RESUMO
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.
Assuntos
Cisteína Endopeptidases/metabolismo , Morte Súbita , Canais de Potássio KCNQ/metabolismo , Convulsões/genética , Convulsões/fisiopatologia , Estimulação Acústica , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Análise de Variância , Animais , Animais Recém-Nascidos , Células Cultivadas , Cisteína Endopeptidases/genética , Modelos Animais de Doenças , Estimulação Elétrica , Eletrocardiografia , Eletroencefalografia , Hipocampo/citologia , Imunoprecipitação , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Convulsões/patologiaRESUMO
Over the past decade, therapies for several previously untreatable types of cancer have emerged or have improved; thus, more focus has been given to long-term complications of cancer therapy. The most commonly known cardiac toxicities of cancer therapy are cardiac dysfunction or congestive heart failure. Vascular complications--such as ischemia, myocardial infarction, venous or arterial thrombosis, and newly developed or worsened hypertension--are also relatively common following cancer treatment, particularly in patients with advanced-stage cancer. Experimental studies have suggested a number of potential mechanisms that might account for vascular complications of cancer therapies, which include dysfunction or damage of endothelial cells, increased platelet aggregation, and modulation of nitric oxide levels. This Review describes the vascular complications of treatment with 5-fluorouracil, bevacizumab, and several new tyrosine kinase inhibitors, with special emphasis on thrombotic complications and hypertension.