IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0174742.html
   My bibliography  Save this article

Screening for AMPA receptor auxiliary subunit specific modulators

Author

Listed:
  • Caleigh M Azumaya
  • Emily L Days
  • Paige N Vinson
  • Shaun Stauffer
  • Gary Sulikowski
  • C David Weaver
  • Terunaga Nakagawa

Abstract

AMPA receptors (AMPAR) are ligand gated ion channels critical for synaptic transmission and plasticity. Their dysfunction is implicated in a variety of psychiatric and neurological diseases ranging from major depressive disorder to amyotrophic lateral sclerosis. Attempting to potentiate or depress AMPAR activity is an inherently difficult balancing act between effective treatments and debilitating side effects. A newly explored strategy to target subsets of AMPARs in the central nervous system is to identify compounds that affect specific AMPAR-auxiliary subunit complexes. This exploits diverse spatio-temporal expression patterns of known AMPAR auxiliary subunits, providing means for designing brain region-selective compounds. Here we report a high-throughput screening-based pipeline that can identify compounds that are selective for GluA2-CNIH3 and GluA2-stargazin complexes. These compounds will help us build upon the growing library of AMPAR-auxiliary subunit specific inhibitors, which have thus far all been targeted to TARP γ-8. We used a cell-based assay combined with a voltage-sensitive dye (VSD) to identify changes in glutamate-gated cation flow across the membranes of HEK cells co-expressing GluA2 and an auxiliary subunit. We then used a calcium flux assay to further validate hits picked from the VSD assay. VU0612951 and VU0627849 are candidate compounds from the initial screen that were identified as negative and positive allosteric modulators (NAM and PAM), respectively. They both have lower IC50/EC50s on complexes containing stargazin and CNIH3 than GSG1L or the AMPAR alone. We have also identified a candidate compound, VU0539491, that has NAM activity in GluA2(R)-CNIH3 and GluA2(Q) complexes and PAM activity in GluA2(Q)-GSG1L complexes.

Suggested Citation

  • Caleigh M Azumaya & Emily L Days & Paige N Vinson & Shaun Stauffer & Gary Sulikowski & C David Weaver & Terunaga Nakagawa, 2017. "Screening for AMPA receptor auxiliary subunit specific modulators," PLOS ONE, Public Library of Science, vol. 12(3), pages 1-23, March.
  • Handle: RePEc:plo:pone00:0174742
    DOI: 10.1371/journal.pone.0174742
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174742
    Download Restriction: no

    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0174742&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pone.0174742?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Xinglong Gu & Xia Mao & Marc P. Lussier & Mary Anne Hutchison & Liang Zhou & F. Kent Hamra & Katherine W. Roche & Wei Lu, 2016. "GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons," Nature Communications, Nature, vol. 7(1), pages 1-18, April.
    2. Lu Chen & Dane M. Chetkovich & Ronald S. Petralia & Neal T. Sweeney & Yoshimi Kawasaki & Robert J. Wenthold & David S. Bredt & Roger A. Nicoll, 2000. "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms," Nature, Nature, vol. 408(6815), pages 936-943, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Danyang Zhang & Remigijus Lape & Saher A. Shaikh & Bianka K. Kohegyi & Jake F. Watson & Ondrej Cais & Terunaga Nakagawa & Ingo H. Greger, 2023. "Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Diogo Bessa-Neto & Gerti Beliu & Alexander Kuhlemann & Valeria Pecoraro & Sören Doose & Natacha Retailleau & Nicolas Chevrier & David Perrais & Markus Sauer & Daniel Choquet, 2021. "Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Amanda M. Perozzo & Jochen Schwenk & Aichurok Kamalova & Terunaga Nakagawa & Bernd Fakler & Derek Bowie, 2023. "GSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Hang Zhou & Guo-Qiang Bi & Guosong Liu, 2024. "Intracellular magnesium optimizes transmission efficiency and plasticity of hippocampal synapses by reconfiguring their connectivity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pone00:0174742. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.