Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain

Authors

  • Alexandre Favereaux,

    Corresponding author
    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
    • Corresponding author. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Université de Bordeaux 2, 146 rue Léo Saignat, Bordeaux Cedex 33077, France. Tel.: +33 55 757 4077; Fax: +33 55 757 5051; E-mail: alexandre.favereaux@u-bordeaux2.fr

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  • Olivier Thoumine,

    1. Université de Bordeaux, Bordeaux Cedex, France
    2. CNRS, IINS, UMR 5297 ‘Biophysics of Adhesion and Cytoskeleton’, Bordeaux Cedex, France
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  • Rabia Bouali-Benazzouz,

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
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  • Virginie Roques,

    1. Université de Bordeaux, Bordeaux Cedex, France
    2. INSERM U862, Neurocentre François Magendie, Bordeaux Cedex, France
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  • Marie-Amélie Papon,

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
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  • Sherine Abdel Salam,

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
    3. Department of Zoology, University of Alexandria, Alexandria, Egypt
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  • Guillaume Drutel,

    1. Université de Bordeaux, Bordeaux Cedex, France
    2. INSERM U862, Neurocentre François Magendie, Bordeaux Cedex, France
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  • Claire Léger,

    1. Université de Bordeaux, Bordeaux Cedex, France
    2. INSERM U862, Neurocentre François Magendie, Bordeaux Cedex, France
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  • André Calas,

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
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  • Frédéric Nagy,

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
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    • These authors contributed equally to this work
  • Marc Landry

    1. CNRS, IINS, UMR 5297 ‘Central Mechanisms of Pain Sensitization’, Bordeaux Cedex, France
    2. Université de Bordeaux, Bordeaux Cedex, France
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    • These authors contributed equally to this work

Abstract

Chronic pain states are characterized by long-term sensitization of spinal cord neurons that relay nociceptive information to the brain. Among the mechanisms involved, up-regulation of Cav1.2-comprising L-type calcium channel (Cav1.2-LTC) in spinal dorsal horn have a crucial role in chronic neuropathic pain. Here, we address a mechanism of translational regulation of this calcium channel. Translational regulation by microRNAs is a key factor in the expression and function of eukaryotic genomes. Because perfect matching to target sequence is not required for inhibition, theoretically, microRNAs could regulate simultaneously multiple mRNAs. We show here that a single microRNA, miR-103, simultaneously regulates the expression of the three subunits forming Cav1.2-LTC in a novel integrative regulation. This regulation is bidirectional since knocking-down or over-expressing miR-103, respectively, up- or down-regulate the level of Cav1.2-LTC translation. Functionally, we show that miR-103 knockdown in naive rats results in hypersensitivity to pain. Moreover, we demonstrate that miR-103 is down-regulated in neuropathic animals and that miR-103 intrathecal applications successfully relieve pain, identifying miR-103 as a novel possible therapeutic target in neuropathic chronic pain.

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