GRM2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | GRM2 , GPRC1B, MGLUR2, mGlu2, glutamate metabotropic receptor 2, mGluR2, GLUR2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 604099 MGI: 1351339 HomoloGene: 20229 GeneCards: GRM2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
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.
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.
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]
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.
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 mGluR2/3 have potential as antidepressant drugs. [14] [15] [16] [17] [18]
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.
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.
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.
Fenobam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. Subsequently, it was determined that fenobam acts as a potent and selective negative allosteric modulator of the metabotropic glutamate receptor subtype mGluR5, and it has been used as a lead compound for the development of a range of newer mGluR5 antagonists.
The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein.
Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory Gi/G0-coupled G-protein coupled receptor (GPCR) generally localized to presynaptic sites of neurons in classical circuits. However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity. In humans, mGluR3 is encoded by the GRM3 gene. Deficits in mGluR3 signaling have been linked to impaired cognition in humans, and to increased risk of schizophrenia, consistent with their expanding role in cortical evolution.
Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.
Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the GRM5 gene.
Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.
Metabotropic glutamate receptor 8 is a protein that in humans is encoded by the GRM8 gene.
LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors (mGluR2/3).
Biphenylindanone A is a research agent which acts as a potent and selective positive allosteric modulator for the group II metabotropic glutamate receptor subtype mGluR2.
ADX-47273 is a research pharmaceutical developed by Addex Therapeutics which acts as a positive allosteric modulator (PAM) selective for the metabotropic glutamate receptor subtype mGluR5. It has nootropic and antipsychotic effects in animal studies, and has been used as a lead compound to develop improved derivatives.
SIB-1893 is a drug used in scientific research which was one of the first compounds developed that acts as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It has anticonvulsant and neuroprotective effects, and reduces glutamate release. It has also been found to act as a positive allosteric modulator of mGluR4.
CDPPB is a drug used in scientific research which acts as a positive allosteric modulator selective for the metabotropic glutamate receptor subtype mGluR5. It has antipsychotic effects in animal models, and mGluR5 modulators are under investigation as potential drugs for the treatment of schizophrenia, as well as other applications.
Ro01-6128 is a drug used in scientific research, which acts as a selective positive allosteric modulator for the metabotropic glutamate receptor subtype mGluR1. It was derived by modification of a lead compound found via high-throughput screening, and was further developed to give the improved compound Ro67-4853.
Ro67-4853 is a drug used in scientific research, which acts as a selective positive allosteric modulator for the metabotropic glutamate receptor subtype mGluR1. It was derived by modification of the simpler compound Ro01-6128, and has itself subsequently been used as a lead compound to develop a range of potent and selective mGluR1 positive modulators.
LY-487,379 is a drug used in scientific research that acts as a selective positive allosteric modulator for the metabotropic glutamate receptor group II subtype mGluR2. It is used to study the structure and function of this receptor subtype, and LY-487,379 along with various other mGluR2/3 agonists and positive modulators are being investigated as possible antipsychotic and anxiolytic drugs.
VU-0238429 is a drug which acts as a selective positive allosteric modulator for the muscarinic acetylcholine receptor M5. It was the first selective ligand developed for the M5 subtype, and is structurally derived from older M1-selective positive allosteric modulators such as VU-0119498. Replacing the O-methyl- by a phenyl group further improves the receptor subtype selectivity.
CBiPES is a drug used in scientific research that acts as a selective positive allosteric modulator for the metabotropic glutamate receptor group II subtype mGluR2. It has potentially antipsychotic effects in animal models, and is used for researching the role of mGluR2 receptors in schizophrenia and related disorders.
ADX-71149, also known as JNJ-40411813 and JNJ-mGluR2-PAM, is a selective positive allosteric modulator of the mGlu2 receptor. It is being studied by Addex Therapeutics and Janssen Pharmaceuticals for the treatment of schizophrenia. It was also researched by these companies for the treatment of anxious depression, but although some efficacy was observed in clinical trials, it was not enough to warrant further development for this indication. As of 2015, ADX-71149 is in phase II clinical trials for schizophrenia.
AZD 9272 is a drug which acts as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It was unsuccessful in human trials as an analgesic, but continues to be widely used in research especially as its radiolabelled forms.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.