Function of Slack potassium channels in early onset epilepsy and intellectual disabilities

Slack钾通道在早发性癫痫和智力障碍中的功能

• 批准号: 9394578
• 负责人: Syed Rydwan Ali
• 金额: $ 5.67万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394578
• 关键词: Actins; Action Potentials; Binding; Binding Proteins; Biochemical; Biological Assay; Biosensor; Brain Diseases; C-terminal; Cell membrane; Dissociation; Electrophysiology (science); Epilepsy; FMR1; Fluorescence Resonance Energy Transfer; Focal Seizure; Frontal Lobe Epilepsy; Genes; Genetic Translation; Immunohistochemistry; Impairment; Intellectual functioning disability; Ions; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Link; Location; Malignant - descriptor; Measures; Messenger RNA; Methodology; Molecular; Monitor; Mutation; Neuraxis; Neurons; Neurotransmitter Receptor; Neurotransmitters; Optics; Outcome; Outcome Study; Pathway interactions; Phosphoric Monoester Hydrolases; Positioning Attribute; Potassium; Potassium Channel; Property; Protein phosphatase; Proteins; RNA-Binding Proteins; Regulation; Reporter; Roentgen Rays; Role; Signal Transduction; Signaling Protein; Sodium; Sodium Channel; Structure; Syndrome; Tail; Techniques; Testing; Training; Translations; base; cognitive development; disease-causing mutation; early onset; epileptic encephalopathies; human disease; infancy; patch clamp; sodium ion; therapy development

Project Summary/Abstract: The Slack gene encodes potassium channels that are abundantly expressed in the central nervous system. These channels are regulated by changes in the intracellular sodium ion concentration. The rapid influx of sodium ions through sodium channels or neurotransmitter receptors results in a sodium-sensitive potassium current (IKNa). Alterations in IKNa due to mutations in Slack channels cause several early onset epileptic encephalopathies. Additionally, epilepsies associated with mutations in Slack channels are associated with a severe delay in cognitive development. The large cytoplasmic C-terminal tail of Slack channel interacts primarily with a protein termed Phactr-1 (Phosphatase and Actin regulator-1) and with the Fragile-X Mental Retardation protein (FMRP). In this proposal, I plan to study how disease-causing mutations modify the association of Slack channels with these binding partners, and how these interactions are linked to changes in neuronal protein translation. The outcome of this study will contribute to our understanding of the regulation of Slack channel activity, and is likely to lead to potential therapies for the devastating condition produced by Slack mutations.

项目概要/摘要： Slack基因编码在中枢神经系统中大量表达的钾通道。 这些通道受细胞内钠离子浓度变化的调节。快速涌入的 钠离子通过钠通道或神经递质受体导致钠敏感性钾 电流（IKNa）。由于Slack通道突变导致的IKNa改变导致几种早发性癫痫 脑病此外，与Slack通道突变相关的癫痫与 认知发展严重滞后。Slack通道的大细胞质C末端尾区相互作用 主要与称为Phactr-1（磷酸酶和肌动蛋白调节因子-1）的蛋白质和脆性X金属蛋白酶（脆性X金属蛋白酶）有关。 阻滞蛋白（FMRP）。在这个建议中，我计划研究致病突变如何改变 Slack通道与这些结合伙伴的关联，以及这些相互作用如何与 神经元蛋白质翻译这项研究的结果将有助于我们了解的调控， 松弛的通道活动，并可能导致潜在的治疗方法所产生的破坏性条件 松弛突变。