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  1. Article ; Online: The many faces of the AMPA-type ionotropic glutamate receptor.

    Bowie, Derek

    Neuropharmacology

    2022  Volume 208, Page(s) 108975

    Abstract: Knowledge of the biology of ionotropic glutamate receptors (iGluRs) is a prerequisite for any student of the neurosciences. But yet, half a century ago, the situation was quite different. There was fierce debate on whether simple amino acids, such as l- ... ...

    Abstract Knowledge of the biology of ionotropic glutamate receptors (iGluRs) is a prerequisite for any student of the neurosciences. But yet, half a century ago, the situation was quite different. There was fierce debate on whether simple amino acids, such as l-glutamic acid (L-Glu), should even be considered as putative neurotransmitter candidates that drive excitatory synaptic signaling in the vertebrate brain. Organic chemist, Jeff Watkins, and physiologist, Dick Evans, were amongst the pioneering scientists who shed light on these tribulations. By combining their technical expertise, they performed foundational work that explained that the actions of L-Glu were, in fact, mediated by a family of ion-channels that they named NMDA-, AMPA- and kainate-selective iGluRs. To celebrate and reflect upon their seminal work, Neuropharmacology has commissioned a series of issues that are dedicated to each member of the Glutamate receptor superfamily that includes both ionotropic and metabotropic classes. This issue brings together nine timely reviews from researchers whose work has brought renewed focus on AMPA receptors (AMPARs), the predominant neurotransmitter receptor at central synapses. Together with the larger collection of papers on other GluR family members, these issues highlight that the excitement, passion, and clarity that Watkins and Evans brought to the study of iGluRs is unlikely to fade as we move into a new era on this most interesting of ion-channel families.
    MeSH term(s) Glutamic Acid/metabolism ; Humans ; Receptors, Glutamate/metabolism ; Receptors, Ionotropic Glutamate/chemistry ; Synapses/metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
    Chemical Substances Receptors, Glutamate ; Receptors, Ionotropic Glutamate ; Glutamic Acid (3KX376GY7L) ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (77521-29-0)
    Language English
    Publishing date 2022-01-21
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2022.108975
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Neurotransmitter-gated ion channels, still front and centre stage.

    Bowie, Derek

    The Journal of physiology

    2021  Volume 599, Issue 2, Page(s) 389–395

    MeSH term(s) Ion Channels ; Neurotransmitter Agents ; Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate
    Chemical Substances Ion Channels ; Neurotransmitter Agents ; Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2021-01-15
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP280800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ionotropic glutamate receptors: structure, function and dysfunction.

    Wyllie, David J A / Bowie, Derek

    The Journal of physiology

    2022  Volume 600, Issue 2, Page(s) 175–179

    MeSH term(s) Glutamic Acid ; Kainic Acid ; Receptors, AMPA ; Receptors, Ionotropic Glutamate ; Receptors, Kainic Acid ; Receptors, N-Methyl-D-Aspartate
    Chemical Substances Receptors, AMPA ; Receptors, Ionotropic Glutamate ; Receptors, Kainic Acid ; Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L) ; Kainic Acid (SIV03811UC)
    Language English
    Publishing date 2022-01-14
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP282389
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The open gate of the AMPA receptor forms a Ca

    Nakagawa, Terunaga / Wang, Xin-Tong / Miguez-Cabello, Federico J / Bowie, Derek

    Nature structural & molecular biology

    2024  Volume 31, Issue 4, Page(s) 688–700

    Abstract: Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are cation-selective ion channels that mediate most fast excitatory neurotransmission in the brain. Although their gating mechanism has been studied extensively, understanding ... ...

    Abstract Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are cation-selective ion channels that mediate most fast excitatory neurotransmission in the brain. Although their gating mechanism has been studied extensively, understanding how cations traverse the pore has remained elusive. Here we investigated putative ion and water densities in the open pore of Ca
    MeSH term(s) Rats ; Animals ; Receptors, AMPA/genetics ; Mutation ; Cations ; Ion Transport ; Binding Sites
    Chemical Substances Receptors, AMPA ; Cations
    Language English
    Publishing date 2024-02-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-024-01228-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Polyamine-mediated channel block of ionotropic glutamate receptors and its regulation by auxiliary proteins.

