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, respo ...

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 ba ...

. 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 referred ...

. 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 syn ...

, 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

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. N ...

s as well as astrocytes. Subcellularly, mGluR2 is predominantly positioned at the presynaptic terminal, 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 condu ...

. 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 The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and ...

and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes mGluR2 (this receptor) and

GRM3 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 lo ...

while Group III includes

GRM4 Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the ''GRM4'' gene. Together with GRM6, GRM7 and GRM8 it belongs to group III of the metabotropic glutamate receptor family. Group III receptors are linked to the inhibi ...

GRM6 Glutamate receptor, metabotropic 6, also known as GRM6 or mGluR6, is a protein which in humans is encoded by the ''GRM6'' gene. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ion ...

GRM7 Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the ''GRM7'' gene. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamat ...

and

GRM8 Metabotropic glutamate receptor 8 is a protein that in humans is encoded by the ''GRM8'' gene. Function L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamat ...

. 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 transd ...

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 Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the ''GRM4'' gene. Together with GRM6, GRM7 and GRM8 it belongs to Metabotropic glutamate receptor#Group II & Group III, group III of the metabotropic glutamate receptor ...

. 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 In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

(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-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

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'' The comma is a punctuation mark that appears in several variants in different languages. It has the same shape as an apostrophe or single closing quotation mark () in many typefaces, but it differs from them in being placed on the baseline o ...

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)phenyl The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as such. ...

1,3-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 activi ...

- 4-

-(2,6-dimethylpyridin-4-yl)phenyl The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as such. ...

7-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, v ...

) 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 sh ...

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 agon ...

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. 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 Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...

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