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Metabotropic gutamate receptor (mGluR) mini-review

Metabotropic glutamate receptor mini reviewOverview

Metabotropic 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].

mGlu receptor structuremGluR Structure

mGlu 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 groupGroup IGroup IIGroup III
mGluR subtypemGlu1mGlu5mGlu2, mGlu3mGlu4, mGlu7, mGlu8
Agonists-facilitate STP into persistent LTPraise LTP thresholdraise LTP threshold
Antagonistsimpair CA1 & DG persistent LTP by reducing inductionreduce induction & prevent maintenance in CA1 & DGNo effectNo effect
Knockoutimpaired CA1 LTP, impaired mf LTPimpaired CA1 & DG LTP, normal mf LTPnormal mf LTP-

 

Table 2: Summary of the influence of mGlu receptors on Long-Term Depression

mGluR groupGroup IGroup IIGroup III
mGluR subtypemGlu1mGlu5mGlu2, mGlu3mGlu4, mGlu7, mGlu8
Agonists-facilitate STD into persistent LTDfacilitate STD into LTDfacilitate STD into LTD
Antagonistsimpair LTD by reducing induction and preventing maintenance in CA1 & DGimpair LTD in CA1 & DGblock persistent LTDblock persistent LTD
Knockoutnormal 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-HydroxyphenylglycinemGlu1 agonist
(R,S)-3,5-DHPGSelective mGlu1/mGlu5 receptor agonist
(S)-3,5-DHPGSelective mGlu1/mGlu5 receptor agonist
L-cysteinesulfinic acid monohydratemGlu / mGlu5a agonist
CHPGSelective mGlu5 agonist
(S)-4-CarboxyphenylglycineCompetitive, selective group 1 mGlu antagonist
JNJ 16259685Potent, selective, non-competitive mGlu1 antagonist
MPEP hydrochloridePotent, selective mGlu5 antagonist / mGlu4 positive allosteric modulator
MTEP hydrochlorideSelective, non-competitive mGlu5 negative allosteric modulator
VU 0360172 hydrochloridePotent, selective, non-competitive mGlu1 antagonist

 


 

Group II (mGlu2, mGlu3) receptors

LY 354740 hydratePotent, selective group II receptor agonist
LY 341495Potent, selective group II mGlu receptor antagonist
MAP4Selective, competitive mGlu3 antagonist
LY 487379Selective mGlu2 positive allosteric modulator
BINAPotent, selective mGlu2 positive allosteric modulator
ML 289Selective mGlu3 negative allosteric modulator

 


 

Group I & II receptors

±-trans-ACPDSelective group I and group II mGlu agonist

 


 

Group III (mGlu4, mGlu6, mGlu7, mGlu8) receptors

AMN 082 dihydrochloridePotent, selective mGlu7 agonist
(S)-3,4-DCPGPotent, selective mGlu8a agonist
L-AP4Potent, selective mGlu group III agonist
Cinnabarinic acidSelective mGlu4 agonist
XAP 044Novel, selective mGlu7 antagonist
MDCPGSelective mGlu8 receptor antagonist
MSOPSelective group III mGlu antagonist
VU0155041 sodium saltWater soluble mGlu4 positive allosteric modulator
AZ 12216052Novel mGlu8 positive allosteric modulator

 


 

mGlu General

L-Quisqualic acidmGlu / AMPA receptor agonist

 


 

