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Metabotropic glutamate receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [80]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [27]. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu1 and mGlu5), Group-II (mGlu2 and mGlu3) and Group-III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading).
Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [46,60,66,87]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to that of other GPCRs, although the helices appear more compacted [11,15,92]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [43,49] and heterodimers [17]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [16]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [29,50,58,62,70,94]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [27]).
The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [5] and antagonised by (S)-hexylhomoibotenic acid [53]. Group-II mGlu receptors may be activated by LY389795 [61], LY379268 [61], eglumegad [81,93], DCG-IV and (2R,3R)-APDC [82], and antagonised by eGlu [34] and LY307452 [20,91]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [23]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu4, mGlu5, and mGlu7 in the micromolar range [39]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.
Receptors
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mGlu1 receptor
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mGlu2 receptor
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mGlu3 receptor
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mGlu4 receptor
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mGlu5 receptor
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mGlu6 receptor
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mGlu7 receptor
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mGlu8 receptor
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Further reading
* Key recommended reading is highlighted with an asterisk
Anwyl R. (2009) Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology, 56 (4): 735-40. [PMID:19705571]
Bird MK, Lawrence AJ. (2009) The promiscuous mGlu5 receptor--a range of partners for therapeutic possibilities?. Trends Pharmacol Sci, 30 (12): 617-23. [PMID:19892412]
Bradley SJ, Challiss RA. (2012) G protein-coupled receptor signalling in astrocytes in health and disease: a focus on metabotropic glutamate receptors. Biochem Pharmacol, 84 (3): 249-59. [PMID:22531220]
Chaki S. (2010) Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia. Eur J Pharmacol, 639 (1-3): 59-66. [PMID:20371240]
Chiechio S, Copani A, Zammataro M, Battaglia G, Gereau RW, Nicoletti F. (2010) Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain. Trends Pharmacol Sci, 31 (4): 153-60. [PMID:20064669]
Conn PJ, Lindsley CW, Jones CK. (2009) Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci, 30 (1): 25-31. [PMID:19058862]
Conn PJ, Pin JP. (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol, 37: 205-37. [PMID:9131252]
D'Antoni S, Berretta A, Bonaccorso CM, Bruno V, Aronica E, Nicoletti F, Catania MV. (2008) Metabotropic glutamate receptors in glial cells. Neurochem Res, 33 (12): 2436-43. [PMID:18438710]
Durand D, Pampillo M, Caruso C, Lasaga M. (2008) Role of metabotropic glutamate receptors in the control of neuroendocrine function. Neuropharmacology, 55 (4): 577-83. [PMID:18616955]
Duty S. (2010) Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease. Br J Pharmacol, 161 (2): 271-87. [PMID:20735415]
* Ferraguti F, Shigemoto R. (2006) Metabotropic glutamate receptors. Cell Tissue Res, 326 (2): 483-504. [PMID:16847639]
Flor PJ, Acher FC. (2012) Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem Pharmacol, 84 (4): 414-24. [PMID:22554564]
Gladding CM, Fitzjohn SM, Molnár E. (2009) Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev, 61 (4): 395-412. [PMID:19926678]
Goudet C, Magnaghi V, Landry M, Nagy F, Gereau RW, Pin JP. (2009) Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev, 60 (1): 43-56. [PMID:19146876]
* Gregory KJ, Goudet C. (2021) International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors. Pharmacol Rev, 73 (1): 521-569. [PMID:33361406]
Julio-Pieper M, Flor PJ, Dinan TG, Cryan JF. (2011) Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues. Pharmacol Rev, 63 (1): 35-58. [PMID:21228260]
Kim CH, Lee J, Lee JY, Roche KW. (2008) Metabotropic glutamate receptors: phosphorylation and receptor signaling. J Neurosci Res, 86 (1): 1-10. [PMID:17663464]
Krivoy A, Fischel T, Weizman A. (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol, 18 (6): 395-405. [PMID:18063347]