    Bowie, Derek

    The Journal of biological chemistry

    2018  Volume 293, Issue 48, Page(s) 18789–18802

    Abstract: Most excitatory neurotransmission in the mammalian brain is mediated by a family of plasma membrane-bound signaling proteins called ionotropic glutamate receptors (iGluRs). iGluRs assemble at central synapses as tetramers, forming a central ion-channel ... ...

    Abstract Most excitatory neurotransmission in the mammalian brain is mediated by a family of plasma membrane-bound signaling proteins called ionotropic glutamate receptors (iGluRs). iGluRs assemble at central synapses as tetramers, forming a central ion-channel pore whose primary function is to rapidly transport Na
    MeSH term(s) Animals ; Biological Transport ; Central Nervous System/metabolism ; Neoplasms/metabolism ; Neurodevelopmental Disorders/metabolism ; Polyamines/metabolism ; Proteins/physiology ; Receptors, Ionotropic Glutamate/antagonists & inhibitors ; Receptors, Ionotropic Glutamate/chemistry
    Chemical Substances Polyamines ; Proteins ; Receptors, Ionotropic Glutamate
    Language English
    Publishing date 2018-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.TM118.003794
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Shared and unique aspects of ligand- and voltage-gated ion-channel gating.

    Bowie, Derek

    The Journal of physiology

    2017  Volume 596, Issue 10, Page(s) 1829–1832

    MeSH term(s) Animals ; Humans ; Ion Channel Gating ; Ligands ; Potassium Channels, Voltage-Gated/physiology
    Chemical Substances Ligands ; Potassium Channels, Voltage-Gated
    Language English
    Publishing date 2017-08-02
    Publishing country England
    Document type Editorial
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP275877
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Alternative Splicing of the Flip/Flop Cassette and TARP Auxiliary Subunits Engage in a Privileged Relationship That Fine-Tunes AMPA Receptor Gating.

    Perozzo, Amanda M / Brown, Patricia M G E / Bowie, Derek

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2023  Volume 43, Issue 16, Page(s) 2837–2849

    Abstract: Alternative splicing of AMPA-type glutamate receptors (AMPARs) and allosteric modulation by auxiliary subunits, such as transmembrane AMPAR regulatory proteins (TARPs), are two important mechanisms that regulate the time course of glutamatergic ... ...

    Abstract Alternative splicing of AMPA-type glutamate receptors (AMPARs) and allosteric modulation by auxiliary subunits, such as transmembrane AMPAR regulatory proteins (TARPs), are two important mechanisms that regulate the time course of glutamatergic neurotransmission. Prior work has shown that alternative splicing of the flip/flop cassette profoundly regulates TARP γ2 modulation, where flip receptor gating exhibits robust sensitivity to TARPs while flop isoforms are relatively insensitive to TARP modulation. Whether this splice variant-specific regulation extends to other auxiliary subunit families, such as cornichons (CNIHs), GSG1L, or CKAMPs, remains unknown. Here, we demonstrate that CNIH-3 modulation is unaffected by AMPAR alternative splicing due to inherent differences in how CNIH-3 and TARP γ2 modify channel gating. CNIH-3 slows receptor deactivation from the outset of current decay, consistent with structural evidence showing its point of contact at the level of the pore. In contrast, TARP γ2 acts via the KGK site of the ligand-binding domain (LBD) to slow the onset of desensitization. Although GSG1L and CKAMP44 primarily slow recovery from desensitization, their effects on channel gating are unaffected by alternative splicing, further underlining that structural events leading to the onset and recovery from desensitization are separable. Together, this work establishes that alternative splicing and TARP auxiliary subunits form a unique partnership that governs fast glutamatergic signaling at central synapses. Since proteomic studies suggest that all native AMPARs co-assemble with at least two TARPs, allosteric coupling between the flip/flop cassette and TARPs may represent a common design element in all AMPAR complexes of the mammalian brain.
    MeSH term(s) Animals ; Receptors, AMPA/metabolism ; Alternative Splicing/genetics ; Proteomics ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; Glutamic Acid/metabolism ; Mammals
    Chemical Substances TARP ; Receptors, AMPA ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (77521-29-0) ; Glutamic Acid (3KX376GY7L)
    Language English
    Publishing date 2023-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2293-22.2023
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  8. Article ; Online: Recovery from desensitization in GluA2 AMPA receptors is affected by a single mutation in the N-terminal domain interface.

