-
Neuron Oct 2018Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity,... (Review)
Review
Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1-GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose "the AMPAR code" as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/homeostatic scaling down.
Topics: Animals; Brain; Humans; Neuronal Plasticity; Receptors, AMPA; Synapses
PubMed: 30359599
DOI: 10.1016/j.neuron.2018.10.018 -
The Journal of Physiology Jan 2021Fast excitatory synaptic transmission in the mammalian brain is largely mediated by AMPA-type ionotropic glutamate receptors (AMPARs), which are activated by the... (Review)
Review
Fast excitatory synaptic transmission in the mammalian brain is largely mediated by AMPA-type ionotropic glutamate receptors (AMPARs), which are activated by the neurotransmitter glutamate. In synapses, the function of AMPARs is tuned by their auxiliary subunits, a diverse set of membrane proteins associated with the core pore-forming subunits of the AMPARs. Each auxiliary subunit provides distinct functional modulation of AMPARs, ranging from regulation of trafficking to shaping ion channel gating kinetics. Understanding the molecular mechanism of the function of these complexes is key to decoding synaptic modulation and their global roles in cognitive activities, such as learning and memory. Here, we review the structural and molecular complexity of AMPAR-auxiliary subunit complexes, as well as their functional diversity in different brain regions. We suggest that the recent structural information provides new insights into the molecular mechanisms underlying synaptic functions of AMPAR-auxiliary subunit complexes.
Topics: Animals; Glutamic Acid; Ion Channel Gating; Protein Subunits; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 32004381
DOI: 10.1113/JP278701 -
Neuron May 2017AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority... (Review)
Review
AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition. Furthermore, AMPAR assembly, trafficking, and functional heterogeneity depends on a large repertoire of auxiliary subunits-a feature that is particularly striking for this type of iGluR. Here, we discuss how the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity.
Topics: Animals; Glutamic Acid; Humans; Neuronal Plasticity; Protein Isoforms; Protein Processing, Post-Translational; Protein Subunits; Protein Transport; RNA Processing, Post-Transcriptional; Receptors, AMPA; Synaptic Transmission
PubMed: 28521126
DOI: 10.1016/j.neuron.2017.04.009 -
Nature Jun 2021AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and...
AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.
Topics: Allosteric Regulation; Animals; Binding Sites; Calcium Channels; Carrier Proteins; Cryoelectron Microscopy; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Models, Molecular; Receptors, AMPA
PubMed: 33981040
DOI: 10.1038/s41586-021-03540-0 -
Frontiers in Neural Circuits 2021Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously... (Review)
Review
Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca influx-triggered excitotoxicity through Ca-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.
Topics: Calcium; Glutamic Acid; Humans; Nervous System Diseases; Receptors, AMPA; Receptors, Calcium-Sensing
PubMed: 34483848
DOI: 10.3389/fncir.2021.711564 -
The Journal of General Physiology Jan 2020JGP study suggests how the regulatory protein γ8 reopens AMPA receptor channels in the continued presence of glutamate.
JGP study suggests how the regulatory protein γ8 reopens AMPA receptor channels in the continued presence of glutamate.
Topics: Calcium Channels; Glutamic Acid; Nuclear Proteins; Receptors, AMPA
PubMed: 31825464
DOI: 10.1085/jgp.201912542 -
Neuropharmacology Nov 2021RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such... (Review)
Review
RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such as inhibiting the target activity, with high potency and selectivity. Antagonists, such as RNA aptamers, acting on AMPA receptors, a major subtype of ionotropic glutamate receptors, are potential drug candidates for treatment of a number of CNS diseases that involve excessive receptor activation and/or elevated receptor expression. Here we review the approach to discover RNA aptamers targeting AMPA receptors from a random sequence library (∼10 sequences) through a process called systematic evolution of ligands by exponential enrichment (SELEX). As compared with small-molecule compounds, RNA aptamers are a new class of regulatory agents with interesting and desirable pharmacological properties. Some AMPA receptor aptamers we have developed are presented in this review. The promises and challenges of translating RNA aptamers into potential drugs and treatment options are also discussed. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Aptamers, Nucleotide; Central Nervous System Diseases; Humans; Receptors, AMPA
PubMed: 34509496
DOI: 10.1016/j.neuropharm.2021.108761 -
Neuropharmacology Oct 2021AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic... (Review)
Review
AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic plasticity which contributes to learning and memory formation, relies on the accumulation of AMPARs at the postsynapse. This phenomenon requires the coordinated recruitment of different elements in the AMPAR complex. Based on recent research reviewed herein, we propose an updated AMPAR trafficking and LTP model which incorporates both extracellular as well as intracellular mechanisms. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Humans; Long-Term Potentiation; Receptors, AMPA
PubMed: 34271016
DOI: 10.1016/j.neuropharm.2021.108710 -
Cell Reports Dec 2022Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial...
Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPAR complexes are largely unclear. Using cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice and by generating a hippocampus-specific interactome, we show that WWC1 is a major regulatory platform in AMPAR signaling networks. Under basal conditions, the Hippo pathway members WWC1 and large tumor-suppressor kinase (LATS) are associated, which might prevent WWC1 effects on synaptic proteins. Reduction of WWC1/LATS binding through a point mutation at WWC1 elevates the abundance of WWC1 in AMPAR complexes and improves hippocampal-dependent learning and memory. Thus, uncoupling of WWC1 from the Hippo pathway to AMPAR-regulatory complexes provides an innovative strategy to enhance synaptic transmission.
Topics: Animals; Mice; Receptors, AMPA; Proteomics
PubMed: 36476872
DOI: 10.1016/j.celrep.2022.111766 -
Nature Jun 2021AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR...
AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1-GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.
Topics: Amino Acid Sequence; Animals; Calcium Channels; Cryoelectron Microscopy; Hippocampus; Ion Channel Gating; Lipid Metabolism; Lipids; Mice; Mice, Inbred C57BL; Models, Molecular; Protein Multimerization; Protein Subunits; Pyramidal Cells; Receptors, AMPA; Rotation
PubMed: 34079129
DOI: 10.1038/s41586-021-03613-0