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Neuron Oct 2022Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neurexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent...
Excitatory synapses are formed and matured by the cooperative actions of synaptic organizers, such as neurexins (Nrxns), neuroligins (Nlgns), LRRTMs, and Cbln1. Recent super-resolution nanoscopy developments have revealed that many synaptic organizers, as well as glutamate receptors and glutamate release machinery, exist as nanoclusters within synapses. However, it is unclear how such nanodomains interact with each other to organize excitatory synapses in vivo. By applying X10 expansion microscopy to epitope tag knockin mice, we found that Cbln1, Nlgn1, and LRRTM1, which share Nrxn as a common presynaptic receptor, form overlapping or separate nanodomains depending on Nrxn with or without a sequence encoded by splice site 4. The size and position of glutamate receptor nanodomains of GluD1, NMDA, and AMPA receptors were regulated by Cbln1, Nlgn1, and LRRTM1 nanodomains, respectively. These findings indicate that Nrxns anterogradely regulate the postsynaptic nanoscopic architecture of glutamate receptors through competition and coordination of Nrxn ligands.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Epitopes; Glutamic Acid; Ligands; Membrane Proteins; Mice; N-Methylaspartate; Nerve Tissue Proteins; Receptors, AMPA; Receptors, Glutamate; Receptors, Presynaptic; Synapses
PubMed: 36007521
DOI: 10.1016/j.neuron.2022.07.027 -
Journal of Neurochemistry May 2016Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory... (Review)
Review
Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.
Topics: Animals; DNA Methylation; Humans; Memory; Neuronal Plasticity; Receptors, Glutamate; Synapses
PubMed: 26849493
DOI: 10.1111/jnc.13564 -
The Journal of Physiology Jan 2015Glutamate receptors are ligand-gated ion channels that mediate fast excitatory synaptic transmission throughout the central nervous system. Functional receptors are... (Review)
Review
Glutamate receptors are ligand-gated ion channels that mediate fast excitatory synaptic transmission throughout the central nervous system. Functional receptors are homo- or heteromeric tetramers with each subunit contributing a re-entrant pore loop that dips into the membrane from the cytoplasmic side. The pore loops form a narrow constriction near their apex with a wide vestibule toward the cytoplasm and an aqueous central cavity facing the extracellular solution. This article focuses on the pore region, reviewing how structural differences among glutamate receptor subtypes determine their distinct functional properties.
Topics: Animals; Humans; Ion Channel Gating; Protein Conformation; Receptors, Glutamate
PubMed: 25556787
DOI: 10.1113/jphysiol.2014.272724 -
Biophysical Journal Nov 2017Ion channels activated by glutamate mediate excitatory synaptic transmission in the central nervous system. Similar to other ligand-gated ion channels, their gating... (Review)
Review
Ion channels activated by glutamate mediate excitatory synaptic transmission in the central nervous system. Similar to other ligand-gated ion channels, their gating cycle begins with transitions from a ligand-free closed state to glutamate-bound active and desensitized states. In an attempt to reveal the molecular mechanisms underlying gating, numerous structures for glutamate receptors have been solved in complexes with agonists, antagonists, allosteric modulators, and auxiliary proteins. The embarrassingly rich library of structures emerging from this work reveals very dynamic molecules with a more complex conformational spectrum than anticipated from functional studies. Unanticipated conformations solved for complexes with competitive antagonists and a lack of understanding of the structural basis for ion channel subconductance states further highlight challenges that have yet to be addressed.
Topics: Animals; Cryoelectron Microscopy; Excitatory Amino Acid Antagonists; Humans; Ion Channel Gating; Ion Channels; Protein Domains; Receptors, Glutamate
PubMed: 28844473
DOI: 10.1016/j.bpj.2017.07.028 -
Pharmacology, Biochemistry, and Behavior Apr 2023The metabotropic glutamate receptor 7 (mGlu), encoded by the GRM7 gene in humans, is a presynaptic, G protein-coupled glutamate receptor that is essential for modulating... (Review)
Review
The metabotropic glutamate receptor 7 (mGlu), encoded by the GRM7 gene in humans, is a presynaptic, G protein-coupled glutamate receptor that is essential for modulating neurotransmission. Mutations in or reduced expression of GRM7 have been identified in different genetic neurodevelopmental disorders (NDDs), and rare biallelic missense variants have been proposed to underlie a subset of NDDs. Clinical GRM7 variants have been associated with a range of symptoms consistent with neurodevelopmental molecular features, including hypomyelination, brain atrophy and defects in axon outgrowth. Here, we review the newest findings regarding the cellular and molecular defects caused by GRM7 variants in NDD patients.
