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Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties

Author

Listed:
  • Laura Fedele

    (UCL School of Pharmacy Brunswick Square
    Physiology & Pharmacology UCL)

  • Joseph Newcombe

    (University of London)

  • Maya Topf

    (University of London)

  • Alasdair Gibb

    (Physiology & Pharmacology UCL)

  • Robert J. Harvey

    (University of the Sunshine Coast
    Sunshine Coast Health Institute)

  • Trevor G. Smart

    (Physiology & Pharmacology UCL)

Abstract

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2BV618G unusually allowed Mg2+ permeation, whereas nearby N615I reduced Ca2+ permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations.

Suggested Citation

  • Laura Fedele & Joseph Newcombe & Maya Topf & Alasdair Gibb & Robert J. Harvey & Trevor G. Smart, 2018. "Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02927-4
    DOI: 10.1038/s41467-018-02927-4
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    Cited by:

    1. 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.
    2. Ru-Siou Hsu & Ssu-Ju Li & Jen-Hung Fang & I-Chi Lee & Li-An Chu & Yu-Chun Lo & Yu-Jen Lu & You-Yin Chen & Shang-Hsiu Hu, 2022. "Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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