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

Hyun Ji Kim, Myong Ho Jeong, Kyung Ran Kim, Chang Yun Jung, Seul Yi Lee, Hanna Kim, Jewoo Koh, Tuan Anh Vuong, Seungmoon Jung, Hyunwoo Yang, Su Kyung Park, Dahee Choi, Sung Hun Kim, Kyeongjin Kang, Jong Woo Sohn, Joo Min Park, Daejong Jeon, Seung-Hoi Koo, Won Kyung Ho, Jong Sun KangSeong Tae Kim, Hana Cho

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Article numbere17159
JournaleLife
Volume5
Issue numberJULY
DOIs
Publication statusPublished - 2016 Jul 28

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

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    Kim, H. J., Jeong, M. H., Kim, K. R., Jung, C. Y., Lee, S. Y., Kim, H., Koh, J., Vuong, T. A., Jung, S., Yang, H., Park, S. K., Choi, D., Kim, S. H., Kang, K., Sohn, J. W., Park, J. M., Jeon, D., Koo, S-H., Ho, W. K., ... Cho, H. (2016). Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression. eLife, 5(JULY), [e17159]. https://doi.org/10.7554/eLife.17159