CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis

Jiye Liu, Jia Ye, Xiaolong Zou, Zhenghao Xu, Yan Feng, Xianxian Zou, Zhong Chen, Yuezhou Li and Yong Cang ()
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Jiye Liu: Life Sciences Institute, Zhejiang University
Jia Ye: School of Medicine, Zhejiang University
Xiaolong Zou: Life Sciences Institute, Zhejiang University
Zhenghao Xu: School of Medicine, Zhejiang University
Yan Feng: Life Sciences Institute, Zhejiang University
Xianxian Zou: Life Sciences Institute, Zhejiang University
Zhong Chen: School of Medicine, Zhejiang University
Yuezhou Li: School of Medicine, Zhejiang University
Yong Cang: Life Sciences Institute, Zhejiang University

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: Abstract Ion channels regulate membrane excitation, and mutations of ion channels often cause serious neurological disorders including epilepsy. Compared with extensive analyses of channel protein structure and function, much less is known about the fine tuning of channel activity by post-translational modification. Here we report that the large conductance, Ca2+- and voltage-activated K+ (BK) channels are targeted by the E3 ubiquitin ligase CRL4ACRBN for polyubiquitination and retained in the endoplasmic reticulum (ER). Inactivation of CRL4ACRBN releases deubiquitinated BK channels from the ER to the plasma membrane, leading to markedly enhanced channel activity. Mice with CRL4ACRBN mutation in the brain or treated with a CRL4ACRBN inhibitor are very sensitive to seizure induction, which can be attenuated by blocking BK channels. Finally, the mutant mice develop spontaneous epilepsy when aged. Therefore, ubiquitination of BK channels before their cell surface expression is an important step to prevent systemic neuronal excitability and epileptogenesis.

Date: 2014
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DOI: 10.1038/ncomms4924

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