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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Acoustic Stimulation
  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Death, Sudden*
  • Disease Models, Animal
  • Electric Stimulation
  • Electrocardiography
  • Electroencephalography
  • Hippocampus / cytology
  • Immunoprecipitation
  • In Vitro Techniques
  • KCNQ Potassium Channels / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / physiology
  • Potassium Channel Blockers / pharmacology
  • Seizures / genetics*
  • Seizures / pathology
  • Seizures / physiopathology*


  • KCNQ Potassium Channels
  • Potassium Channel Blockers
  • Cysteine Endopeptidases
  • Senp2 protein, mouse