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Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2021, 64, 18, 13299-13311
    Article

    Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket
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    • Lilia Leisle*
      Lilia Leisle
      Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
      *Email: [email protected]
      More by Lilia Leisle
    • Michael Margreiter
      Michael Margreiter
      Computational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany
      Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
      More by Michael Margreiter
    • Audrey Ortega-Ramírez
      Audrey Ortega-Ramírez
      Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
      More by Audrey Ortega-Ramírez
    • Elinor Cleuvers
      Elinor Cleuvers
      Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
      More by Elinor Cleuvers
    • Michèle Bachmann
      Michèle Bachmann
      Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
      More by Michèle Bachmann
    • Giulia Rossetti
      Giulia Rossetti
      Computational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany
      Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52425 Jülich, Germany
      Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany
      More by Giulia Rossetti
      Orcidhttps://orcid.org/0000-0002-2032-4630
    • Stefan Gründer*
      Stefan Gründer
      Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
      *Email: [email protected]
      More by Stefan Gründer
      Orcidhttps://orcid.org/0000-0002-7635-9883
    Other Access OptionsSupporting Information (3)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 18, 13299–13311
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00447
    Published August 30, 2021
    Copyright © 2021 The Authors. Published by American Chemical Society
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    Abstract

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    Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis. The molecular determinants and dynamics of this interaction remain unclear, however. Here, we present a molecular interaction model showing a dynorphin peptide inserting deep into the acidic pocket of ASIC1a. We confirmed experimentally that the interaction is predominantly driven by electrostatic forces, and using noncanonical amino acids as photo-cross-linkers, we identified 16 residues in ASIC1a contributing to Big Dyn binding. Covalently tethering Big Dyn to its ASIC1a binding site dramatically decreased the proton sensitivity of channel activation, suggesting that Big Dyn stabilizes a resting conformation of ASIC1a and dissociates from its binding site during channel opening.

    Copyright © 2021 The Authors. Published by American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00447.

    • (1) Nine supporting figures, illustrating details of MD simulation, additional western blots, functional analysis and representative current traces of ASIC1a mutants, and purity of Big Dyn (PDF)

    • (2) Homology model (PDB)

    • (3) Video of the last 40 ns of the MD simulation of the ASIC1a-Dyn A(1-13) interaction during complex (MP4)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 3 publications.

    1. Stefan Gründer, Audrey Ortega Ramírez, Gáspár Jékely. Neuropeptides and degenerin/epithelial Na + channels: a relationship from mammals to cnidarians. The Journal of Physiology 2022, 9 https://doi.org/10.1113/JP282309
    2. Stephanie A Heusser, Christian B Borg, Janne M Colding, Stephan A Pless. Conformational decoupling in acid-sensing ion channels uncovers mechanism and stoichiometry of PcTx1-mediated inhibition. eLife 2022, 11 https://doi.org/10.7554/eLife.73384
    3. Xin Yi Yeo, Grace Cunliffe, Roger C. Ho, Su Seong Lee, Sangyong Jung. Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases. Biomedicines 2022, 10 (2) , 343. https://doi.org/10.3390/biomedicines10020343
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2021, 64, 18, 13299–13311
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c00447
    Published August 30, 2021
    Copyright © 2021 The Authors. Published by American Chemical Society
    Request reuse permissions

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