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.

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.

* Key recommended reading is highlighted with an asterisk

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Subcommittee members: Cyril Goudet, PhD (Chairperson) Neuroreceptors, dynamics and function Institut de Genomique Fonctionnelle CNRS UMR5203, INSERM U1191, University of Montpellier 141 rue de la Cardonille F34094 Montpellier cedex 5 France Francine Acher Université René Descarte Lab. de chimie et de biochimie pharmacologiques et toxicologiques CNRS UMR-8601 45, rue des Saints Pères Paris 75270 France Giuseppe Battaglia IRCCS NEUROMED Mediterranean Neurological Institute Via Atinense, 18 Pozzilli 86077 Italy Hans Bräuner-Osborne Professor, DSc, PhD Head of Section for Experimental Pharmacology Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Universitetsparken 2 2100 Copenhagen Denmark P. Jeffrey Conn Vanderbilt Center for Neuroscience Drug Discovery Vanderbilt University 1205 Light Hall Nashville TN 37232-0697 USA Robert Duvoisin Neurological Sciences Institute Oregon Health & Science University 505 NW 185th Avenue Beaverton OR 97006 USA Francesco Ferraguti Innsbruck University Pharmacology Peter Mayr Strasse 1a Innsbruck A-6020 Austria Peter J. Flor Novartis Institutes for Biomedical Research Novartis Pharma AG Basel CH-4002 Switzerland Karen J. Gregory, Ph.D. NH&MRC Overseas Biomedical Postdoctoral Research Fellow NARSAD Maltz Investigator 2010 Drug Discovery Biology MIPS, Monash University Parkville, VIC Australia James Monn Neuroscience Research Division Eli Lilly and Company Indianapolis IN 46285 USA Ferdinando Nicoletti Department of Human Physiology and Pharmacology University of Rome 'La Sapienza' Faculty of Medicine Ple. A. Moro 5 Rome 00185 Italy Colleen Niswender Vanderbilt University School of Medicine 215 Light Hall Nashville TN 37232 USA Jean-Philippe Pin (Past chairperson) Institut de Génomique Fonctionnelle UMR 5203 CNRS – U 1191 INSERM – Univ. Montpellier 141 rue de la cardonille 34094 Montpellier Cedex 05 - France Philippe Rondard Institut de Génomique Fonctionelle Department of Pharmacologie Moléculaire UMR 5203 CNRS - U 661 INSERM Univ. Montpellier 141 Rue de la Cardonille Montpellier 34094 France Ryuichi Shigemoto Institute of Science and Technology Austria (IST Austria) Am Campus 1 A – 3400 Klosterneuburg

Other contributors: David Hampson Department of Pharmaceutical Sciences University of Toronto 19 Russell Street Toronto Ontario M5S 2S2 Canada Michael P. Johnson Lilly Research Labs., NSD Lilly Corporate Center Indianapolis IN 46285 USA Yoshihiro Kubo Division of Biophysics and Neurobiology, Department of Molecular Physiology National Institute for Physiological Sciences Myodaiji Okazaki Aichi Japan Shigetada Nakanishi Department of Biological Sciences Kyoto University Faculty of Medicine Yoshida Sakyo-ku Kyoto 606-8501 Japan Darryle D. Schoepp Neuroscience Discovery Research Lilly Research Laboratories Eli Lilly and Company Lilly Corporate Center 0510 Indianapolis IN 46285 USA Michihiro Tateyama Div. of Biophysics and Neurobiology, Dept. of Molecular. Physiology National Institute for Physiological Sciences Myodaiji Okazaki 444-8585 Japan