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Dexamethasone, a direct modulator of AQP2 in Menière’s disease

Robin Mom, View ORCID ProfileJulien Robert-Paganin, View ORCID ProfileThierry Mom, View ORCID ProfileChristian Chabbert, View ORCID ProfileStéphane Réty, View ORCID ProfileDaniel Auguin
doi: https://doi.org/10.1101/2022.01.25.477763
Robin Mom
1Research Group on Vestibular Pathophysiology; CNRS, Unit GDR2074
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  • For correspondence: mom.robin.63@gmail.com auguin@univ-orleans.fr stephane.rety@ens-lyon.fr
Julien Robert-Paganin
2Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France
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Thierry Mom
1Research Group on Vestibular Pathophysiology; CNRS, Unit GDR2074
3Service d’ORL et de chirurgie cervicofaciale, Hôpital Gabriel Montpied, CHU Clermont-Ferrand
4Unité Mixte de Recherche (UMR) 1107 Neurodol, Institut National de la Santé et de la Recherche Médicale (Inserm)
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Christian Chabbert
1Research Group on Vestibular Pathophysiology; CNRS, Unit GDR2074
5Aix Marseille University-CNRS, Laboratory of Cognitive Neurosciences, UMR7291. Team Pathophysiology and Therapy of Vestibular Disorders, Marseille, France
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Stéphane Réty
6Laboratoire de Biologie et Modélisation de la Cellule, ENS de Lyon, University Claude Bernard, CNRS UMR 5239, INSERM U1210, 46 Allée d’Italie Site Jacques Monod, F-69007, Lyon, France
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  • For correspondence: mom.robin.63@gmail.com auguin@univ-orleans.fr stephane.rety@ens-lyon.fr
Daniel Auguin
2Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, 75005 Paris, France
7Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), Université d’Orléans
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  • For correspondence: mom.robin.63@gmail.com auguin@univ-orleans.fr stephane.rety@ens-lyon.fr
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Abstract

Menière’s disease is a chronic illness characterized by intermittent episodes of vertigo associated with fluctuating sensorineural hearing loss, tinnitus and aural pressure. This pathology strongly correlates with a dilatation of the fluid compartment of the endolymph, so-called hydrops. Dexamethasone is one of the therapeutic approaches recommended when conventional antivertigo treatments have failed. Several mechanisms of actions have been hypothesized for the mode of action of dexamethasone such as anti-inflammatory effect or as a regulator of the inner ear water homeostasis. However, none of them have been experimentally confirmed so far. Aquaporins (AQPs) are transmembrane water channels and are hence central in the regulation of trans-cellular water fluxes. In the present study we investigated the hypothesis that dexamethasone could impact water fluxes in the inner ear through direct interaction with AQP2. We addressed this question through molecular dynamics simulations approaches and managed to demonstrate a direct interaction between AQP2 and dexamethasone and its significant impact on the channel water permeability. We also describe the molecular mechanisms involved in dexamethasone binding and in its regulatory action upon AQP2 function.

Highlights

  • AQP2 water permeability is modulated by dexamethasone at physiological concentrations

  • The interaction impacts water fluxes through a direct interaction with the extra-cellular surface of the aquaporin

  • Key interactions implicate conserved residues of the ar/R constriction

  • New insights on corticosteroids mode of actions in Menière’s disease treatment

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵& co-last authors

  • Conflicts of Interest : The authors declare no competing interest.

  • Abbreviations

    MD
    Menière’s disease
    EH
    endolymphatic hydrops
    AQP2
    aquaporin 2
    Å
    Angströms
    PDB code
    Protein Data Bank code
    POPC
    1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
    TIP3
    transferable intermolecular potential 3
    mM
    milliMolar
    KCl
    potassium chloride ns : nanoseconds
    pf
    permeability coefficient
  • Copyright 
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    Posted January 26, 2022.
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    Dexamethasone, a direct modulator of AQP2 in Menière’s disease
    Robin Mom, Julien Robert-Paganin, Thierry Mom, Christian Chabbert, Stéphane Réty, Daniel Auguin
    bioRxiv 2022.01.25.477763; doi: https://doi.org/10.1101/2022.01.25.477763
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    Dexamethasone, a direct modulator of AQP2 in Menière’s disease
    Robin Mom, Julien Robert-Paganin, Thierry Mom, Christian Chabbert, Stéphane Réty, Daniel Auguin
    bioRxiv 2022.01.25.477763; doi: https://doi.org/10.1101/2022.01.25.477763

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