Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression
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...
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| Format: | Online |
| Language: | English |
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eLife Sciences Publications, Ltd
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996652/ |
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pubmed-4996652 |
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pubmed-49966522016-08-29 Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression Kim, Hyun-Ji Jeong, Myong-Ho Kim, Kyung-Ran Jung, Chang-Yun Lee, Seul-Yi Kim, Hanna Koh, Jewoo Vuong, Tuan Anh Jung, Seungmoon Yang, Hyunwoo Park, Su-Kyung Choi, Dahee Kim, Sung Hun Kang, KyeongJin Sohn, Jong-Woo Park, Joo Min Jeon, Daejong Koo, Seung-Hoi Ho, Won-Kyung Kang, Jong-Sun Kim, Seong-Tae Cho, Hana Human Biology and Medicine 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. eLife Sciences Publications, Ltd 2016-07-28 /pmc/articles/PMC4996652/ /pubmed/27466704 http://dx.doi.org/10.7554/eLife.17159 Text en © 2016, Kim et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Kim, Hyun-Ji Jeong, Myong-Ho Kim, Kyung-Ran Jung, Chang-Yun Lee, Seul-Yi Kim, Hanna Koh, Jewoo Vuong, Tuan Anh Jung, Seungmoon Yang, Hyunwoo Park, Su-Kyung Choi, Dahee Kim, Sung Hun Kang, KyeongJin Sohn, Jong-Woo Park, Joo Min Jeon, Daejong Koo, Seung-Hoi Ho, Won-Kyung Kang, Jong-Sun Kim, Seong-Tae Cho, Hana |
| spellingShingle |
Kim, Hyun-Ji Jeong, Myong-Ho Kim, Kyung-Ran Jung, Chang-Yun Lee, Seul-Yi Kim, Hanna Koh, Jewoo Vuong, Tuan Anh Jung, Seungmoon Yang, Hyunwoo Park, Su-Kyung Choi, Dahee Kim, Sung Hun Kang, KyeongJin Sohn, Jong-Woo Park, Joo Min Jeon, Daejong Koo, Seung-Hoi Ho, Won-Kyung Kang, Jong-Sun Kim, Seong-Tae Cho, Hana Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| author_facet |
Kim, Hyun-Ji Jeong, Myong-Ho Kim, Kyung-Ran Jung, Chang-Yun Lee, Seul-Yi Kim, Hanna Koh, Jewoo Vuong, Tuan Anh Jung, Seungmoon Yang, Hyunwoo Park, Su-Kyung Choi, Dahee Kim, Sung Hun Kang, KyeongJin Sohn, Jong-Woo Park, Joo Min Jeon, Daejong Koo, Seung-Hoi Ho, Won-Kyung Kang, Jong-Sun Kim, Seong-Tae Cho, Hana |
| author_sort |
Kim, Hyun-Ji |
| title |
Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| title_short |
Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| title_full |
Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| title_fullStr |
Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| title_full_unstemmed |
Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression |
| title_sort |
protein arginine methylation facilitates kcnq channel-pip2 interaction leading to seizure suppression |
| description |
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 |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996652/ |
| _version_ |
1613634038544728064 |