IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F40/2021.3
Metabotropic glutamate receptors in GtoPdb v.2021.3
Francine Acher1, Giuseppe Battaglia2, Hans Bräuner-Osborne3, P. Jeffrey Conn4, Robert Duvoisin5,
Francesco Ferraguti6, Peter J. Flor7, Cyril Goudet8, Karen J. Gregory9, David Hampson10, Michael P.
Johnson11, Yoshihiro Kubo12, James Monn13, Shigetada Nakanishi14, Ferdinando Nicoletti15, Colleen
Niswender4, Jean-Philippe Pin8, Philippe Rondard8, Darryle D. Schoepp11, Ryuichi Shigemoto16 and
Michihiro Tateyama12
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Université René Descarte, France
IRCCS NEUROMED, Italy
University of Copenhagen, Denmark
Vanderbilt University, USA
Oregon Health & Science University, USA
Innsbruck University, Austria
Novartis Institutes for Biomedical Research, Switzerland
Université de Montpellier, France
Monash University, Australia
University of Toronto, Canada
Lilly Research Laboratories, USA
National Institute for Physiological Sciences, Japan
Eli Lilly and Company, USA
Kyoto University Faculty of Medicine, Japan
University of Rome 'La Sapienza', Italy
Institute of Science and Technology, Austria
Abstract
Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR
Subcommittee on Metabotropic Glutamate Receptors [347]) are a family of G protein-coupled
receptors activated by the neurotransmitter glutamate [138]. 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 seventransmembrane 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 [198, 271, 264, 399]. The structure of the
7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general
helical organization similar to that of other GPCRs, although the helices appear more compacted [87,
429, 61]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu
receptor dimers [189]. Studies have revealed the possible formation of heterodimers between either
group-I receptors, or within and between group-II and -III receptors [88]. First well characterized in
transfected cells, co-localization and specific pharmacological properties also suggest the existence
of such heterodimers in the brain [266].[436, 143, 279]. Beyond heteromerization with other mGlu
receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order
complexes with class A GPCRs (reviewed in [138]).
The endogenous ligands of mGlu are L-glutamic acid, L-serine-O-phosphate, Nacetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Group-I mGlu receptors may be
activated by 3,5-DHPG and (S)-3HPG [30] and antagonized by (S)-hexylhomoibotenic acid [232].
Group-II mGlu receptors may be activated by LY389795 [265], LY379268 [265], eglumegad [350,
430], DCG-IV and (2R,3R)-APDC [351], and antagonised by eGlu [168] and LY307452 [421, 103].
Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [128]. 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 [183]. 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.
Contents
This is a citation summary for Metabotropic glutamate receptors in the Guide to Pharmacology
database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of
citations to and from the database by citation analyzers. Readers will almost certainly want to visit
the relevant sections of the database which are given here under database links.
GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them.
GtoPdb is a reference work which is most usefully represented as an on-line database. As in any
publication this work should be appropriately cited, and the papers it cites should also be recognized.
This document provides a citation for the relevant parts of the database, and also provides a
reference list for the research cited by those parts. For further details see [42].
Please note that the database version for the citations given in GtoPdb are to the most recent
preceding version in which the family or its subfamilies and targets were substantially changed. The
links below are to the current version. If you need to consult the cited version, rather than the most
recent version, please contact the GtoPdb curators.
Database links
Metabotropic glutamate receptors
https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=40
Introduction to Metabotropic glutamate receptors
https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=40
Receptors
mGlu1 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=289
mGlu2 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=290
mGlu3 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=291
mGlu4 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=292
mGlu5 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=293
mGlu6 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=294
mGlu7 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=295
mGlu8 receptor
https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=296
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