1. Neuroscience
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Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

  1. Hyun-Ji Kim
  2. Myong-Ho Jeong
  3. Kyung-Ran Kim
  4. Chang-Yun Jung
  5. Seul-Yi Lee
  6. Hanna Kim
  7. Jewoo Koh
  8. Tuan Anh Vuong
  9. Seungmoon Jung
  10. Hyunwoo Yang
  11. Su-Kyung Park
  12. Dahee Choi
  13. Sung Hun Kim
  14. KyeongJin Kang
  15. Jong-Woo Sohn
  16. Joo Min Park
  17. Daejong Jeon
  18. Seung-Hoi Koo
  19. Won-Kyung Ho
  20. Jong-Sun Kang  Is a corresponding author
  21. Seong-Tae Kim  Is a corresponding author
  22. Hana Cho  Is a corresponding author
  1. Sungkyunkwan University School of Medicine, Republic of Korea
  2. Seoul National University Medical Research Center, Republic of Korea
  3. Korea Advanced Institute of Science and Technology, Republic of Korea
  4. Kangwon National University, Republic of Korea
  5. Institute for Basic Science, Republic of Korea
  6. Seoul National University Hospital, Republic of Korea
  7. Korea University, Republic of Korea
Research Article
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Cite this article as: eLife 2016;5:e17159 doi: 10.7554/eLife.17159

Abstract

KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca2+/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities. Consistently, exogenous PIP2 addition to Prmt1+/- neurons restores KCNQ currents and neuronal excitability to the WT level. Collectively, we propose that Prmt1-dependent facilitation of KCNQ-PIP2 interaction underlies the positive regulation of KCNQ activity by arginine methylation, which may serve as a key target for prevention of neuronal hyperexcitability and seizures.

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Author details

  1. Hyun-Ji Kim

    Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. Myong-Ho Jeong

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Kyung-Ran Kim

    Department of Physiology, Seoul National University Medical Research Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Chang-Yun Jung

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Seul-Yi Lee

    Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Hanna Kim

    Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Jewoo Koh

    Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4977-3728
  8. Tuan Anh Vuong

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Seungmoon Jung

    Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Hyunwoo Yang

    Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Su-Kyung Park

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  12. Dahee Choi

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7672-461X
  13. Sung Hun Kim

    Department of Neurology, Kangwon National University, Chuncheon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  14. KyeongJin Kang

    Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0446-469X
  15. Jong-Woo Sohn

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. Joo Min Park

    Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  17. Daejong Jeon

    Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  18. Seung-Hoi Koo

    Division of Life Sciences, Korea University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  19. Won-Kyung Ho

    Department of Physiology, Seoul National University Medical Research Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1568-1710
  20. Jong-Sun Kang

    Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    For correspondence
    kangj01@skku.edu
    Competing interests
    The authors declare that no competing interests exist.
  21. Seong-Tae Kim

    Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    For correspondence
    stkim@skku.edu
    Competing interests
    The authors declare that no competing interests exist.
  22. Hana Cho

    Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    For correspondence
    hanacho@skku.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9394-8671

Funding

National Research Foundation of Korea (NRF-2012R1A2A2A01046878)

  • Hyun-Ji Kim
  • Seul-Yi Lee
  • Hanna Kim
  • Jewoo Koh
  • Hana Cho

National Research Foundation of Korea (NRF-2015R1A2A1A15051998)

  • Myong-Ho Jeong
  • Tuan Anh Vuong
  • Jong-Sun Kang

National Research Foundation of Korea (2015-048055)

  • Kyung-Ran Kim
  • Won-Kyung Ho

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Research Advisory Committee at Sungkyunkwan University School of Medicine Laboratory Animal Research Center (Approval No. IACUC-11-39).

Reviewing Editor

  1. Indira M Raman, Northwestern University, United States

Publication history

  1. Received: April 22, 2016
  2. Accepted: July 27, 2016
  3. Accepted Manuscript published: July 28, 2016 (version 1)
  4. Version of Record published: August 24, 2016 (version 2)

Copyright

© 2016, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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