Metabotropic gutamate receptor (mGluR) mini-review
Overview
OverviewMetabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCRs) that bind glutamate to activate signaling cascades [1,2,3]. mGluRs modulate other receptors such as NMDA, AMPA and kainate receptors and are linked to many diseases, disorders and processes. These include chronic pain, learning and memory, anxiety disorders, epilepsy, pain, drug addiction, Parkinsons Disease, Schizophrenia. hypoxic brain damage and excitotoxic neuronal death [4,5,6,7,8,9,10]. Written by our expert PhD qualified technical team, and endorsed by our Scientific Advisory Board, this mini-review provides a summary of the structure, function and known pharmacology of mGluRs to date.
Metabotropic Glutamate Receptor Groups
Metabotropic glutamate receptors are separated into Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8) receptors[11] and are found in both the central and peripheral nervous systems. This classification is based on sequence similarities, pharmacological properties, and intracellular signal transduction mechanisms [12].
mGluR Structure
mGluR StructuremGlu receptors join the GABAB receptor, Ca2+ sensing receptors, pheremone receptors and taste receptors to form a superfamily of receptors that are distinct from adrenergic-type GPCRs. Both receptor superfamilies possess a 7-transmembrane domain motif (TMD), but mGlu receptors possess a much larger N-terminal domain and no large inter-helical loops, in contrast to the adrenergic-type GPCRs. Alternative splice variants are also found for mGlu1, mGlu3, mGlu5, mGlu6, mGlu7 and mGlu8 receptors.
mGlu receptor dimerization
mGluRs can be activated as individual, monomeric receptors but also exist as dimers. This involves the formation of di-sulphide linkages between the N-terminal domains of the two individual receptors. Under non-reducing conditions, nearly all mGluR populations exist in this form [13]. Thus the individual receptor proteins can be viewed as subunits while the dimer is viewed as the receptor proper.
Ligand Binding Domain (LBD) - the Venus Fly Trap
The large N-terminal domain of the mGlu receptor contains the ligand binding site, which is formed by two hinged globular domains - the “Venus Flytrap Domain” (VFD). Binding of glutamate causes the two domains to close, causing changes in the TMD that leads to G-protein activation.[14]
Activation of mGluRs and the G-protein cascade
Glutamate, the main excitatory amino acid neurotransmitter in the central nervous system (CNS), activates mGluRs. This then leads to activation of associated G proteins; bound GTP is exchanged for GDP and second messenger cascades are activated causing depolarization and excitatory neurotransmission [15].
The second messenger cascades can be different for different mGluRs. Group I mGluRs are coupled with phospholipase C (PLC) through Gq proteins; excitation causes increased levels of IP3 and diacylglycerol followed by Ca2+ release from intracellular stores and protein kinase C (PKC) activation [16]. Group II and III mGluRs are associated primarily with Gi/o class G proteins and inhibit adenylyl cyclase. [15].These G proteins are coupled to ion channels or PLC; they can also suppress cAMP synthesis after strong activation of adenylyl cyclase
Functions of mGluRs
mGluRs are involved in many biological functions, including:
- Slow excitatory and inhibitory responses
- Regulation of Ca2+, K+, and nonselective cation channels
- Inhibition and facilitation of transmitter release
- Induction of LTP/LTD
- Formation of various types of memory
- Regulation of iGluR trafficking
- Modification of NMDAR-mediated synaptic transmission
- Regulation of neuronal development
- Signalling between neurons and glial cells
Metabotropic glutamate receptors are intimately involved in synaptic plasticity and learning and memory, and their role is complex. In vivo studies show that the involvement of mGlu receptors in hippocampal-dependent learning depends on the task and its relationship to synaptic plasticity. Electrophysiological studies demonstrate a crucial role for mGlu receptors in persistent forms of hippocampus-dependent synaptic plasticity.
Long-term potentiation and long-term depression (LTD) represent the best characterized forms of plasticity. Long-term potentiation (LTP ) is the biological process by which certain types of synaptic stimulation – such as prolonged high frequency input – result in a long-lasting increase in the strength of synaptic transmission. LTD is a long-lasting decrease in the efficacy and strength of synaptic transmission [17]
Recent studies indicate that group II and group III mGlu receptors may be less important for the regulation of LTP, but have a crucial role in the regulation of persistent LTD and long-term spatial memory. In contrast, group I mGlu receptors are critically involved in both persistent LTP and LTD and in hippocampus-dependent forms of memory [18]. The tables below summarises the influence of mGlu receptors on LTP and LTD. Multiple signaling mechanisms have been implicated in mGluR-LTD, illustrating the complexity of this form of plasticity. For a summary of the mechanisms involving mGlu5 and mGlu1, please see the Hello Bio pathway poster: Major signaling mechanisms involved in mGlu5 and mGlu1 LTD
Table 1: Summary of the influence of mGlu receptors on Long-Term Potentiation
| mGluR group | Group I | Group II | Group III | |
| mGluR subtype | mGlu1 | mGlu5 | mGlu2, mGlu3 | mGlu4, mGlu7, mGlu8 |
| Agonists | - | facilitate STP into persistent LTP | raise LTP threshold | raise LTP threshold |
| Antagonists | impair CA1 & DG persistent LTP by reducing induction | reduce induction & prevent maintenance in CA1 & DG | No effect | No effect |
| Knockout | impaired CA1 LTP, impaired mf LTP | impaired CA1 & DG LTP, normal mf LTP | normal mf LTP | - |
Table 2: Summary of the influence of mGlu receptors on Long-Term Depression
| mGluR group | Group I | Group II | Group III | |
| mGluR subtype | mGlu1 | mGlu5 | mGlu2, mGlu3 | mGlu4, mGlu7, mGlu8 |
| Agonists | - | facilitate STD into persistent LTD | facilitate STD into LTD | facilitate STD into LTD |
| Antagonists | impair LTD by reducing induction and preventing maintenance in CA1 & DG | impair LTD in CA1 & DG | block persistent LTD | block persistent LTD |
| Knockout | normal CA1 LTD | - | - | - |
Abbreviations: dentate gyrus (DG); long-term potentiation (LTP); long-term depression (LTD); mossy fibre (mf); short-term depression (STD); short-term potentiation (STP). For review see [15]
Metaplasticity is also mediated by mGluRs in which prior changes in a synapse and prior activation of mGluRs alters the expression of synaptic plasticity. Group I mGluRs mediate persistent stable LTP due to increased protein synthesis at the synapse. Group II mGluR priming increases dentate gyrus LTD expression and inhibits LTP expression [18].
