 38 . 10 . 1485–1492 . October 1999 . 10530810 . 10.1016/S0028-3908(99)00099-4 . 31175440 .
• Francesconi A, Duvoisin RM . Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling: selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain . Proceedings of the National Academy of Sciences of the United States of America . 97 . 11 . 6185–6190 . May 2000 . 10823959 . 18579 . 10.1073/pnas.97.11.6185 . free . 2000PNAS...97.6185F .
• Ganesh S, Amano K, Yamakawa K . Assignment of the gene GRM1 coding for metabotropic glutamate receptor 1 to human chromosome band 6q24 by in situ hybridization . Cytogenetics and Cell Genetics . 88 . 3–4 . 314–315 . 2000 . 10828618 . 10.1159/000015517 . 26499807 .
• Ray K, Hauschild BC . Cys-140 is critical for metabotropic glutamate receptor-1 dimerization . The Journal of Biological Chemistry . 275 . 44 . 34245–34251 . November 2000 . 10945991 . 10.1074/jbc.M005581200 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .

External links

• Web site: Metabotropic Glutamate Receptors: mGlu₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-05 . 2016-03-03 . https://web.archive.org/web/20160303204041/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2268 . dead .

Notes and References

1. Web site: Entrez Gene: GRM1 glutamate receptor, metabotropic 1.
2. Stephan D, Bon C, Holzwarth JA, Galvan M, Pruss RM . Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants . Neuropharmacology . 35 . 12 . 1649–1660 . 1996 . 9076744 . 10.1016/S0028-3908(96)00108-6 . 37222391 .
3. Makoff AJ, Phillips T, Pilling C, Emson P . Expression of a novel splice variant of human mGluR1 in the cerebellum . NeuroReport . 8 . 13 . 2943–2947 . September 1997 . 9376535 . 10.1097/00001756-199709080-00027 . 28116484 .
4. Smith RS, Weitz CJ, Araneda RC . Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb . Journal of Neurophysiology . 102 . 2 . 1103–1114 . August 2009 . 19474170 . 2724365 . 10.1152/jn.91093.2008 .
5. Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, Bordi F, Franz-Bacon K, Reggiani A, Matarese V, Condé F . 6 . Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1 . Nature . 372 . 6503 . 237–243 . November 1994 . 7969468 . 10.1038/372237a0 . 4256888 . 1994Natur.372..237C .
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 . 6 . Genetic analysis of the GRM1 gene in human melanoma susceptibility . European Journal of Human Genetics . 15 . 11 . 1176–1182 . November 2007 . 17609672 . 10.1038/sj.ejhg.5201887 . free .
7. Mitoma H, Honnorat J, Yamaguchi K, Manto M . LTDpathies: a Novel Clinical Concept . Cerebellum . 20 . 6 . 948–951 . December 2021 . 33754326 . 8674158 . 10.1007/s12311-021-01259-2 . free .
8. Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D, Tamagnan GD, Conn PJ . 6 . A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators . Molecular Pharmacology . 70 . 2 . 616–626 . August 2006 . 16645124 . 10.1124/mol.105.021857 . 2719603 .
9. based on a plain PubMed review
10. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, Lesage AS . 6 . JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist . Neuropharmacology . 47 . 7 . 961–972 . December 2004 . 15555631 . 10.1016/j.neuropharm.2004.08.007 . 601322 .
11. Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS . [3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists . Molecular Pharmacology . 63 . 5 . 1082–1093 . May 2003 . 12695537 . 10.1124/mol.63.5.1082 .
12. Kohara A, Takahashi M, Yatsugi S, Tamura S, Shitaka Y, Hayashibe S, Kawabata S, Okada M . 6 . Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models . Brain Research . 1191 . 168–179 . January 2008 . 18164695 . 10.1016/j.brainres.2007.11.035 . 3236484 .
13. Kohara A, Nagakura Y, Kiso T, Toya T, Watabiki T, Tamura S, Shitaka Y, Itahana H, Okada M . 6 . Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models . European Journal of Pharmacology . 571 . 1 . 8–16 . September 2007 . 17597604 . 10.1016/j.ejphar.2007.05.030 .
14. Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y, Hayashibe S, Kawabata S, Okada M . 6 . 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 . The Journal of Pharmacology and Experimental Therapeutics . 315 . 1 . 163–169 . October 2005 . 15976016 . 10.1124/jpet.105.087171 . 15291494 .
15. 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 . 6 . 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) . The Journal of Pharmacology and Experimental Therapeutics . 321 . 3 . 1144–1153 . June 2007 . 17360958 . 10.1124/jpet.106.116574 . 10065500 .
16. 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 . 6 . 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 . British Journal of Pharmacology . 149 . 6 . 761–774 . November 2006 . 17016515 . 2014656 . 10.1038/sj.bjp.0706877 .
17. Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J . Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers . Bioorganic & Medicinal Chemistry Letters . 19 . 6 . 1666–1669 . March 2009 . 19233648 . 10.1016/j.bmcl.2009.01.108 .
18. Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT . Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists . Neuropharmacology . 52 . 3 . 744–754 . March 2007 . 17095021 . 1876747 . 10.1016/j.neuropharm.2006.09.018 .
19. Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT . Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists . Neuropharmacology . 52 . 3 . 744–754 . March 2007 . 17095021 . 1876747 . 10.1016/j.neuropharm.2006.09.018 .
20. Lemieszek MK, Stepulak A, Sawa-Wejksza K, Czerwonka A, Ikonomidou C, Rzeski W . Riluzole Inhibits Proliferation, Migration and Cell Cycle Progression and Induces Apoptosis in Tumor Cells of Various Origins . Anti-Cancer Agents in Medicinal Chemistry . 18 . 4 . 565–572 . 2018 . 29493465 . 10.2174/1871520618666180228152713 . 3605151 .
21. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S . Possible involvement of group I mGluRs in neuroprotective effect of theanine . Biochemical and Biophysical Research Communications . 320 . 1 . 116–122 . July 2004 . 15207710 . 10.1016/j.bbrc.2004.05.143 .