title: Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death.
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.
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Neurology, Neuroscience, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Bomben
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Departments of Neurology, Neuroscience, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Reed
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
authors.affiliation: Departments of Neurology, Neuroscience, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.affiliation: 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.
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000161:Acoustic Stimulation; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003645:Death, Sudden; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004562:Electrocardiography; D004569:Electroencephalography; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012640:Seizures / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D003546:Cysteine Endopeptidases; C439066:Senp2 protein, mouse