Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of
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.[2] They are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum,[3] and the cerebral cortex, as well as other parts of the brain and in peripheral tissues.[4]
Like other
A dimeric organization of mGluRs is required for signaling induced by agonists.[9]
Classification
Eight different types of mGluRs, labeled mGluR1 to mGluR8 (GRM1 to GRM8), are divided into groups I, II, and III.[1][3][4][8] Receptor types are grouped based on receptor structure and physiological activity.[2] The mGluRs are further divided into subtypes, such as mGluR7a and mGluR7b.
Overview
Family | Receptors [10][11] | Gene | Mechanism[10] | Function | Agonists & Activators | Antagonists | Synapse site |
---|---|---|---|---|---|---|---|
Group I | mGluR1 | GRM1 |
glutamate[8]
|
|
|
|
mainly postsynaptic[14] |
mGluR5 | GRM5 |
glutamate[8]
| |||||
Group II | mGluR2 | GRM2 |
Gi/G0
|
|
|
mainly presynaptic[14] | |
mGluR3 | GRM3 |
Gi/G0
| |||||
Group III | mGluR4 | GRM4 |
Gi/G0
|
|
|
mainly presynaptic[14] | |
mGluR6 | GRM6 |
Gi/G0
| |||||
mGluR7 | GRM7 |
Gi/G0
| |||||
mGluR8 | GRM8 |
Gi/G0
|
Group I
The mGluRs in group I, including mGluR1 and mGluR5, are stimulated most strongly by the excitatory
These receptors are also associated with
Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine (DHPG),[14] a fact that is useful to experimenters because it allows them to isolate and identify them.
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.[1][3][4][17] These receptors are involved in presynaptic inhibition,[8] 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.[4]
The chemicals
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,[14] though they have been found on both pre- and postsynaptic membranes.[8]
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.[20] All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex.[14]
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
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[25] and III[23] mGluRs tend to protect neurons from excitotoxicity,[15][26][27] possibly by reducing the activity of NMDARs.
Metabotropic glutamate receptors are also thought to affect dopaminergic and adrenergic neurotransmission.[28]
Role in plasticity
Like other
They participate in
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 mGluR1 may be involved in the development of certain types of cancer.[31] In addition, manipulating mGluRs can be useful in treating some conditions. For example, clinical trial suggested that an mGlu2/3 agonist, LY354740, was effective in the treatment of generalized anxiety disorder.[32] Also, some researchers have suggested that activation of mGluR4 could be used as a treatment for Parkinson's disease.[33] Most recently, Group I mGluRs, have been implicated in the pathogenesis of
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.[45] 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.[46] In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned.[47] More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems[48][49] suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.
References
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Further reading
- Jin, Chaobin; Ma, Shutao (2017). "Recent advances in the medicinal chemistry of group II and group III mGlu receptors". Med. Chem. Commun. 8 (3): 501–515. PMID 30108768.
- O'Brien DE, Conn PJ (2016). "Neurobiological Insights from mGlu Receptor Allosteric Modulation". Int. J. Neuropsychopharmacol. 19 (5): pyv133. PMID 26647381.
- Gregory KJ, Conn PJ (2015). "Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation". Mol. Pharmacol. 88 (1): 188–202. PMID 25808929.
External links
- Metabotropic+Glutamate+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)