Metabotropic glutamate receptor 1

Structure

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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.

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

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.

Clinical significance

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

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. 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).

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

References

References

1. "Entrez Gene: GRM1 glutamate receptor, metabotropic 1".
2. (1996). "Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants". Neuropharmacology.
3. (September 1997). "Expression of a novel splice variant of human mGluR1 in the cerebellum". NeuroReport.
4. (2014). "Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator". Science.
5. (2000). "Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor". Nature.
6. (August 2009). "Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb". Journal of Neurophysiology.
7. (November 1994). "Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1". Nature.
8. (November 2007). "Genetic analysis of the GRM1 gene in human melanoma susceptibility". European Journal of Human Genetics.
9. (December 2021). "LTDpathies: a Novel Clinical Concept". Cerebellum.
10. (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.
11. based on a plain [[PubMed]] review
12. (December 2004). "JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist". Neuropharmacology.
13. (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.
14. (January 2008). "Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models". Brain Research.
15. (September 2007). "Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models". European Journal of Pharmacology.
16. (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.
17. (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.
18. (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.
19. (March 2009). "Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers". Bioorganic & Medicinal Chemistry Letters.
20. (March 2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology.
21. (March 2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology.
22. (2018). "Riluzole Inhibits Proliferation, Migration and Cell Cycle Progression and Induces Apoptosis in Tumor Cells of Various Origins". Anti-Cancer Agents in Medicinal Chemistry.
23. (July 2004). "Possible involvement of group I mGluRs in neuroprotective effect of theanine". Biochemical and Biophysical Research Communications.