Mechanisms by which mGlu receptors are thought to exert their influence on synaptic plasticity include:
- initiating signaling cascades that lead to stabilization of synaptic plasticity,
- regulating the permeability of NMDA receptors [19] to influence the induction phases of synaptic plasticity
- influencing protein–protein interactions within the synaptic scaffold, thus altering synaptic communication [20]
Pathology
Metabotropic glutamate receptors are vital for learning and memory; dysfunctional mGluRs are associated with memory-impairing neurological diseases such as Fragile X Syndrome, intellectually disability and autism [21,22]. The receptors are also potential therapeutic targets for a multitude of other neurological conditions, such as neurodegenerative diseases (eg. Parkinson’s and Alzheimer’s Disease), Schizophrenia, pain, drug addiction, epilepsy, depression and anxiety disorders such as obsessive compulsive disorder (OCD) [8,9,10].
Pharmacology
mGluRs are activated by the endogenous ligands L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Over recent years, a growing number of ligands have been developed with selectivity for the different mGluR groups, and mGluR subtypes.
Group selectivity
Examples of agonists selective for mGlu receptors compared with ionotropic glutamate receptors are (1S,3R)-ACPD and L-CCG-I, which show limited selectivity for Group-II receptors. In terms of an mGIuR antagonist, LY 341495, blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range.
Group-I mGlu receptors may be activated by (S)-3,5-DHPG. Group-II mGlu receptors may be activated by LY 354740 and antagonised by (+/-) -LY395756. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG and antagonised by MSOP.
Subtype selectivity
A wealth of subtype selective agonists and antagonists have been developed, for example: CHPG (mGlu5 agonist), MTEP (mGlu5 antagonist), AMN082 (mGlu8 agonist) MDCPG (mGlu8 antagonist) and XAP 044 (mGlu7 antagonist).
Modulators
In addition to orthosteric ligands that directly interact with the glutamate recognition site directly, allosteric modulators have been reported. Positive allosteric modulators (PAMs) often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist. Examples are BINA (a PAM for mGlu2), VU0361737 (PAM for mGlu4) and VU 0360172 (PAM for mGlu5). Negative allosteric modulators (NAMs) include ADX 10059 (selective for mGlu5) and ML 289 (selective for mGlu3).
New tools for modulating mGluR desensitization
In addition to subtype selective agonists, antagonists and modulators, tools have recently been developed to allow the investigation of GPCR desensitization – examples include the GRK2/3 inhibitor Cmpd 101.
Key ligands for metabotropic glutamate receptors are summarised below, or view the full metabotropic glutamate receptor range
Group I (mGlu1, mGlu5) receptors
| (S)-3-Hydroxyphenylglycine | mGlu1 agonist |
| (R,S)-3,5-DHPG | Selective mGlu1/mGlu5 receptor agonist |
| (S)-3,5-DHPG | Selective mGlu1/mGlu5 receptor agonist |
| L-cysteinesulfinic acid monohydrate | mGlu1α / mGlu5a agonist |
| CHPG | Selective mGlu5 agonist |
| (S)-4-Carboxyphenylglycine | Competitive, selective group 1 mGlu antagonist |
| JNJ 16259685 | Potent, selective, non-competitive mGlu1 antagonist |
| MPEP hydrochloride | Potent, selective mGlu5 antagonist / mGlu4 positive allosteric modulator |
| MTEP hydrochloride | Selective, non-competitive mGlu5 negative allosteric modulator |
| VU 0360172 hydrochloride | Potent, selective, non-competitive mGlu1 antagonist |
Group II (mGlu2, mGlu3) receptors
| LY 354740 hydrate | Potent, selective group II receptor agonist |
| LY 341495 | Potent, selective group II mGlu receptor antagonist |
| MAP4 | Selective, competitive mGlu3 antagonist |
| LY 487379 | Selective mGlu2 positive allosteric modulator |
| BINA | Potent, selective mGlu2 positive allosteric modulator |
| ML 289 | Selective mGlu3 negative allosteric modulator |
Group I & II receptors
| ±-trans-ACPD | Selective group I and group II mGlu agonist |
Group III (mGlu4, mGlu6, mGlu7, mGlu8) receptors
| AMN 082 dihydrochloride | Potent, selective mGlu7 agonist |
| (S)-3,4-DCPG | Potent, selective mGlu8a agonist |
| L-AP4 | Potent, selective mGlu group III agonist |
| Cinnabarinic acid | Selective mGlu4 agonist |
| XAP 044 | Novel, selective mGlu7 antagonist |
| MDCPG | Selective mGlu8 receptor antagonist |
| MSOP | Selective group III mGlu antagonist |
| VU0155041 sodium salt | Water soluble mGlu4 positive allosteric modulator |
| AZ 12216052 | Novel mGlu8 positive allosteric modulator |
mGlu General
| L-Quisqualic acid | mGlu / AMPA receptor agonist |
References
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