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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 -
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 -
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 -
Cellular and Molecular Life Sciences :... Jun 2019To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity,... (Review)
Review
To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.
Topics: Animals; Carrier Proteins; Egg Proteins; Gene Expression Regulation; Glutamic Acid; Humans; Membrane Proteins; Nerve Net; Nerve Tissue Proteins; Neural Networks, Computer; Neuronal Plasticity; Neurons; Nuclear Proteins; Protein Transport; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 30937469
DOI: 10.1007/s00018-019-03068-7 -
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 -
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 -
Current Opinion in Structural Biology Feb 2019Ionotropic glutamate receptors in vertebrates are composed of three major subtypes - AMPA, kainate, and NMDA receptors - and mediate the majority of fast excitatory... (Review)
Review
Ionotropic glutamate receptors in vertebrates are composed of three major subtypes - AMPA, kainate, and NMDA receptors - and mediate the majority of fast excitatory neurotransmission at chemical synapses of the central nervous system. Among the three major families, native AMPA receptors function as complexes with a variety of auxiliary subunits, which in turn modulate receptor trafficking, gating, pharmacology, and permeation. Despite the long history of structure-mechanism studies using soluble receptor domains or intact yet isolated receptors, structures of AMPA receptor-auxiliary subunit complexes have not been available until recent breakthroughs in single-particle cryo-electron microscopy. Single particle cryo-EM studies have, in turn, provided new insights into the structure and organization of AMPA receptor - auxiliary protein complexes and into the molecular mechanisms of AMPA receptor activation and desensitization.
Topics: Animals; Protein Subunits; Receptors, AMPA
PubMed: 30825796
DOI: 10.1016/j.sbi.2019.01.011 -
Molecular and Cellular Neurosciences Sep 2018A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent... (Review)
Review
A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent on synaptic plasticity. It is now appreciated that for excitatory synapses, a significant part of synaptic plasticity depends upon changes in the post synaptic response to glutamate released from nerve terminals. Modification of the post synaptic response depends, in turn, on changes in the abundances of AMPA receptors in the post synaptic membrane. In this review, we consider mechanisms of trafficking of AMPA receptors to and from synapses that take place in the early trafficking stages, starting in the endoplasmic reticulum (ER) and continuing into the secretory pathway. We consider mechanisms of AMPA receptor assembly in the ER, highlighting the role of protein synthesis and the selective properties of specific AMPA receptor subunits, as well as regulation of ER exit, including the roles of chaperones and accessory proteins and the incorporation of AMPA receptors into COPII vesicles. We consider these processes in the context of the mechanism of mGluR LTD and discuss a compelling role for the dendritic ER membrane that is found proximal to synapses. The review illustrates the important, yet little studied, contribution of the early stages of AMPA receptor trafficking to synaptic plasticity.
Topics: Animals; Endoplasmic Reticulum; Humans; Neuronal Plasticity; Neurons; Protein Transport; Receptors, AMPA
PubMed: 29545119
DOI: 10.1016/j.mcn.2018.03.004