title: Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression.
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, Ca(2+)/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.
authors.affiliation: Department of Physiology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Myong-Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Physiology and bioMembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul, Korea.|Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Chang-Yun
authors.initials: CY
authors.lastname: Jung
authors.affiliation: Department of Physiology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Seul-Yi
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Physiology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Physiology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Jewoo
authors.identifier: 0000-0003-4977-3728
authors.initials: J
authors.lastname: Koh
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Tuan Anh
authors.initials: TA
authors.lastname: Vuong
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Seungmoon
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Su-Kyung
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.|Division of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Dahee
authors.initials: D
authors.lastname: Choi
authors.affiliation: Department of Neurology, College of Medicine, Kangwon National University, Chuncheon, Korea.
authors.forename: Sung Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: KyeongJin
authors.identifier: 0000-0003-0446-469X
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Korea.
authors.forename: Joo Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Seoul National University Hospital, Seoul, Korea.|Advanced Neural Technologies, Seoul, Republic of Korea.
authors.forename: Daejong
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Division of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Department of Physiology and bioMembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul, Korea.|Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, Korea.
authors.forename: Won-Kyung
authors.identifier: 0000-0003-1568-1710
authors.initials: WK
authors.lastname: Ho
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Department of Physiology, Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Hana
authors.identifier: 0000-0002-9394-8671
authors.initials: H
authors.lastname: Cho
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology*; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008745:Methylation; D008810:Mice, Inbred C57BL; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*
chemical_list: D051656:KCNQ Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D001120:Arginine; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
keywords: KCNQ channel; human; human biology; medicine; mouse; neuronal excitability; neuroscience; protein arginine methylation; rat