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Neuron. 2014 Sep 3;83(5):1159-71. doi: 10.1016/j.neuron.2014.07.042.

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

Author information

1
Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Departments of Neurology, Neuroscience, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
5
Texas Heart Institute, Houston, TX 77030, USA.
6
Texas Heart Institute, Houston, TX 77030, USA; Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
7
Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: etyeh@mdanderson.org.

Abstract

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.

PMID:
25189211
PMCID:
PMC4877174
DOI:
10.1016/j.neuron.2014.07.042
[Indexed for MEDLINE]
Free PMC Article
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