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Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels

Author

Listed:
  • Shanti Pal Gangwar

    (Columbia University)

  • Maria V. Yelshanskaya

    (Columbia University)

  • Muhammed Aktolun

    (Carnegie Mellon University)

  • Laura Y. Yen

    (Columbia University
    Columbia University Irving Medical Center)

  • Thomas P. Newton

    (Columbia University
    Columbia University Irving Medical Center)

  • Kristian Strømgaard

    (University of Copenhagen)

  • Maria G. Kurnikova

    (Carnegie Mellon University)

  • Alexander I. Sobolevsky

    (Columbia University)

Abstract

Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge. Here, we present closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. We find that blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. Our structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies.

Suggested Citation

  • Shanti Pal Gangwar & Maria V. Yelshanskaya & Muhammed Aktolun & Laura Y. Yen & Thomas P. Newton & Kristian Strømgaard & Maria G. Kurnikova & Alexander I. Sobolevsky, 2024. "Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54538-x
    DOI: 10.1038/s41467-024-54538-x
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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.
    2. Joel R. Meyerson & Sagar Chittori & Alan Merk & Prashant Rao & Tae Hee Han & Mihaela Serpe & Mark L. Mayer & Sriram Subramaniam, 2016. "Structural basis of kainate subtype glutamate receptor desensitization," Nature, Nature, vol. 537(7621), pages 567-571, September.
    3. Andrei Rozov & Nail Burnashev, 1999. "Polyamine-dependent facilitation of postsynaptic AMPA receptors counteracts paired-pulse depression," Nature, Nature, vol. 401(6753), pages 594-598, October.
    4. Shanti Pal Gangwar & Maria V. Yelshanskaya & Kirill D. Nadezhdin & Laura Y. Yen & Thomas P. Newton & Muhammed Aktolun & Maria G. Kurnikova & Alexander I. Sobolevsky, 2024. "Kainate receptor channel opening and gating mechanism," Nature, Nature, vol. 630(8017), pages 762-768, June.
    5. Jonas Petersen & Mette Q. Ludwig & Vaida Juozaityte & Pablo Ranea-Robles & Charlotte Svendsen & Eunsang Hwang & Amalie W. Kristensen & Nicole Fadahunsi & Jens Lund & Alberte W. Breum & Cecilie V. Math, 2024. "GLP-1-directed NMDA receptor antagonism for obesity treatment," Nature, Nature, vol. 629(8014), pages 1133-1141, May.
    6. 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.
    7. 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.
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