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Development and characterization of functional antibodies targeting NMDA receptors

Author

Listed:
  • Nami Tajima

    (Cold Spring Harbor)

  • Noriko Simorowski

    (Cold Spring Harbor)

  • Remy A. Yovanno

    (Johns Hopkins University School of Medicine)

  • Michael C. Regan

    (Cold Spring Harbor)

  • Kevin Michalski

    (Cold Spring Harbor)

  • Ricardo Gómez

    (Cold Spring Harbor)

  • Albert Y. Lau

    (Johns Hopkins University School of Medicine)

  • Hiro Furukawa

    (Cold Spring Harbor)

Abstract

N-methyl-D-aspartate receptors (NMDARs) are critically involved in basic brain functions and neurodegeneration as well as tumor invasiveness. Targeting specific subtypes of NMDARs with distinct activities has been considered an effective therapeutic strategy for neurological disorders and diseases. However, complete elimination of off-target effects of small chemical compounds has been challenging and thus, there is a need to explore alternative strategies for targeting NMDAR subtypes. Here we report identification of a functional antibody that specifically targets the GluN1-GluN2B NMDAR subtype and allosterically down-regulates ion channel activity as assessed by electrophysiology. Through biochemical analysis, x-ray crystallography, single-particle electron cryomicroscopy, and molecular dynamics simulations, we show that this inhibitory antibody recognizes the amino terminal domain of the GluN2B subunit and increases the population of the non-active conformational state. The current study demonstrates that antibodies may serve as specific reagents to regulate NMDAR functions for basic research and therapeutic objectives.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28559-3
    DOI: 10.1038/s41467-022-28559-3
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    References listed on IDEAS

    as
    1. Nami Tajima & Erkan Karakas & Timothy Grant & Noriko Simorowski & Ruben Diaz-Avalos & Nikolaus Grigorieff & Hiro Furukawa, 2016. "Activation of NMDA receptors and the mechanism of inhibition by ifenprodil," Nature, Nature, vol. 534(7605), pages 63-68, June.
    2. Katie M. Vance & Noriko Simorowski & Stephen F. Traynelis & Hiro Furukawa, 2011. "Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors," Nature Communications, Nature, vol. 2(1), pages 1-11, September.
    3. Kelvin Chan & Jacquelyn Nestor & Tomás S. Huerta & Noele Certain & Gabrielle Moody & Czeslawa Kowal & Patricio T. Huerta & Bruce T. Volpe & Betty Diamond & Lonnie P. Wollmuth, 2020. "Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Hiroyasu Furukawa & Satinder K Singh & Romina Mancusso & Eric Gouaux, 2005. "Subunit arrangement and function in NMDA receptors," Nature, Nature, vol. 438(7065), pages 185-192, November.
    5. Michael C. Regan & Zongjian Zhu & Hongjie Yuan & Scott J. Myers & Dave S. Menaldino & Yesim A. Tahirovic & Dennis C. Liotta & Stephen F. Traynelis & Hiro Furukawa, 2019. "Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    6. Jue Xiang Wang & Mark W. Irvine & Erica S. Burnell & Kiran Sapkota & Robert J. Thatcher & Minjun Li & Noriko Simorowski & Arturas Volianskis & Graham L. Collingridge & Daniel T. Monaghan & David E. Ja, 2020. "Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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    8. Xianqiang Song & Morten Ø. Jensen & Vishwanath Jogini & Richard A. Stein & Chia-Hsueh Lee & Hassane S. Mchaourab & David E. Shaw & Eric Gouaux, 2018. "Mechanism of NMDA receptor channel block by MK-801 and memantine," Nature, Nature, vol. 556(7702), pages 515-519, April.
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