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.
Function and structure
The mGluRs perform a variety of functions in the central and peripheral nervous systems: For example, they are involved in
learning,
memory,
anxiety, and the perception of
pain.
They are found in pre- and postsynaptic
in
of the
hippocampus,
cerebellum,
and the
cerebral cortex, as well as other parts of the
brain and in peripheral tissues.
Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane.[Sladeczek F., Momiyama A.,Takahashi T. (1992). "Presynaptic inhibitory action of metabotropic glutamate receptor agonist on excitatory transmission in visual cortical neurons". Proc. Roy. Soc. Lond. B 1993 253, 297-303.] or modulation and even induction of postsynaptic responses.
A GPCR oligomer of mGluRs is required for signaling induced by .
Classification
Eight different types of mGluRs, labeled mGluR
1 to mGluR
8 ( to ), are divided into groups I, II, and III.
Receptor types are grouped based on receptor structure and physiological activity.
The mGluRs are further divided into subtypes, such as mGluR
7a and mGluR
7b.
Overview
| +Overview of glutamate receptors |
|
|
| mGluR5 | Gq, ↑sodium channel, |
|
| mGluR3 | Gi/G0 |
|
| mGluR6 | Gi/G0 |
| mGluR7 | Gi/G0 |
| mGluR8 | Gi/G0 |
|
Group I
The mGluRs in group I, including mGluR
1 and mGluR
5, are stimulated most strongly by the excitatory
amino acid analog L-quisqualic acid.
Stimulating the receptors causes the associated
enzyme phospholipase C to hydrolyze
phosphoinositide in the cell's
plasma membrane.
This leads to the formation of inositol 1,4,5-trisphosphate (IP3) and
diacyl glycerol. Due to its hydrophilic character, IP3 can travel to the endoplasmic reticulum, where it induces, via fixation on its receptor, the opening of
calcium channels increasing in this way the
cytosolic calcium concentrations. The lipophilic
diacylglycerol remains in the membrane, acting as a cofactor for the activation of protein kinase C.
These receptors are also associated with sodium channel and K+ channels.
Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine (DHPG),
Group II and Group III
The receptors in group II, including mGluRs 2 and 3, and group III, including mGluRs 4, 6, 7, and 8, (with some exceptions) prevent the formation of cyclic adenosine monophosphate, or cAMP, by activating a
G protein that inhibits the enzyme
adenylyl cyclase, which forms cAMP from ATP.
[MRC (Medical Research Council), Glutamate receptors: Structures and functions. , University of Bristol Centre for Synaptic Plasticity (2003). Retrieved January 20, 2008.] These receptors are involved in presynaptic inhibition,
and do not appear to affect postsynaptic membrane potential by themselves. Receptors in groups II and III reduce the
activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex.
The chemicals 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) and eglumegad activate only group II mGluRs, while 2-amino-4-phosphonobutyrate (L-AP4) activates only group III mGluRs.
LY-341,495 and MGS-0039 are drugs that act as a selective antagonist blocking both of the group II metabotropic glutamate receptors, mGluR2 and mGluR3.
Localization
Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are located mostly on postsynaptic parts of cells, while groups II and III are mostly located on presynaptic elements,
though they have been found on both pre- and postsynaptic membranes.
Also, different mGluR subtypes are found predominantly in different parts of the body. For example, mGluR4 is located only in the brain, in locations such as the thalamus, hypothalamus and caudate nucleus.[InterPro. InterPro: IPR001786 Metabotropic glutamate receptor 4. Retrieved on January 20, 2008.] All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex.
Roles
It is thought that mGluRs play a role in a variety of different functions.
Modulation of other receptors
Metabotropic glutamate receptors are known to act as modulators of (affect the activity of) other receptors. For example, group I mGluRs are known to increase the activity of
NMDA receptor (NMDARs),
a type of ion channel-linked receptor that is central in a
neurotoxicity process called
excitotoxicity. Proteins called
frequently anchor mGluRs near enough to NMDARs to modulate their activity.
It has been suggested that mGluRs may act as regulators of neurons' vulnerability to excitotoxicity (a deadly neurochemical process involving glutamate receptor overactivation) through their modulation of NMDARs, the receptor most involved in that process.
Group II
Metabotropic glutamate receptors are also thought to affect and adrenergic neurotransmission.
Role in plasticity
Like other glutamate receptors, mGluRs have been shown to be involved in synaptic plasticity
and in neurotoxicity and neuroprotection.
They participate in long term potentiation and long term depression, and they are removed from the synaptic membrane in response to agonist binding.
Roles in disease
Since metabotropic glutamate receptors are involved in a variety of functions, abnormalities in their expression can contribute to disease. For example, studies with mutant mice have suggested that mutations in expression of mGluR
1 may be involved in the development of certain types of cancer.
In addition, manipulating mGluRs can be useful in treating some conditions. For example, clinical trial suggested that an mGlu
2/3 agonist, LY354740, was effective in the treatment of generalized anxiety disorder.
Also, some researchers have suggested that activation of mGluR
4 could be used as a treatment for Parkinson's disease.
Most recently, Group I mGluRs, have been implicated in the pathogenesis of
Fragile X, a type of
autism,
and a number of studies are currently testing the therapeutic potential of drugs that modify these receptors.
There is also growing evidence that group II metabotropic glutamate receptor agonists may play a role in the treatment of schizophrenia. Schizophrenia is associated with deficits in cortical inhibitory interneurons that release GABA and synaptic abnormalities associated with deficits in NMDA receptor function.
These inhibitory deficits may impair cortical function via cortical disinhibition and asynchrony.
The drug
Eglumegad (also known as
Eglumegad, an mGlu
2/3 agonist) was shown to attenuate physiologic and cognitive abnormalities in animal and human studies of NMDA receptor antagonist and
serotonin hallucinogen effects,
supporting the subsequent clinical evidence of efficacy for an mGluR
2/3 agonist in the treatment of schizophrenia.
The same drug has been shown to interfere in the hypothalamic–pituitary–adrenal axis, with chronic oral administration of this drug leading to markedly reduced baseline
cortisol levels in bonnet macaques (
Macaca radiata); acute infusion of
Eglumegad resulted in a marked diminution of
yohimbine-induced
stress response in those animals.
has also been demonstrated to act on the metabotropic glutamate receptor 3 (GRM3) of human
adrenal cortex, downregulating aldosterone synthase, CYP11B1, and the production of
adrenal steroids (i.e.
aldosterone and
cortisol).
History
The first demonstration that glutamate could induce the formation of molecules belonging to a major second messenger system was in 1985, when it was shown that it could stimulate the formation of inositol phosphates.
This finding allowed in 1987 to yield an explanation for oscillatory ionic glutamate responses and to provide further evidence for the existence of metabotropic glutamate receptors.
In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned.
More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems
suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.
Further reading
External links
