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Pharmacological Reviews Sep 2010The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a... (Review)
Review
The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
Topics: Gene Expression; Humans; Ion Channels; Protein Processing, Post-Translational; Protein Subunits; Receptors, Glutamate; Synaptic Transmission; Terminology as Topic
PubMed: 20716669
DOI: 10.1124/pr.109.002451 -
Annual Review of Pharmacology and... 2010The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal... (Review)
Review
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.
Topics: Allosteric Regulation; Alternative Splicing; Animals; Humans; Protein Structure, Tertiary; Receptors, Metabotropic Glutamate; Signal Transduction
PubMed: 20055706
DOI: 10.1146/annurev.pharmtox.011008.145533 -
CNS Drugs May 2021The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring... (Review)
Review
The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
Topics: Animals; Antidepressive Agents; Bipolar Disorder; Depressive Disorder, Major; Excitatory Amino Acid Agents; Glutamic Acid; Humans; Mood Disorders; Receptors, Glutamate
PubMed: 33904154
DOI: 10.1007/s40263-021-00816-x -
Cell Sep 2019In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant...
In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery.
Topics: Animals; CHO Cells; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cold Temperature; Cricetulus; Humans; Mice; Neurons; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; Thermosensing
PubMed: 31474366
DOI: 10.1016/j.cell.2019.07.034 -
Neuron Jun 2018Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range... (Review)
Review
Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range of spatial and temporal scales. This functional diversity is decoded by two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The challenges posed by the complexity and physiological importance of each of these subtypes has limited our appreciation and understanding of how these receptors work in concert. In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.
Topics: Animals; Brain; Central Nervous System; Glutamic Acid; Humans; Neuronal Plasticity; Neurotransmitter Agents; Optogenetics; Receptors, Ionotropic Glutamate; Receptors, Metabotropic Glutamate; Synaptic Transmission
PubMed: 29953871
DOI: 10.1016/j.neuron.2018.05.018 -
Molecular and Cellular Neurosciences Sep 2018The metabotropic glutamate receptors (mGlu receptors) are G protein-coupled receptors that bind to the excitatory neurotransmitter glutamate and are important in the... (Review)
Review
The metabotropic glutamate receptors (mGlu receptors) are G protein-coupled receptors that bind to the excitatory neurotransmitter glutamate and are important in the modulation of neuronal excitability, synaptic transmission, and plasticity in the central nervous system. Trafficking of mGlu receptors in and out of the synaptic plasma membrane is a fundamental mechanism modulating excitatory synaptic function through regulation of receptor abundance, desensitization, and signaling profiles. In this review, we cover the regulatory mechanisms determining surface expression and endocytosis of mGlu receptors, with particular focus on post-translational modifications and receptor-protein interactions. The literature we review broadens our insight into the precise events defining the expression of functional mGlu receptors at synapses, and will likely contribute to the successful development of novel therapeutic targets for a variety of developmental, neurological, and psychiatric disorders.
Topics: Animals; Humans; Neurons; Protein Processing, Post-Translational; Protein Transport; Receptors, Metabotropic Glutamate
PubMed: 29604330
DOI: 10.1016/j.mcn.2018.03.014 -
Pharmacology, Biochemistry, and Behavior Nov 2022Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As... (Review)
Review
Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.
Topics: Humans; Receptors, Metabotropic Glutamate; Nervous System Diseases; Central Nervous System; Glutamic Acid
PubMed: 36402243
DOI: 10.1016/j.pbb.2022.173493 -
The Journal of Physiology Jan 2022
Topics: Glutamic Acid; Kainic Acid; Receptors, AMPA; Receptors, Ionotropic Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate
PubMed: 35028955
DOI: 10.1113/JP282389 -
Cold Spring Harbor Perspectives in... Mar 2012Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how... (Review)
Review
Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.
Topics: Amino Acid Sequence; Binding Sites; Cysteine Loop Ligand-Gated Ion Channel Receptors; Models, Molecular; Molecular Sequence Data; Phosphorylation; Protein Structure, Tertiary; Protein Subunits; Receptors, Glutamate
PubMed: 22233560
DOI: 10.1101/cshperspect.a009662 -
Neuropharmacology Mar 2022On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff Watkins, we describe how their work has impacted the field of... (Review)
Review
On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff Watkins, we describe how their work has impacted the field of synaptic plasticity. We describe their influence in each of the major glutamate receptor subtypes: AMPARs, NMDARs, KARs and mGluRs. Particular emphasis is placed on how their work impacted our own studies in the hippocampus. For example, we describe how the tools and regulators that they identified for studying NMDARs (e.g., NMDA, D-AP5 and Mg) led to the understanding of the molecular basis of the induction of LTP. We also describe how other tools that they introduced (e.g., (1S,3R)-ACPD and MCPG) helped lead to the concept of metaplasticity.
Topics: Animals; Excitatory Amino Acid Antagonists; Hippocampus; History, 20th Century; Humans; Magnesium; Neuronal Plasticity; Neuropharmacology; Receptors, Ionotropic Glutamate; Receptors, Metabotropic Glutamate
PubMed: 34919905
DOI: 10.1016/j.neuropharm.2021.108922