Metabotropic glutamate receptor 3

GRM3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3SM9, 4XAR, 5CNK, 5CNM
Identifiers
Aliases	GRM3 , GLUR3, GPRC1C, MGLUR3, mGlu3, glutamate metabotropic receptor 3
External IDs	OMIM: 601115 MGI: 1351340 HomoloGene: 651 GeneCards: GRM3
Gene location (Human) Chr. Chromosome 7 (human) [1] Band 7q21.11-q21.12 Start 86,643,909 bp [1] End 86,864,879 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell middle frontal gyrus corpus callosum Brodmann area 46 inferior ganglion of vagus nerve Brodmann area 10 putamen orbitofrontal cortex Region I of hippocampus proper caudate nucleus n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function glutamate receptor activity group II metabotropic glutamate receptor activity calcium channel regulator activity signal transducer activity G protein-coupled receptor activity Cellular component integral component of membrane axon neuron projection dendritic spine postsynaptic membrane integral component of plasma membrane postsynaptic density membrane plasma membrane presynaptic membrane glutamatergic synapse integral component of postsynaptic membrane integral component of presynaptic membrane Biological process negative regulation of adenylate cyclase activity signal transduction chemical synaptic transmission regulation of synaptic transmission, glutamatergic adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway G protein-coupled glutamate receptor signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2913 108069 Ensembl ENSG00000198822 ENSMUSG00000003974 UniProt Q14832 Q9QYS2 RefSeq (mRNA) NM_000840 NM_001363522 NM_181850 RefSeq (protein) NP_000831 NP_001350451 NP_862898 Location (UCSC) Chr 7: 86.64 – 86.86 Mb n/a PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory G_i/G₀-coupled G-protein coupled receptor (GPCR) ^[4] generally localized to presynaptic sites of neurons in classical circuits. ^[5] However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity. ^[6] In humans, mGluR3 is encoded by the GRM3 gene. ^{[7] [8]} Deficits in mGluR3 signaling have been linked to impaired cognition in humans, ^[9] and to increased risk of schizophrenia, ^[10] consistent with their expanding role in cortical evolution.

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. ^[8]

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 ^[11] as well as schizophrenia. ^{[12] [10]}

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. ^[11] Subsequently, a marker in GRM3 was implicated in a large genome-wide association study of schizophrenia with statistical significance of p<10⁻⁹. ^[13] A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism. ^[14] 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. ^[11] 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. ^[15]

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 ^[16]
  • LY404040 ^[17]
  • LY379268 ^[18]
  • LY354740; ^[19] its (+)-C4α-methyl analog is a GluR2 agonist / GluR3 antagonist ^[20]
  • LY-2794193 ^[21]
• (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid ^[22]

Antagonists

• CECXG – 38x selectivity for mGlu₃ over mGlu₂
• LY-341,495 and its 1-fluoro analog: ^[23] potent orthosteric antagonists
• MGS-0039, ^[24] HYDIA ^[25] (both with bicyclo[3.1.0]hexane skeleton)

D₃-ML337

Allosteric modulators

• D₃-ML337: selective NAM, IC50 = 450 nM for mGluR3, IC50 >30μM for mGluR2 ^[26]
• MNI-137: ^[27] inhibitor
• VU-0650786: NAM ^[28]
• compound 7p: ^[29] non-competitive antagonist (presumably allosteric inhibitor)
• LY 2389575: negative allosteric modulator. ^[30]

Interactions

Metabotropic glutamate receptor 3 has been shown to interact with:

• GRIP1, ^[31]
• PICK1, ^[31] and
• PPM1A. ^[32]

See also

• Metabotropic glutamate receptor

References

1. GRCh38: Ensembl release 89: ENSG00000198822 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Ambrosini A, Bresciani L, Fracchia S, Brunello N, Racagni G (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" (abstract). Molecular Pharmacology. 47 (5): 1057–64. PMID   7746273.
5. Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, et al. (October 1997). "Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus". The Journal of Neuroscience. 17 (19): 7503–22. doi:10.1523/JNEUROSCI.17-19-07503.1997. PMC   6573434 . PMID   9295396.
6. Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AF, Paspalas CD (March 2018). "mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks". Cerebral Cortex. 28 (3): 974–987. doi:10.1093/cercor/bhx005. PMC   5974790 . PMID   28108498.
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8. "Entrez Gene: GRM3 glutamate receptor, metabotropic 3".
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18. Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, et al. (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. 42 (6): 1027–40. doi:10.1021/jm980616n. PMID   10090786.
19. Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, et al. (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. 40 (4): 528–37. doi:10.1021/jm9606756. PMID   9046344.
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21. Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, et al. (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. 61 (6): 2303–2328. doi:10.1021/acs.jmedchem.7b01481. PMID   29350927.
22. Clausen RP, Bräuner-Osborne H, Greenwood JR, Hermit MB, Stensbøl TB, Nielsen B, Krogsgaard-Larsen P (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. 45 (19): 4240–5. doi:10.1021/jm020122x. PMID   12213064.
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30. Zinni M, Mairesse J, Pansiot J, Fazio F, Iacovelli L, Antenucci N, Orlando R, Nicoletti F, Vaiman D, Baud O (January 2021). "mGlu3 receptor regulates microglial cell reactivity in neonatal rats". Journal of Neuroinflammation. 18 (1): 13. doi: 10.1186/s12974-020-02049-z . PMC   7789385 . PMID   33407565.
31. Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". The Journal of Biological Chemistry. 277 (18): 15221–4. doi: 10.1074/jbc.C200112200 . PMID   11891216.
32. Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P (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. 100 (26): 16006–11. Bibcode:2003PNAS..10016006F. doi: 10.1073/pnas.2136600100 . PMC   307683 . PMID   14663150.

