Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death.

Yitao Qi, Jingxiong Wang, Valerie C Bomben, De-Pei Li, Shao-Rui Chen, Hao Sun, Yutao Xi, John G Reed, Jinke Cheng, Hui-Lin Pan, Jeffrey L Noebels, Edward T H Yeh

Neuron 2014 Sep 03

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Sudden unexplained death in epilepsy (SUDEP) is the most common cause of premature mortality in epilepsy and was linked to mutations in ion channels; however, genes within the channel protein interactome might also represent pathogenic candidates. Here we show that mice with partial deficiency of Sentrin/SUMO-specific protease 2 (SENP2) develop spontaneous seizures and sudden death. SENP2 is highly enriched in the hippocampus, often the focus of epileptic seizures. SENP2 deficiency results in hyper-SUMOylation of multiple potassium channels known to regulate neuronal excitability. We demonstrate that the depolarizing M-current conducted by Kv7 channel is significantly diminished in SENP2-deficient hippocampal CA3 neurons, primarily responsible for neuronal hyperexcitability. Following seizures, SENP2-deficient mice develop atrioventricular conduction blocks and cardiac asystole. Both seizures and cardiac conduction blocks can be prevented by retigabine, a Kv7 channel opener. Thus, we uncover a disease-causing role for hyper-SUMOylation in the nervous system and establish an animal model for SUDEP. Copyright © 2014 Elsevier Inc. All rights reserved.

Citation

Yitao Qi, Jingxiong Wang, Valerie C Bomben, De-Pei Li, Shao-Rui Chen, Hao Sun, Yutao Xi, John G Reed, Jinke Cheng, Hui-Lin Pan, Jeffrey L Noebels, Edward T H Yeh. Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron. 2014 Sep 03;83(5):1159-71