Metabotropic glutamate receptor 2

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene.^[5][6] mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit.^[7] The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

GRM2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4XAQ, 4XAS, 5CNI, 5CNJ
Identifiers
Aliases	GRM2, GPRC1B, MGLUR2, mGlu2, glutamate metabotropic receptor 2, mGluR2, GLUR2
External IDs	OMIM: 604099; MGI: 1351339; HomoloGene: 20229; GeneCards: GRM2; OMA:GRM2 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p21.2 Start 51,707,068 bp[1] End 51,718,613 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 F1 Start 106,520,294 bp[2] End 106,533,281 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in vena cava right frontal lobe prefrontal cortex right testis left testis Brodmann area 9 endothelial cell ganglionic eminence Pons gonad Top expressed in zygote secondary oocyte primary oocyte dentate gyrus of hippocampal formation granule cell primary visual cortex mammillary body prefrontal cortex olfactory bulb hippocampus proper superior frontal gyrus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function glutamate receptor activity G protein-coupled receptor activity group II metabotropic glutamate receptor activity calcium channel regulator activity signal transducer activity protein binding Cellular component integral component of membrane cell projection membrane plasma membrane synapse integral component of plasma membrane intracellular anatomical structure axon cell junction dendrite neuron projection presynaptic membrane integral component of postsynaptic membrane Biological process negative regulation of adenylate cyclase activity glutamate secretion 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 glutamate homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2912 108068 Ensembl ENSG00000164082 ENSMUSG00000023192 UniProt Q14416 Q14BI2 RefSeq (mRNA) NM_000839 NM_001349116 NM_001349117 NM_001160353 RefSeq (protein) NP_000830 NP_001336045 NP_001336046 NP_001153825 Location (UCSC) Chr 3: 51.71 – 51.72 Mb Chr 9: 106.52 – 106.53 Mb PubMed search [3] [4]
Wikidata
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Structure

In humans, mGluR2 is encoded by the GRM2 gene on chromosome 3. At least three protein-coding isoforms are predicted based on genomic information, as well as numerous non-coding isoforms. The mGluR2 protein is a seven-pass transmembrane protein.

Function

In humans, mGluR2 is only expressed in the brain, and not in any other tissue.^[8] In the brain, mGluR2 is expressed in neurons as well as astrocytes. Subcellularly, mGluR2 is predominantly positioned at the presynaptic terminal, although it is also expressed at the postsynaptic terminal.^[9]

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 mGluR2 (this receptor) 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.^[6]

Protein–protein interactions

mGluR2 is able to form a heteromeric complex with various other different GPCRs. One example is with isoform mGluR4. The mGluR2-mGluR4 heteromer exhibits a pharmacological profile distinct from the parent receptor monomers.^[10] Another example is with serotonin receptor 2A (5HT2A); see below.

Pharmacology

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.^[11] mGluR2 potentiation is a new approach for the treatment of schizophrenia.^[12][13] On the other hand, antagonists and negative allosteric modulators of mGluR_2/3 have potential as antidepressant drugs.^{[14][15][16][17][18]}

Agonists

• Compound 1d (see reference)^[19][20]
• LY-2812223

PAMs

Highly selective mGluR2 PAM (2010),^[21] analog of BINA

• JNJ-46356479^[22]
• JNJ-40411813^[23]
• GSK-1331258^[24]
• Imidazo[1,2-a]pyridines^[25]
• 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones^[26]
• 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable^[27]
• BINA:^[28][29] potent; modest ago-allosteric modulator; robust in-vivo activity.
• LY-487,379:^[30][31][32] devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides^[33][34] the first subtype-2-selective potentiator published (2003).

Antagonists

• LY-341,495
• MGS-0039
• EGLU

NAMs

• 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.^[35]
• MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one^[36]
• RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one^[37]

Role in hallucinogenesis

Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors.^[38][39] Lisuride acts preferentially or exclusively on the non-heteromerized 5HT2A receptors, which are not capable of inducing psychedelic effects. Due to this, lisuride is capable of reducing the hallucinogenic effects of these drugs through competitive antagonistic activity (producing the effect of a silent antagonist in the presence of these drugs).

Strong agonists for either subunit of the 5HT2A-mGlu2R heterocomplex suppress signaling through the partner subunit and inverse agonists for either subunit potentiate the signaling through the partner subunit.

Role in rabies virus infection

mGluR2 has been found to be a novel receptor for rabies virus.^[40] The virus has a glycoprotein on its surface which interacts with the receptor. Rabies virus can bind to mGLuR2 directly and the virus-receptor complex is internalized into the cell together. The complex is then transported into early and late endosomes. Rabies virus enters the cells by clathrin-independent endocytosis which could suggest that mGLuR2 also uses this pathway. It is still to be clarified whether the Rabies virus glycoprotein can act as a PAM or NAM and in such a way affect the function of the receptor.

See also

• Metabotropic glutamate receptor