Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression
- Sungkyunkwan University School of Medicine, Republic of Korea
- Seoul National University Medical Research Center, Republic of Korea
- Korea Advanced Institute of Science and Technology, Republic of Korea
- Kangwon National University, Republic of Korea
- Institute for Basic Science, Republic of Korea
- Seoul National University Hospital, Republic of Korea
- Korea University, Republic of Korea
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
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).
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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