Hyper-SUMOylation of the Kv7 Potassium Channel Diminishes the M-Current Leading to Seizures and Sudden Death

• DOI: 10.1016/j.neuron.2014.07.042
• Publication Date: 2014-09-03T11:46:49Z
• Authors: 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
• Keywords: Neurons; Analysis of Variance; 0303 health sciences; KCNQ Potassium Channels; Neuroscience(all); Action Potentials; Electroencephalography; Mice, Transgenic; In Vitro Techniques; Hippocampus; Electric Stimulation; 3. Good health; Cysteine Endopeptidases; Death, Sudden; Disease Models, Animal; Electrocardiography; Mice; 03 medical and health sciences; Acoustic Stimulation; Animals, Newborn; Potassium Channel Blockers; Animals; Immunoprecipitation; Cells, Cultured

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.