Metabotropic glutamate receptor 2 (mGluR2) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that, in humans, is encoded by the ''GRM2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. mGluR2 is a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

(GPCR) that couples with the

Gi alpha subunit Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referre ...

. The receptor functions as an autoreceptor for

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

, that upon activation, inhibits the emptying of vesicular contents at the

presynaptic terminal Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

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

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

s as well as

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s. Subcellularly, mGluR2 is predominantly positioned at the

, although it is also expressed at the

postsynaptic terminal Axon terminals (also called synaptic boutons, terminal boutons, or end-feet) are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that con ...

. The metabotropic glutamate receptors are a family of

s, 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 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. Function The amino acid L-glutamate is the ...

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 Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...

cascade but differ in their agonist selectivities.

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. 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 mGluR_2/3 have potential as

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...

drugs.

Agonists

* Compound 1d (see reference) * LY-2812223

PAMs

* JNJ-46356479 *

JNJ-40411813 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 r ...

*GSK-1331258 *Imidazo ,2-''a''yridines *3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones *3-(Imidazolyl methyl)-3-aza-bicyclo .1.0exan-6-yl)methyl ethers: potent, orally stable * BINA: potent; modest ago-allosteric modulator; robust in-vivo activity. *

LY-487,379 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 ...

: devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides the first subtype-2-selective potentiator published (2003).

Antagonists

LY-341,495 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). It is used in scientific research in severa ...

MGS-0039 MGS-0039 is a drug that is used in neuroscientific research, which acts as a potent and selective antagonist for group II of the metabotropic glutamate receptors ( mGluR2/3). It produces antidepressant and anxiolytic effects in animal studies, ...

EGLU EGLU ((2S)-α-ethylglutamic acid ) is a drug that is used in neuroscience research. It was one of the first compounds found that acts as a selective antagonist for the group II metabotropic glutamate receptors (mGluR2/3), and so has been useful ...

NAMs

* 7,8-dichloro-4- -(2-methylpyridin-4-yl)phenyl1,3-dihydro-1,5-benzodiazepin-2-one and related compounds. * MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo 1,4]diazepin-2(3H)-one *

RO4491533 RO-4491533 is a drug developed by Hoffmann-La Roche which acts as a potent and selective negative allosteric modulator for group II of the metabotropic glutamate receptors ( mGluR2/3), being equipotent at mGluR2 and mGluR3 but without activity ...

- 4- -(2,6-dimethylpyridin-4-yl)phenyl7-methyl-8-trifluoromethyl-1,3-dihydrobenzo 1,4]diazepin-2-one

Role in hallucinogenesis

Many psychedelic drug, psychedelic drugs (e.g.

LSD-25 Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...

) produce their effects by binding to the oligomerized complexes of the

5HT2A The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is s ...

and mGlu2 receptors.

Lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...

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 agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse ago ...

s 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 Rabies virus, scientific name ''Rabies lyssavirus'', is a neurotropic virus that causes rabies in humans and animals. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. ''Rabies lys ...

. 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.

References

External links

* {{Metabotropic glutamate receptor modulators Metabotropic glutamate receptors