IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37260-y.html
   My bibliography  Save this article

Two gates mediate NMDA receptor activity and are under subunit-specific regulation

Author

Listed:
  • Johansen B. Amin

    (Stony Brook University
    Stony Brook University)

  • Miaomiao He

    (Stony Brook University)

  • Ramesh Prasad

    (University of Illinois at Chicago)

  • Xiaoling Leng

    (University of Illinois at Chicago)

  • Huan-Xiang Zhou

    (University of Illinois at Chicago
    University of Illinois at Chicago)

  • Lonnie P. Wollmuth

    (Stony Brook University
    Stony Brook University
    Stony Brook University)

Abstract

Kinetics of NMDA receptor (NMDAR) ion channel opening and closing contribute to their unique role in synaptic signaling. Agonist binding generates free energy to open a canonical gate at the M3 helix bundle crossing. Single channel activity is characterized by clusters, or periods of rapid opening and closing, that are separated by long silent periods. A conserved glycine in the outer most transmembrane helices, the M4 helices, regulates NMDAR function. Here we find that the GluN1 glycine mainly regulates single channel events within a cluster, whereas the GluN2 glycine mainly regulates entry and exit from clusters. Molecular dynamics simulations suggest that, whereas the GluN2 M4 (along with GluN2 pre-M1) regulates the gate at the M3 helix bundle crossing, the GluN1 glycine regulates a ‘gate’ at the M2 loop. Subsequent functional experiments support this interpretation. Thus, the distinct kinetics of NMDARs are mediated by two gates that are under subunit-specific regulation.

