Metabotropic glutamate receptor 1

Last updated

GRM1
7dgd mGluR1 homodimer inactive.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRM1 , GPRC1A, MGLU1, MGLUR1, PPP1R85, SCAR13, glutamate metabotropic receptor 1, SCA44
External IDs OMIM: 604473; MGI: 1351338; HomoloGene: 649; GeneCards: GRM1; OMA:GRM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001114333
NM_016976

RefSeq (protein)

NP_001264993
NP_001264994
NP_001264995
NP_001264996

Contents

NP_001107805
NP_058672

Location (UCSC) Chr 6: 146.03 – 146.44 Mb Chr 10: 10.56 – 10.96 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein. [5] [6] [7]

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. [5]

A possible connection has been suggested between mGluRs and neuromodulators, as mGluR1 antagonists block adrenergic receptor activation in neurons. [8]

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. [9]

Clinical significance

Mutations in the GRM1 gene may contribute to melanoma susceptibility. [10] Antibodies against mGluR1 receptors cause cerebellar ataxia and impair long-term depression (LTDpathies) in the cerebellum. [11]

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. [12] 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). [13]

Chemical structures of mGluR1 selective ligands. Selective mGluR1 ligands.png
Chemical structures of mGluR1 selective ligands.

See also

Related Research Articles

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Fenobam</span> Chemical compound

Fenobam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. Subsequently, it was determined that fenobam acts as a potent and selective negative allosteric modulator of the metabotropic glutamate receptor subtype mGluR5, and it has been used as a lead compound for the development of a range of newer mGluR5 antagonists.

<span class="mw-page-title-main">Metabotropic glutamate receptor 2</span> Mammalian protein found in humans

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

<span class="mw-page-title-main">Metabotropic glutamate receptor 3</span> Mammalian protein found in humans

Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory Gi/G0-coupled G-protein coupled receptor (GPCR) generally localized to presynaptic sites of neurons in classical circuits. However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity. In humans, mGluR3 is encoded by the GRM3 gene. Deficits in mGluR3 signaling have been linked to impaired cognition in humans, and to increased risk of schizophrenia, consistent with their expanding role in cortical evolution.

<span class="mw-page-title-main">Metabotropic glutamate receptor 4</span> Mammalian protein found in humans

Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 5</span> Mammalian protein found in humans

Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the GRM5 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 7</span> Mammalian protein found in humans

Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 8</span> Mammalian protein found in humans

Metabotropic glutamate receptor 8 is a protein that in humans is encoded by the GRM8 gene.

<span class="mw-page-title-main">LY-341495</span> Chemical compound

LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors (mGluR2/3).

<span class="mw-page-title-main">2-Methyl-6-(phenylethynyl)pyridine</span> Chemical compound

2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s. It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.

<span class="mw-page-title-main">MTEP</span> Chemical compound

3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.

<span class="mw-page-title-main">SIB-1893</span> Chemical compound

SIB-1893 is a drug used in scientific research which was one of the first compounds developed that acts as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It has anticonvulsant and neuroprotective effects, and reduces glutamate release. It has also been found to act as a positive allosteric modulator of mGluR4.

<span class="mw-page-title-main">CPCCOEt</span> Chemical compound

CPCCOEt is a drug used in scientific research, which acts as a non-competitive antagonist at the metabotropic glutamate receptor subtype mGluR1, with high selectivity although only moderate binding affinity. It is used mainly in basic research into the function of the mGluR1 receptor, including the study of behavioural effects in animals including effects on memory and addiction.

<span class="mw-page-title-main">Ro67-4853</span> Chemical compound

Ro67-4853 is a drug used in scientific research, which acts as a selective positive allosteric modulator for the metabotropic glutamate receptor subtype mGluR1. It was derived by modification of the simpler compound Ro01-6128, and has itself subsequently been used as a lead compound to develop a range of potent and selective mGluR1 positive modulators.

<span class="mw-page-title-main">LY-379,268</span> Chemical compound

LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).

<span class="mw-page-title-main">LY-487,379</span> Chemical compound

LY-487,379 is a drug used in scientific research that acts as a selective positive allosteric modulator for the metabotropic glutamate receptor group II subtype mGluR2. It is used to study the structure and function of this receptor subtype, and LY-487,379 along with various other mGluR2/3 agonists and positive modulators are being investigated as possible antipsychotic and anxiolytic drugs.

<span class="mw-page-title-main">PCCG-4</span> Chemical compound

PCCG-4 is a research drug which acts as a selective antagonist for the group II metabotropic glutamate receptors (mGluR2/3), with slight selectivity for mGluR2 although not sufficient to distinguish mGluR2 and mGluR3 responses from each other. It is used in research into the function of the group II metabotropic glutamate receptors.