Marek GJ. (2010) Metabotropic glutamate2/3 (mGlu2/3) receptors, schizophrenia and cognition. Eur J Pharmacol, 639 (1-3): 81-90. [PMID:20371229]
Moreno JL, Sealfon SC, González-Maeso J. (2009) Group II metabotropic glutamate receptors and schizophrenia. Cell Mol Life Sci, 66 (23): 3777-85. [PMID:19707855]
Moussawi K, Kalivas PW. (2010) Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol, 639 (1-3): 115-22. [PMID:20371233]
* Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP. (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology, 60 (7-8): 1017-41. [PMID:21036182]
* Niswender CM, Conn PJ. (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol, 50: 295-322. [PMID:20055706]
O'Connor RM, Finger BC, Flor PJ, Cryan JF. (2010) Metabotropic glutamate receptor 7: at the interface of cognition and emotion. Eur J Pharmacol, 639 (1-3): 123-31. [PMID:20371242]
Olive MF. (2010) Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction. Eur J Pharmacol, 639 (1-3): 47-58. [PMID:20371237]
Pilc A, Chaki S, Nowak G, Witkin JM. (2008) Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol, 75 (5): 997-1006. [PMID:18164691]
* Pin JP, Bettler B. (2016) Organization and functions of mGlu and GABAB receptor complexes. Nature, 540 (7631): 60-68. [PMID:27905440]
Robichaud AJ, Engers DW, Lindsley CW, Hopkins CR. (2011) Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics. ACS Chem Neurosci, 2 (8): 433-49. [PMID:22860170]
* Rondard P, Goudet C, Kniazeff J, Pin JP, Prézeau L. (2011) The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors. Neuropharmacology, 60 (1): 82-92. [PMID:20713070]
Schoepp DD, Alexander SP, Beart P, Conn PJ, Lodge D, Nakanishi S et al.. (2000) Metabotropic glutamate receptors. In IUPHAR Compendium of Receptor Characterization and Classification Edited by Watson SP, Girdlestone D (IUPHAR Press) 195-208.
Shin SS, Martino JJ, Chen S. (2008) Metabotropic glutamate receptors (mGlus) and cellular transformation. Neuropharmacology, 55 (4): 396-402. [PMID:18554669]
Simonyi A, Schachtman TR, Christoffersen GR. (2010) Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur J Pharmacol, 639 (1-3): 17-25. [PMID:20363219]
Tang FR, Bradford HF, Ling EA. (2009) Metabotropic glutamate receptors in the control of neuronal activity and as targets for development of anti-epileptogenic drugs. Curr Med Chem, 16 (17): 2189-204. [PMID:19519386]
Wierońska JM, Pilc A. (2009) Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs. Neurochem Int, 55 (1-3): 85-97. [PMID:19428811]
Wood MR, Hopkins CR, Brogan JT, Conn PJ, Lindsley CW. (2011) "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry, 50 (13): 2403-10. [PMID:21341760]
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Cyril Goudet, PhD (Chairperson)
Francine Acher
Giuseppe Battaglia
Hans Bräuner-Osborne
P. Jeffrey Conn
Robert Duvoisin
Francesco Ferraguti
Peter J. Flor
Karen J. Gregory, Ph.D.
James Monn
Ferdinando Nicoletti
Colleen Niswender
Jean-Philippe Pin (Past chairperson)
Philippe Rondard
Ryuichi Shigemoto |
Other contributors:
David Hampson
Michael P. Johnson
Yoshihiro Kubo
Shigetada Nakanishi
Darryle D. Schoepp
Michihiro Tateyama |
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Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
The activity of NAAG as an agonist at mGlu3 receptors was questioned on the basis of contamination with glutamate [10,21], but this has been refuted [67].
Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [3H]R214127 [47] and [3H]YM298198 [44] at mGlu1 receptors and [3H]M-MPEP [22] and [3H]methoxymethyl-MTEP [1] at mGlu5 receptors; [3H]LY341495 and [3H]eglumegad for mGlu2 and mGlu3 receptors [35,83]). Although a number of radioligands have been used to examine binding in native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors and may have unappreciated biased or neutral activity at other subtypes [31]. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.
(S)-(+)-CBPG is an antagonist at mGlu1, but is an agonist (albeit of reduced efficacy) at mGlu5 receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors [89], and is an antagonist at all Group-III mGluRs with an IC50 of 30µM. A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to LY341495 [12]. There are also reports of a distinct metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification [41,71]
A related class C receptor composed of two distinct subunits, T1R1 + T1R3 is also activated by glutamate and is responsible for umami taste detection.
All selective antagonists at metabotropic glutamate receptors are competitive.