    Larsen, Andreas Haahr / Perozzo, Amanda M / Biggin, Philip C / Bowie, Derek / Kastrup, Jette Sandholm

    The Journal of biological chemistry

    2024  Volume 300, Issue 3, Page(s) 105717

    Abstract: AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain ( ...

    Abstract AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization.
    MeSH term(s) Humans ; HEK293 Cells ; Ligands ; Molecular Dynamics Simulation ; Mutation ; Protein Domains ; Receptors, AMPA/genetics ; Receptors, AMPA/metabolism ; Allosteric Regulation
    Chemical Substances glutamate receptor ionotropic, AMPA 2 (P6W5IXV8V9) ; Ligands ; Receptors, AMPA
    Language English
    Publishing date 2024-02-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2024.105717
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Ionotropic glutamate receptors: alive and kicking.

    Bowie, Derek

    The Journal of physiology

    2015  Volume 593, Issue 1, Page(s) 25–27

    MeSH term(s) Protein Conformation ; Receptors, Ionotropic Glutamate/chemistry ; Receptors, Ionotropic Glutamate/physiology
    Chemical Substances Receptors, Ionotropic Glutamate
    Language English
    Publishing date 2015-01-01
    Publishing country England
    Document type Editorial
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/jphysiol.2014.284448
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Intrinsic plasticity of cerebellar stellate cells is mediated by NMDA receptor regulation of voltage-gated Na

    Alexander, Ryan P D / Bowie, Derek

    The Journal of physiology

    2020  Volume 599, Issue 2, Page(s) 647–665

    Abstract: Key points: We show that NMDA receptors (NMDARs) elicit a long-term increase in the firing rates of inhibitory stellate cells of the cerebellum NMDARs induce intrinsic plasticity through a Ca: Abstract: Memory storage in the mammalian brain is ... ...

    Abstract Key points: We show that NMDA receptors (NMDARs) elicit a long-term increase in the firing rates of inhibitory stellate cells of the cerebellum NMDARs induce intrinsic plasticity through a Ca
    Abstract: Memory storage in the mammalian brain is mediated not only by long-lasting changes in the efficacy of neurotransmitter receptors but also by long-term modifications to the activity of voltage-gated ion channels. Activity-dependent plasticity of voltage-gated ion channels, or intrinsic plasticity, is found throughout the brain in virtually all neuronal types, including principal cells and interneurons. Although intrinsic plasticity has been identified in neurons of the cerebellum, it has yet to be studied in inhibitory cerebellar stellate cells of the molecular layer which regulate activity outflow from the cerebellar cortex by feedforward inhibition onto Purkinje cells. The study of intrinsic plasticity in stellate cells has been particularly challenging as membrane patch breakthrough in electrophysiology experiments unintentionally triggers changes in spontaneous firing rates. Using cell-attached patch recordings to avoid disruption, we show that activation of extrasynaptic N-methyl-d-aspartate receptors (NMDARs) elicits a long-term increase in the firing properties of stellate cells by stimulating a rise in cytosolic Ca
    MeSH term(s) Action Potentials ; Animals ; Cerebellum/metabolism ; Patch-Clamp Techniques ; Receptors, N-Methyl-D-Aspartate/metabolism ; Sodium
    Chemical Substances Receptors, N-Methyl-D-Aspartate ; Sodium (9NEZ333N27)
    Language English
    Publishing date 2020-11-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3115-x
    ISSN 1469-7793 ; 0022-3751
    ISSN (online) 1469-7793
    ISSN 0022-3751
    DOI 10.1113/JP280627
    Database MEDical Literature Analysis and Retrieval System OnLINE

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