References

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2. Nicoletti et al (1986)  Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus.J Neurochem. 46(1):40-6 http://www.ncbi.nlm.nih.gov/pubmed/2866236
3. De Blasi et al (2001) Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci. 22(3):114-20  http://www.ncbi.nlm.nih.gov/pubmed/11239574
4. Lees et al (2013)  Peripheral group II and III metabotropic glutamate receptors in the knee joint attenuate carrageenan-induced nociceptive behavior in rats.Neurosci Lett. 10;542:21-5 http://www.ncbi.nlm.nih.gov/pubmed/23500028
5. Mukherjee S et al (2013) Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning. Neuropharmacology. 66:65-81. http://www.ncbi.nlm.nih.gov/pubmed/22743159
6. De Filippis et al (2015) The role of group II metabotropic glutamate receptors in cognition and anxiety: comparative studies in GRM2(-/-), GRM3(-/-) and GRM2/3(-/-) knockout mice.Neuropharmacology. 89:19-32  http://www.ncbi.nlm.nih.gov/pubmed/25158312
7. Walker and Conn (2015)  Group I and group II metabotropic glutamate receptor allosteric modulators as novel potential antipsychotics.Curr Opin Pharmacol. 20:40-5. http://www.ncbi.nlm.nih.gov/pubmed/25462291
8. Mercier MS, Lodge D (2014). Group III metabotropic glutamate receptors: pharmacology, physiology and therapeutic potential. Neurochem Res. 39(10):1876-94 http://www.ncbi.nlm.nih.gov/pubmed/25146900
9. Yin S, Niswender CM (2014) Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cell Signal. 26(10):2284-97 http://www.ncbi.nlm.nih.gov/pubmed/24793301
10. Nicoletti F, Bruno V, Ngomba RT, Gradini R, Battaglia G. Metabotropic glutamate receptors as drug targets: what's new? Curr Opin Pharmacol. ;20:89-94 http://www.ncbi.nlm.nih.gov/pubmed/25506748
11. Foord SM et al (2005) Pharmacol Rev.  57(2):279-88 International Union of Pharmacology. XLVI. G protein-coupled receptor list. http://www.ncbi.nlm.nih.gov/pubmed/15914470 
12. Conn PJ, Pin JP (1997) Annu Rev Pharmacol Toxicol. 37():205-37. Pharmacology and functions of metabotropic glutamate receptors. http://www.ncbi.nlm.nih.gov/pubmed/9131252/
13. Ramano et al (1996) J Biol Chem. 8;271(45):28612-6. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. http://www.ncbi.nlm.nih.gov/pubmed/8910492 
14. Pin and Acher (2002) The metabotropic glutamate receptors: structure, activation mechanism and pharmacology.Curr Drug Targets CNS Neurol Disord. ;1(3):297-317.  http://www.ncbi.nlm.nih.gov/pubmed/12769621 
15. Gerber U et al (2007) Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol.  7(1):56-61.  http://www.ncbi.nlm.nih.gov/pubmed/17055336/ 
16. Ferraguti et al (2008) Metabotropic glutamate 1 receptor: current concepts and perspectives.Pharmacol Rev. 60(4):536-81. http://www.ncbi.nlm.nih.gov/pubmed/19112153/
17. Gladding et al (2009)  Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev. 61(4):395-412.  http://www.ncbi.nlm.nih.gov/pubmed/19926678
18. Mukherjee S, Manahan-Vaughan D (2013).  Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning. Neuropharmacology. 2013 66:65-81. http://www.ncbi.nlm.nih.gov/pubmed/22743159
19. Mannaioni and Conn, (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J. Neurosci., 21:5925–5934  http://www.ncbi.nlm.nih.gov/pubmed/1487615 
20. Bockaert et al., (2010)  GPCR interacting proteins (GIPs) in the nervous system: roles in physiology and pathologies. Ann. Rev. Pharmacol. Toxicol., 50:89–109 http://www.ncbi.nlm.nih.gov/pubmed/20055699 
21. Dolen et al (2008)  Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol. 15;586(6):1503-8 http://www.ncbi.nlm.nih.gov/pubmed/18202092 
22. D'Antoni et al (2014)  Dysregulation of group-I metabotropic glutamate (mGlu) receptor mediated signalling in disorders associated with Intellectual Disability and Autism. Neurosci Biobehav Rev. 46 Pt 2:228-41. http://www.ncbi.nlm.nih.gov/pubmed/24548786

 

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