Topics: Humans; Mutation; Receptors, Metabotropic Glutamate
PubMed: 37003303
DOI: 10.1016/j.pbb.2023.173546 -
ChemMedChem Jan 2021Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of eight subtypes that are omnipresently expressed in the central nervous system. mGlus... (Review)
Review
Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of eight subtypes that are omnipresently expressed in the central nervous system. mGlus have relevance in several psychiatric and neurological disorders, therefore they raise considerable interest as drug targets. Allosteric modulators of mGlus offer advantages over orthosteric ligands owing to their increased potential to achieve subtype selectivity, and this has prompted discovery programs that have produced a large number of reported allosteric mGlu ligands. However, the optimization of allosteric ligands into drug candidates has proved to be challenging owing to induced-fit effects, flat or steep structure-activity relationships and unexpected changes in theirpharmacology. Subtle structural changes identified as molecular switches might modulate the functional activity of allosteric ligands. Here we review these switches discovered in the metabotropic glutamate receptor family..
Topics: Allosteric Regulation; Allosteric Site; Benzopyrans; Drug Discovery; Humans; Ligands; Molecular Dynamics Simulation; Pyrimidines; Receptors, Metabotropic Glutamate; Structure-Activity Relationship
PubMed: 32686363
DOI: 10.1002/cmdc.202000444 -
Science (New York, N.Y.) Dec 2023γ-Aminobutyric acid acts on a glutamate receptor, evoking synaptic plasticity.
γ-Aminobutyric acid acts on a glutamate receptor, evoking synaptic plasticity.
Topics: gamma-Aminobutyric Acid; Glutamic Acid; Neuronal Plasticity; Receptors, Glutamate; Animals; Mice
PubMed: 38127768
DOI: 10.1126/science.adm6771 -
Neurobiology of Learning and Memory Feb 2019The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely... (Review)
Review
The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely distributed in the mammalian nervous system. Drugs that inhibit the inactivation of synaptically released NAAG have procognitive activity in object recognition and other behavioral models. These inhibitors also reverse cognitive deficits in animal models of clinical disorders. Antagonists of mGluR3 block these actions and mice that are null mutant for this receptor are insensitive to the actions of these procognitive drugs. A positive allosteric modulator of this receptor also has procognitive activity. While some data suggest that drugs acting on mGluR3 achieve their procognitive action by increasing arousal during acquisition training, exploration of the procognitive efficacy of NAAG is in its early stages and thus substantial opportunities exist to define the breadth and nature of this activity.
Topics: Animals; Cognition; Dipeptides; Glutamate Carboxypeptidase II; Memory; Receptors, Metabotropic Glutamate
PubMed: 30630041
DOI: 10.1016/j.nlm.2019.01.006 -
Current Opinion in Neurobiology Jun 2012At excitatory synapses in the brain, glutamate released from nerve terminals binds to glutamate receptors to mediate signaling between neurons. Glutamate receptors... (Review)
Review
At excitatory synapses in the brain, glutamate released from nerve terminals binds to glutamate receptors to mediate signaling between neurons. Glutamate receptors expressed in heterologous cells show ion channel activity. Recently, native glutamate receptors were shown to contain auxiliary subunits that modulate the trafficking and/or channel properties. The AMPA receptor (AMPAR) can contain TARP and CNIHs as the auxiliary subunits, whereas kainate receptor (KAR) can contain the Neto auxiliary subunit. Each of these auxiliary subunits uniquely modulates the glutamate receptors, and determines properties of native glutamate receptors. A thorough elucidation of the properties of native glutamate receptor complexes is indispensable for the understanding of the molecular machinery that regulates glutamate receptors and excitatory synaptic transmission in the brain.
Topics: Animals; Models, Biological; Nuclear Proteins; Protein Subunits; Protein Transport; Receptors, Glutamate
PubMed: 21993243
DOI: 10.1016/j.conb.2011.09.005 -
International Journal of Molecular... May 2019Neuronal calcium (Ca) influx has long been ascribed mainly to voltage-gated Ca channels and glutamate receptor channels. Recent research has shown that it is also... (Review)
Review
Neuronal calcium (Ca) influx has long been ascribed mainly to voltage-gated Ca channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca entry (SOCE). SOCE is described as Ca flow into cells in response to the depletion of endoplasmic reticulum Ca stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer's disease and Huntington's disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.
Topics: Animals; Glutamic Acid; Humans; Models, Biological; Neurodegenerative Diseases; Neurons; Receptors, Glutamate; Stromal Interaction Molecule 1
PubMed: 31075835
DOI: 10.3390/ijms20092289