Further reading

• Makoff A, Volpe F, Lelchuk R, Harrington K, Emson P (August 1996). "Molecular characterization and localization of human metabotropic glutamate receptor type 3". Brain Research. Molecular Brain Research. 40 (1): 55–63. doi:10.1016/0169-328X(96)00037-X. PMID   8840013.
• Emile L, Mercken L, Apiou F, Pradier L, Bock MD, Menager J, et al. (May 1996). "Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3". Neuropharmacology. 35 (5): 523–30. doi:10.1016/0028-3908(96)84622-3. PMID   8887960. S2CID   12697831.
• Corti C, Sala CF, Yang F, Corsi M, Xuereb JH, Ferraguti F (December 2000). "Genomic organization of the human metabotropic glutamate receptor subtype 3". Journal of Neurogenetics. 14 (4): 207–25, 271. doi:10.3109/01677060009084499. PMID   11342382. S2CID   44398182.
• Corti C, Xuereb JH, Corsi M, Ferraguti F (August 2001). "Identification and characterization of the promoter region of the GRM3 gene". Biochemical and Biophysical Research Communications. 286 (2): 381–7. doi:10.1006/bbrc.2001.5391. PMID   11500049.
• Tomiyama M, Kimura T, Maeda T, Tanaka H, Furusawa K, Kurahashi K, Matsunaga M (August 2001). "Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis". Journal of the Neurological Sciences. 189 (1–2): 65–9. doi:10.1016/S0022-510X(01)00561-5. PMID   11535235. S2CID   34762564.
• Rosemond E, Peltekova V, Naples M, Thøgersen H, Hampson DR (March 2002). "Molecular determinants of high affinity binding to group III metabotropic glutamate receptors". The Journal of Biological Chemistry. 277 (9): 7333–40. doi: 10.1074/jbc.M110476200 . PMID   11744707.
• Martí SB, Cichon S, Propping P, Nöthen M (January 2002). "Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population". American Journal of Medical Genetics. 114 (1): 46–50. doi:10.1002/ajmg.1624. PMID   11840505.
• Kitano J, Kimura K, Yamazaki Y, Soda T, Shigemoto R, Nakajima Y, Nakanishi S (February 2002). "Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins". The Journal of Neuroscience. 22 (4): 1280–9. doi:10.1523/JNEUROSCI.22-04-01280.2002. PMC   6757580 . PMID   11850456.
• Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". The Journal of Biological Chemistry. 277 (18): 15221–4. doi: 10.1074/jbc.C200112200 . PMID   11891216.
• Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, et al. (June 2003). "Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia". Psychiatric Genetics. 13 (2): 71–6. doi:10.1097/01.ypg.0000056682.82896.b0. PMID   12782962. S2CID   22535773.
• Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (May 2003). "Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins". The European Journal of Neuroscience. 17 (10): 2106–18. doi:10.1046/j.1460-9568.2003.02657.x. PMID   12786977. S2CID   23408003.
• Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P (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. 100 (26): 16006–11. Bibcode:2003PNAS..10016006F. doi: 10.1073/pnas.2136600100 . PMC   307683 . PMID   14663150.
• Yao Y, Koo JC, Wells JW, Hampson DR (June 2004). "Expression of a truncated secreted form of the mGluR3 subtype of metabotropic glutamate receptor". Biochemical and Biophysical Research Communications. 319 (2): 622–8. doi:10.1016/j.bbrc.2004.05.032. PMID   15178451.
• Tang FR, Chia SC, Chen PM, Gao H, Lee WL, Yeo TS, et al. (2004). "Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus". Epilepsy Research. 59 (2–3): 167–80. doi:10.1016/j.eplepsyres.2004.04.002. PMID   15246118. S2CID   6205182.
• Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, et al. (August 2004). "Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia". Proceedings of the National Academy of Sciences of the United States of America. 101 (34): 12604–9. Bibcode:2004PNAS..10112604E. doi: 10.1073/pnas.0405077101 . PMC   515104 . PMID   15310849.

External links

• "Metabotropic Glutamate Receptors: mGlu₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

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