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

项目摘要/摘要： Slack基因编码钾通道，钾通道在中枢神经系统中大量表达。 这些通道受细胞内钠离子浓度变化的调节。迅速涌入的 钠离子通过钠通道或神经递质受体导致钠敏感的钾 当前(IKNa)。松弛通道突变导致的IKNa改变可导致几种早发性癫痫 脑病。此外，与松弛通道突变相关的癫痫与 认知发育严重迟缓。Slack通道的大细胞质C末端尾巴相互作用 主要是一种名为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 迟滞蛋白(FMRP)。在这项提案中，我计划研究致病突变是如何改变 Slack渠道与这些绑定伙伴的关联，以及这些交互如何与 神经元蛋白质翻译。这项研究的结果将有助于我们理解对 松弛的通道活动，并可能导致潜在的治疗方法产生的破坏性条件 松弛的突变。

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.