CRL4A(CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis.
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, Ca(2+)- and voltage-activated K(+) (BK) channels are targeted by the E3 ubiquitin ligase CRL4A(CRBN) for polyubiquitination and retained in the endoplasmic reticulum (ER). Inactivation of CRL4A(CRBN) releases deubiquitinated BK channels from the ER to the plasma membrane, leading to markedly enhanced channel activity. Mice with CRL4A(CRBN) mutation in the brain or treated with a CRL4A(CRBN) 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.
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Jiye
J
Liu
School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Jia
J
Ye
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Xiaolong
X
Zou
School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Zhenghao
Z
Xu
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Yan
Y
Feng
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Xianxian
X
Zou
School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Zhong
Z
Chen
School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Yuezhou
Y
Li
1] Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Yong
Y
Cang
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012640:Seizures / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C114234:CUL4A protein, human; C549921:Crbn protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009419:Nerve Tissue Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases