Novel Aspects of Glutamatergic Signalling in the Neuroendocrine System (original) (raw)
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Molecular Pharmacology and Physiology of Glutamate Receptors
Glutamate and Addiction, 2002
Glutamate receptors represent the main excitatory receptors in synaptic transmission in the brain and have been intensively studied over the last 15 yr. Although clinical settings involving glutamate receptor modulators or antagonists usually involve stroke, acute brain injury, epilepsy, and neuropathic pain, both metabotropic and ionotropic classes of glutamate receptor also appear to play a role in addiction and cognition. For example, sensitization to cocaine upon chronic exposure to this stimulant appears to be mediated in part by Ca 2+ influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (1), and an mGluR2 agonist attenuates the disruptive effects of phencyclidine on working memory (2). We will provide an overview of the molecular and physiological properties of glutamate receptors and review their subunit-specific pharmacology. As much as possible, we will focus on features of glutamate receptor activation and desensitization that may be most relevant to addiction and cognitive processing. More extensive information on glutamate receptor pharmacology can be found in the literature (3-5). 2. METABOTROPIC RECEPTORS 2.1. Introduction into mGluR Classifications and Their Classical G-Protein-Coupled Signaling Pathways The metabotropic receptors all contain seven transmembrane domains (TM) and are coupled to Gproteins. They are classified into three groups according to their pharmacology (Table 1). Many excellent extensive reviews for the mGluRs are avaible (e.g., refs. 6-9). Metabotropic glutamate receptors are widely expressed in the brain, except for mGluR6, which only occurs in the retina. Group II mGluRs are found in presynaptic membranes or extrasynaptically, group III receptors function as autoreceptors in the presynaptic terminal membrane, and group I mGluRs are often expressed perisynaptically, near the postsynaptic density (10). Astrocytes can express mGluR3 and mGluR5 (reviewed in ref. 11) and outside the brain, mGluRs occur, for example, in the heart (12). Group I receptors are coupled to G q-proteins, which, by activating phospholipase C, produce inositol triphosphate (IP 3), which then activates the endoplasmic IP 3 receptor and triggers the release of calcium from intracellular stores. Group I receptors also activate or inhibit voltage-gated ion channels. Group II and III receptors couple to G i /G 0 proteins that either block adenylate cyclase or calcium channels or activate potassium channels. An example of the different signaling pathways as occurring in the CA1 area of the hippocampus is shown in Fig. 1. The figure also displays the interaction of mGluRs with other receptors and ion channels.
Metabotropic glutamate receptors in GtoPdb v.2023.1
IUPHAR/BPS guide to pharmacology CITE, 2023
Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the nomenclature as agreed by the NC-IUPHAR NC-IUPHAR Subcommittee on Subcommittee on Metabotropic Glutamate Receptors [351] Metabotropic Glutamate Receptors [351]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [140]. The mGlu family is composed of eight members (named mGlu1 to mGlu 8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu 1 and mGlu 5), Group-II (mGlu 2 and mGlu 3) and Group-III (mGlu 4 , mGlu 6 , mGlu 7 and mGlu 8) (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 mGlu 1 , mGlu 2 , mGlu 3 , mGlu 5 and mGlu 7 have been solved [200, 275, 268, 403]. 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 [88, 433, 62]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [217, 191] and heterodimers [91]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and-III receptors [89]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [270, 440, 145, 283, 259, 218]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [140]). 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 [30] and antagonised by (S)-hexylhomoibotenic acid [235]. Group-II mGlu receptors may be activated by LY389795 [269], LY379268 [269], eglumegad [354, 434], DCG-IV and (2R,3R)-APDC [355], and antagonised by eGlu [170] and LY307452 [425, 105]. Group-III mGlu receptors may be activated by L-AP4 and (R,S)-4-PPG [130]. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu 2 and mGlu 3 at low nanomolar concentrations, mGlu 8 at high nanomolar concentrations, and mGlu 4 , mGlu 5 , and mGlu 7 in the micromolar range [185]. 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 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.
Pharmacology and Functions of Metabotropic Glutamate Receptors
Annual Review of Pharmacology and …, 1997
In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR/BPS Guide to Pharmacology CITE, 2019
Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [334]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. 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. The structures of the VFTD of mGlu1, mGlu2, mGlu3, mGlu5 and mGlu7 have been solved [190, 262, 255, 386]. The structure of the 7 transmembrane (TM) domains of...
The Journal of Comparative Neurology, 1998
The mGluR1 metabotropic glutamate receptor is a G-protein-coupled receptor that exists as different C-terminal splice variants. When expressed in mammalian cells, the mGluR1 splice variants exhibit diverse transduction mechanisms and also slightly differ in their apparent agonist affinities. In the present study, we used an affinity-purified antiserum, specifically reactive to the mGluR1b splice variant, in combination with a highly sensitive preembedding immunocytochemical method for light microscopy to investigate the distribution of this receptor in the rat hypothalamus.
Metabotropic glutamate receptors in GtoPdb v.2021.3
IUPHAR/BPS Guide to Pharmacology CITE, 2021
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 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 [...
Naunyn-Schmiedeberg's Archives of Pharmacology, 1995
A cDNA clone encoding the rat metabotropic glutamate receptor mGluR3 was stably transfected into human embryonic kidney 293 cells. Receptor-expressing cell lines were characterized by centrifugation binding assays using [3H]glutamate as radioligand. The rank order of affinity was L-glutamate > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) > L(+)-2-amino-3-phosphonopropionic acid (L-AP3) > quisqualic acid > L(+)-2-amino-4-phosphonobutyric acid (L-AP4) > ibotenic acid. The active enantiomers of several phenylglycines displayed Ki values of 300 to 400 microM. The nonactive enantiomers and the standard ionotropic glutamate receptor ligands N-methyl-D-aspartic acid (NMDA), (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid only weakly displaced [3H]glutamate. In this cell line, L-glutamate and (2S,3S,4S)-alpha-(Carboxycyclopropyl)-glycine (L-CCG-I) reduced cAMP levels in a dose-dependent manner. The sensitivity of this system and its easy applicability make it feasible to envisage ligand binding assays on cell lines expressing cloned receptors as useful screening tools to discover and characterize new and specific agonists and antagonists.
Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease
Annual Review of Pharmacology and Toxicology, 2010
The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.