Protein Arginine Methylation Facilitates KCNQ Channel-PIP2 Interaction Leading to Seizure Suppression

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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
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
Issue Date
2016-07
Language
English
Article Type
Article
Keywords

RECEPTOR-MEDIATED INHIBITION; KCNQ2/KCNQ3 K+ CHANNELS; KV7 POTASSIUM CHANNELS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; SYMPATHETIC NEURONS; SURFACE EXPRESSION; EPILEPTIC SEIZURES; LIVING CELLS; M-CURRENTS; PIP2

Citation

eLife, v.5

ISSN
2050-084X
DOI
10.7554/eLife.17159
URI
http://hdl.handle.net/10203/212918
Appears in Collection
BS-Journal Papers(저널논문)
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