Metabotropic glutamate receptor 2
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.

# 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. 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.
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.

# Proteinprotein 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. 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. mGluR2 potentiation is a new approach for the treatment of schizophrenia. On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.

## Agonists
- Compound 1d (see reference)

## PAMs
- JNJ-46356479
- JNJ-40411813
- GSK-1331258
- Imidazopyridines
- 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones
- 3-(Imidazolyl methyl)-3-aza-bicyclohexan-6-yl)methyl ethers: potent, orally stable
- BINA: potent; modest ago-allosteric modulator; robust in-vivo activity.
- LY-487,379: devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides the first subtype-2-selective potentiator published (2003).

## Antagonists
- LY-341,495
- MGS-0039
- EGLU

## NAMs
- 7,8-dichloro-4--1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.
- MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzodiazepin-2(3H)-one
- RO4491533 - 4--7-methyl-8-trifluoromethyl-1,3-dihydrobenzodiazepin-2-one

# 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. 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 agonistic activity (producing the effect of a silent-agonist 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.