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A role for Piezo2 in EPAC1-dependent mechanical allodynia

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  • N Eijkelkamp

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht 3584 EA, The Netherlands)

  • J.E. Linley

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London)

  • J.M. Torres

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    Molecular Biology and Immunology, Faculty of Medicine, University of Granada)

  • L. Bee

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    Physiology and Pharmacology, University College London)

  • A.H. Dickenson

    (Physiology and Pharmacology, University College London)

  • M. Gringhuis

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London)

  • M.S. Minett

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London)

  • G.S. Hong

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    World Class University Program, Seoul National University)

  • E. Lee

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    World Class University Program, Seoul National University)

  • U. Oh

    (World Class University Program, Seoul National University)

  • Y. Ishikawa

    (Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine)

  • F.J. Zwartkuis

    (University Medical Center Utrecht, Center for Biomedical Genetics and Cancer Genomics Center)

  • J.J. Cox

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London)

  • J.N. Wood

    (Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London
    World Class University Program, Seoul National University)

Abstract

Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1−/− mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1–Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.

Suggested Citation

  • N Eijkelkamp & J.E. Linley & J.M. Torres & L. Bee & A.H. Dickenson & M. Gringhuis & M.S. Minett & G.S. Hong & E. Lee & U. Oh & Y. Ishikawa & F.J. Zwartkuis & J.J. Cox & J.N. Wood, 2013. "A role for Piezo2 in EPAC1-dependent mechanical allodynia," Nature Communications, Nature, vol. 4(1), pages 1-13, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2673
    DOI: 10.1038/ncomms2673
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    Cited by:

    1. Jonathan Madar & Namrata Tiwari & Cristina Smith & Divya Sharma & Shanwei Shen & Alsiddig Elmahdi & Liya Y. Qiao, 2023. "Piezo2 regulates colonic mechanical sensitivity in a sex specific manner in mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Alia M. Obeidat & Matthew J. Wood & Natalie S. Adamczyk & Shingo Ishihara & Jun Li & Lai Wang & Dongjun Ren & David A. Bennett & Richard J. Miller & Anne-Marie Malfait & Rachel E. Miller, 2023. "Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Clement Verkest & Irina Schaefer & Timo A. Nees & Na Wang & Juri M. Jegelka & Francisco J. Taberner & Stefan G. Lechner, 2022. "Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Luis O. Romero & Rebeca Caires & A. Kaitlyn Victor & Juanma Ramirez & Francisco J. Sierra-Valdez & Patrick Walsh & Vincent Truong & Jungsoo Lee & Ugo Mayor & Lawrence T. Reiter & Valeria Vásquez & Jul, 2023. "Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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