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Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Author

Listed:
  • Danyang Zhang

    (MRC Laboratory of Molecular Biology)

  • Remigijus Lape

    (MRC Laboratory of Molecular Biology)

  • Saher A. Shaikh

    (MRC Laboratory of Molecular Biology)

  • Bianka K. Kohegyi

    (MRC Laboratory of Molecular Biology)

  • Jake F. Watson

    (MRC Laboratory of Molecular Biology
    IST Austria)

  • Ondrej Cais

    (MRC Laboratory of Molecular Biology)

  • Terunaga Nakagawa

    (Vanderbilt University, School of Medicine)

  • Ingo H. Greger

    (MRC Laboratory of Molecular Biology)

Abstract

AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37259-5
    DOI: 10.1038/s41467-023-37259-5
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    References listed on IDEAS

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    1. Lingli He & Jiahui Sun & Yiwei Gao & Bin Li & Yuhang Wang & Yanli Dong & Weidong An & Hang Li & Bei Yang & Yuhan Ge & Xuejun Cai Zhang & Yun Stone Shi & Yan Zhao, 2021. "Kainate receptor modulation by NETO2," Nature, Nature, vol. 599(7884), pages 325-329, November.
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    3. Danyang Zhang & Jake F. Watson & Peter M. Matthews & Ondrej Cais & Ingo H. Greger, 2021. "Gating and modulation of a hetero-octameric AMPA glutamate receptor," Nature, Nature, vol. 594(7863), pages 454-458, June.
    4. 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.
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    7. 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.
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