Metabotropic glutamate receptor 3

Structure

In humans, mGluR3 is encoded by the GRM3 gene on chromosome 7. At least five protein-coding isoforms are predicted based on genomic information. The mGluR3 protein is a seven-pass transmembrane protein.

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 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.

mGluR3 assumes an expanded role in the primate association cortex, where it supports higher cognitive functions. In rodents, mGluR3 are located primarily at presynaptic terminals, where they inhibit glutamate release. By contrast, in the primate prefrontal cortex and entorhinal cortex, mGluR3 are predominantly postsynaptic, residing on dendritic spines where they regulate the cAMP-driven activation of calcium signaling.

Feedforward cAMP–calcium signaling can open nearby potassium channels, reducing synaptic efficacy and impairing cognition—a phenomenon termed dynamic network connectivity. mGluR3 counteract this process by closing potassium channels and thereby strengthening the functional connectivity of prefrontal cortical networks. In addition to responding to glutamate, mGluR3 are also activated by N-acetylaspartylglutamic acid (NAAG), which is co-released with glutamate but selectively stimulates mGluR3. Levels of NAAG in the cerebrospinal fluid correlate with cognitive performance. During neuroinflammation, the enzyme glutamate carboxypeptidase II (GCPII) degrades NAAG, thereby impairing prefrontal cortical cognitive function. A gain-of-function variant in the gene encoding GCPII has been linked to cognitive impairment in humans.

Clinical significance

The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with a range of psychiatric disorders, including bipolar affective disorder as well as schizophrenia.

A mutation in the Kozak sequence in the 1st exon of the GRM3 gene was shown to change translation and transcription of cloned GRM3 gene constructs and was significantly associated with bipolar disorder with an odds ratio of 4.4. Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p−9. A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism. The mGluR3 receptor encoded by GRM3 is targetable by several drugs that have been used in previous trials of schizophrenia and anxiety disorder. The agonist, antagonist and allosteric modulator drugs of mGluR3 can now be explored as new treatments for mental illness. Other scientific evidence has been published which shows that the well established anti-manic drug lithium carbonate also changes GRM3 gene expression in the mouse brain after treatment with lithium carbonate.

Ligands

mGluR3 modulators that are significantly selective over the isoform mGluR2 are known since 2013.

Agonists

• with a bicyclo[3.1.0]hexane skeleton
  • MGS-0028
  • LY404040
  • LY379268
  • LY354740; its (+)-C4α-methyl analog is a GluR2 agonist / GluR3 antagonist
  • LY-2794193
• (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

Antagonists

• CECXG – 38x selectivity for mGlu3 over mGlu2
• LY-341,495 and its 1-fluoro analog: potent orthosteric antagonists
• MGS-0039, HYDIA (both with bicyclo[3.1.0]hexane skeleton)

Allosteric modulators

• ML337: selective NAM, IC50 = 450 nM for mGluR3, IC50 30μM for mGluR2
• MNI-137: inhibitor
• VU-0650786: NAM
• compound 7p: non-competitive antagonist (presumably allosteric inhibitor)
• LY 2389575: negative allosteric modulator.

Interactions

Metabotropic glutamate receptor 3 has been shown to interact with:

• GRIP1,
• PICK1, and
• PPM1A.
• Raptin

References

References

1. (May 1995). "Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro". Molecular Pharmacology.
2. (October 1997). "Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus". The Journal of Neuroscience.
3. (March 2018). "mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks". Cerebral Cortex.
4. (January 1996). "Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q". Genomics.
5. "Entrez Gene: GRM3 glutamate receptor, metabotropic 3".
6. (December 2020). "Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition". The American Journal of Psychiatry.
7. (August 2017). "Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk". Translational Psychiatry.
8. (2022). "Glutamate Metabotropic Receptor Type 3 (mGlu3) Localization in the Rat Prelimbic Medial Prefrontal Cortex". Frontiers in Neuroanatomy.
9. (March 2018). "mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks". Cerebral Cortex.
10. (December 2023). "Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease". Cerebral Cortex.
11. (October 2012). "A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP". Neuron.
12. (November 2019). "Maternal polymorphisms in the FADS1 and FADS2 genes modify the association between PUFA ingestion and plasma concentrations of omega-3 polyunsaturated fatty acids". Prostaglandins, Leukotrienes, and Essential Fatty Acids.
13. (September 2025). "Associations between cerebrospinal fluid N-acetyl-aspartyl-glutamate (NAAG) and cognitive function in people with HIV". AIDS.
14. (October 2022). "Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders". Molecular Psychiatry.
15. (July 2020). "Macular hole edge morphology predicts restoration of postoperative retinal microstructure and functional outcome". BMC Ophthalmology.
16. (June 2013). "Genetic association, mutation screening, and functional analysis of a Kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder". JAMA Psychiatry.
17. (February 2014). "De novo mutations in schizophrenia implicate synaptic networks". Nature.
18. (July 2014). "Biological insights from 108 schizophrenia-associated genetic loci". Nature.
19. (December 2014). "The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder". Psychiatric Genetics.
20. (August 2007). "A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder". Pharmacogenetics and Genomics.
21. (December 2000). "Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists". Journal of Medicinal Chemistry.
22. (January 2007). "Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors". Journal of Medicinal Chemistry.
23. (March 1999). "Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors". Journal of Medicinal Chemistry.
24. (February 1997). "Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties". Journal of Medicinal Chemistry.
25. (May 2005). "Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist". Journal of Medicinal Chemistry.
26. (March 2018). "Synthesis and Pharmacological Characterization of C4_β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu₃ Receptor Agonist". Journal of Medicinal Chemistry.
27. (September 2002). "Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid". Journal of Medicinal Chemistry.
28. (April 2008). "Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist". Bioorganic & Medicinal Chemistry.
29. (August 2004). "Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists". Journal of Medicinal Chemistry.
30. (February 2008). "Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA". ChemMedChem.
31. (June 2013). "Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)". Journal of Medicinal Chemistry.
32. (July 2007). "A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors". The Journal of Pharmacology and Experimental Therapeutics.
33. (September 2017). "Design and Synthesis of ''N''-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu₃ NAMs". ACS Medicinal Chemistry Letters.
34. (April 2008). "Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists". Bioorganic & Medicinal Chemistry Letters.
35. (January 2021). "mGlu3 receptor regulates microglial cell reactivity in neonatal rats". Journal of Neuroinflammation.
36. (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". The Journal of Biological Chemistry.
37. (December 2003). "Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3". Proceedings of the National Academy of Sciences of the United States of America.
38. (February 2025). "Raptin, a novel brain hormone links sleep health to body weight gain". Cell Research.