<span class="mw-page-title-main">MGS-0039</span> Chemical compound

MGS-0039 is a drug that is used in neuroscientific research, which acts as a potent and selective antagonist for group II of the metabotropic glutamate receptors (mGluR2/3). It produces antidepressant and anxiolytic effects in animal studies, and has been shown to boost release of dopamine and serotonin in specific brain areas. Research has suggested this may occur through a similar mechanism as that suggested for the similarly glutamatergic drug ketamine.

<span class="mw-page-title-main">AZD9272</span> Medication

AZD 9272 is a drug which acts as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It was unsuccessful in human trials as an analgesic, but continues to be widely used in research especially as its radiolabelled forms.

<span class="mw-page-title-main">AZ12216052</span> Chemical compound

AZ-12216052 is a drug which acts as a potent and selective positive allosteric modulator of the metabotropic glutamate receptor 8, and is used for research into the role of this receptor subtype in various processes including anxiety and neuropathic pain.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000152822 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019828 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: GRM1 glutamate receptor, metabotropic 1".
  6. 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): 1649–1660. doi:10.1016/S0028-3908(96)00108-6. PMID   9076744. S2CID   37222391.
  7. 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): 2943–2947. doi:10.1097/00001756-199709080-00027. PMID   9376535. S2CID   28116484.
  8. Smith RS, Weitz CJ, Araneda RC (August 2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology. 102 (2): 1103–1114. doi:10.1152/jn.91093.2008. PMC   2724365 . PMID   19474170.
  9. 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". Nature. 372 (6503): 237–243. Bibcode:1994Natur.372..237C. doi:10.1038/372237a0. PMID   7969468. S2CID   4256888.
  10. 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". European Journal of Human Genetics. 15 (11): 1176–1182. doi: 10.1038/sj.ejhg.5201887 . PMID   17609672.
  11. Mitoma H, Honnorat J, Yamaguchi K, Manto M (December 2021). "LTDpathies: a Novel Clinical Concept". Cerebellum. 20 (6): 948–951. doi: 10.1007/s12311-021-01259-2 . PMC   8674158 . PMID   33754326.
  12. 1 2 Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D, et al. (August 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". Molecular Pharmacology. 70 (2): 616–626. doi:10.1124/mol.105.021857. PMID   16645124. S2CID   2719603.
  13. based on a plain PubMed review
  14. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, et al. (December 2004). "JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist". Neuropharmacology. 47 (7): 961–972. doi:10.1016/j.neuropharm.2004.08.007. PMID   15555631. S2CID   601322.
  15. Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (May 2003). "[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. doi:10.1124/mol.63.5.1082. PMID   12695537.
  16. Kohara A, Takahashi M, Yatsugi S, Tamura S, Shitaka Y, Hayashibe S, et al. (January 2008). "Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models". Brain Research. 1191: 168–179. doi:10.1016/j.brainres.2007.11.035. PMID   18164695. S2CID   3236484.
  17. Kohara A, Nagakura Y, Kiso T, Toya T, Watabiki T, Tamura S, et al. (September 2007). "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. doi:10.1016/j.ejphar.2007.05.030. PMID   17597604.
  18. Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y, et al. (October 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". The Journal of Pharmacology and Experimental Therapeutics. 315 (1): 163–169. doi:10.1124/jpet.105.087171. PMID   15976016. S2CID   15291494.
  19. Suzuki G, Kimura T, Satow A, Kaneko N, Fukuda J, Hikichi H, et al. (June 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)". The Journal of Pharmacology and Experimental Therapeutics. 321 (3): 1144–1153. doi:10.1124/jpet.106.116574. PMID   17360958. S2CID   10065500.
  20. El-Kouhen O, Lehto SG, Pan JB, Chang R, Baker SJ, Zhong C, et al. (November 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". British Journal of Pharmacology. 149 (6): 761–774. doi:10.1038/sj.bjp.0706877. PMC   2014656 . PMID   17016515.
  21. Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (March 2009). "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. doi:10.1016/j.bmcl.2009.01.108. PMID   19233648.
  22. Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (March 2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology. 52 (3): 744–754. doi:10.1016/j.neuropharm.2006.09.018. PMC   1876747 . PMID   17095021.
  23. Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (March 2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology. 52 (3): 744–754. doi:10.1016/j.neuropharm.2006.09.018. PMC   1876747 . PMID   17095021.
  24. Lemieszek MK, Stepulak A, Sawa-Wejksza K, Czerwonka A, Ikonomidou C, Rzeski W (2018). "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. doi:10.2174/1871520618666180228152713. PMID   29493465. S2CID   3605151.
  25. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S (July 2004). "Possible involvement of group I mGluRs in neuroprotective effect of theanine". Biochemical and Biophysical Research Communications. 320 (1): 116–122. doi:10.1016/j.bbrc.2004.05.143. PMID   15207710.

Further reading

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