# Cellular Regulation of Sodium-activated Potassium Channels

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $366,406

## Abstract

Human mutations in KCNT1, the gene for the Slack Na+-activated K+ channel result in several different
childhood epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI) and Autosomal
Dominant Frontal Lobe Epilepsy (ADNLFE). These mutations are gain-of-function mutations that result in
enhanced channel opening. Although the seizures may abate with adulthood, all disease-causing Slack
mutations are associated with very severe intellectual disability. The intellectual deficits may result from the
fact that the large intracellular C-terminus of Slack channels interacts with several cytoplasmic signaling
molecules, including Phartr-1, Fragile-X Mental Retardation protein (FMRP) and Cytoplasmic FMRP-Interacting Protein (CYFIP1). The two latter proteins are well known regulators of mRNA translation in neurons.
We will record from cortical neurons in cultures and in brain slices from mice expressing the human mutation
R455H Slack, to determine how the firing patterns of neurons are altered to produce increased excitability,
interictal spikes and spontaneous seizures. We will test the actions of a novel inhibitor of Slack channels to
determine whether it reverses the effects of the mutation on neuronal firing and seizures and as well as altered
patterns of behavior in the R455H mutant animals. Finally we will determine whether the interactions of Slack
channels with their cytoplasmic signaling partners are disrupted in the mutant animals, and whether the ability
of activation of Slack channels to modulate mRNA translation in neurons is compromised. This work will
provide a biological basis for treatment of these devastating diseases and provide potential lead compounds
for therapeutic intervention.

## Key facts

- **NIH application ID:** 9851005
- **Project number:** 5R01NS102239-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** LEONARD K KACZMAREK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,406
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851005

## Citation

> US National Institutes of Health, RePORTER application 9851005, Cellular Regulation of Sodium-activated Potassium Channels (5R01NS102239-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851005. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*