Suggested Citation

  • Johansen B. Amin & Miaomiao He & Ramesh Prasad & Xiaoling Leng & Huan-Xiang Zhou & Lonnie P. Wollmuth, 2023. "Two gates mediate NMDA receptor activity and are under subunit-specific regulation," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37260-y
    DOI: 10.1038/s41467-023-37260-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37260-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-37260-y?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. Joel R. Meyerson & Janesh Kumar & Sagar Chittori & Prashant Rao & Jason Pierson & Alberto Bartesaghi & Mark L. Mayer & Sriram Subramaniam, 2014. "Structural mechanism of glutamate receptor activation and desensitization," Nature, Nature, vol. 514(7522), pages 328-334, October.
    2. Zhiguang Jia & Mahdieh Yazdani & Guohui Zhang & Jianmin Cui & Jianhan Chen, 2018. "Hydrophobic gating in BK channels," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    3. Hao Dong & Huan-Xiang Zhou, 2011. "Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor," Nature Communications, Nature, vol. 2(1), pages 1-9, September.
    4. Chia-Hsueh Lee & Wei Lü & Jennifer Carlisle Michel & April Goehring & Juan Du & Xianqiang Song & Eric Gouaux, 2014. "NMDA receptor structures reveal subunit arrangement and pore architecture," Nature, Nature, vol. 511(7508), pages 191-197, July.
    5. Alexander I. Sobolevsky & Michael P. Rosconi & Eric Gouaux, 2009. "X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor," Nature, Nature, vol. 462(7274), pages 745-756, December.
    6. Edward C. Twomey & Maria V. Yelshanskaya & Robert A. Grassucci & Joachim Frank & Alexander I. Sobolevsky, 2017. "Channel opening and gating mechanism in AMPA-subtype glutamate receptors," Nature, Nature, vol. 549(7670), pages 60-65, September.
    7. Katrina A. Black & Sitong He & Ruitao Jin & David M. Miller & Jani R. Bolla & Oliver B. Clarke & Paul Johnson & Monique Windley & Christopher J. Burns & Adam P. Hill & Derek Laver & Carol V. Robinson , 2020. "A constricted opening in Kir channels does not impede potassium conduction," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    8. J. P. Johnson & William N. Zagotta, 2001. "Rotational movement during cyclic nucleotide-gated channel opening," Nature, Nature, vol. 412(6850), pages 917-921, August.
    9. Maria V. Yelshanskaya & Dhilon S. Patel & Christopher M. Kottke & Maria G. Kurnikova & Alexander I. Sobolevsky, 2022. "Opening of glutamate receptor channel to subconductance levels," Nature, Nature, vol. 605(7908), pages 172-178, May.
    10. Johansen B. Amin & Xiaoling Leng & Aaron Gochman & Huan-Xiang Zhou & Lonnie P. Wollmuth, 2018. "A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    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. Beatriz Herguedas & Bianka K. Kohegyi & Jan-Niklas Dohrke & Jake F. Watson & Danyang Zhang & Hinze Ho & Saher A. Shaikh & Remigijus Lape & James M. Krieger & Ingo H. Greger, 2022. "Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. 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.
    3. 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.
    4. Katsumasa Irie & Yoshinori Oda & Takashi Sumikama & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Zoltan Palmai & Kimberley Houenoussi & Sylvia Cohen-Kaminsky & Luba Tchertanov, 2018. "How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?," PLOS ONE, Public Library of Science, vol. 13(8), pages 1-28, August.
    6. Zhongjie Ye & Nicola Galvanetto & Leonardo Puppulin & Simone Pifferi & Holger Flechsig & Melanie Arndt & Cesar Adolfo Sánchez Triviño & Michael Palma & Shifeng Guo & Horst Vogel & Anna Menini & Clemen, 2024. "Structural heterogeneity of the ion and lipid channel TMEM16F," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Félix-Martínez, G.J. & Picones, A. & Godínez-Fernández, J.R., 2024. "Short and long-range correlations in single-channel currents from inwardly rectifying K+ channels," Chaos, Solitons & Fractals, Elsevier, vol. 178(C).
    8. Kirill D. Nadezhdin & Leonor Correia & Chamali Narangoda & Dhilon S. Patel & Arthur Neuberger & Thomas Gudermann & Maria G. Kurnikova & Vladimir Chubanov & Alexander I. Sobolevsky, 2023. "Structural mechanisms of TRPM7 activation and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Nami Tajima & Noriko Simorowski & Remy A. Yovanno & Michael C. Regan & Kevin Michalski & Ricardo Gómez & Albert Y. Lau & Hiro Furukawa, 2022. "Development and characterization of functional antibodies targeting NMDA receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Ruo-Xu Gu & Bert L. Groot, 2023. "Central cavity dehydration as a gating mechanism of potassium channels," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. Guohui Zhang & Xianjin Xu & Zhiguang Jia & Yanyan Geng & Hongwu Liang & Jingyi Shi & Martina Marras & Carlota Abella & Karl L. Magleby & Jonathan R. Silva & Jianhan Chen & Xiaoqin Zou & Jianmin Cui, 2022. "An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Madeleine R. Wilcox & Aparna Nigam & Nathan G. Glasgow & Chamali Narangoda & Matthew B. Phillips & Dhilon S. Patel & Samaneh Mesbahi-Vasey & Andreea L. Turcu & Santiago Vázquez & Maria G. Kurnikova & , 2022. "Inhibition of NMDA receptors through a membrane-to-channel path," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Davide Caprini & Francesco Battista & Paweł Zajdel & Giovanni Di Muccio & Carlo Guardiani & Benjamin Trump & Marcus Carter & Andrey A. Yakovenko & Eder Amayuelas & Luis Bartolomé & Simone Meloni & Yar, 2024. "Bubbles enable volumetric negative compressibility in metastable elastocapillary systems," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    14. Zhengshan Hu & Xiangdong Zheng & Jian Yang, 2023. "Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Gonçalo Paulo & Ke Sun & Giovanni Di Muccio & Alberto Gubbiotti & Blasco Morozzo della Rocca & Jia Geng & Giovanni Maglia & Mauro Chinappi & Alberto Giacomello, 2023. "Hydrophobically gated memristive nanopores for neuromorphic applications," Nature Communications, Nature, vol. 14(1), pages 1-9, 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:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37260-y. 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: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    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.