Metabotropic glutamate receptor 3

Metabotropic glutamate receptor 3 is a is_associated_with::protein that in humans is encoded by the GRM3 is_associated_with::gene.

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.

Clinical significance
The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with is_associated_with::bipolar affective disorder. 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<10−9. A follow-up study of the Kozak sequence variant showed that it was associated with increased risk of bipolar disorder, schizophrenia and alcoholism. Thus GRM3 is likely to contribute to the genetic susceptibility of a variety of mental disorders. 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. This might become the first example of personalised medicine based on genetics for psychiatric disorders. 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 is_associated_with::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
 * (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

Antagonists

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



Allosteric modulators

 * D3-ML337: selective NAM, is_associated_with::IC50 = 450 nM for mGluR3, IC50 >30μM for mGluR2
 * MNI-137: inhibitior
 * compound 7p: non-competitive antagonist (presumably allosteric inhibitor)

Interactions
Metabotropic glutamate receptor 3 has been shown to interact with:
 * GRIP1,
 * is_associated_with::PICK1, and
 * is_associated_with::PPM1A.