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

Yale University, New Haven CT

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Abstract

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.