# Cellular Regulation of Sodium-activated Potassium Channels

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $430,696

## Abstract

ABSTRACT
The KCNT1 gene encodes a Na+-activated K+ channel (KNa channel) termed Slack. These channels are bound
directly to regulators of mRNA translation in neurons. Mutations in KCNT1 give rise to several childhood
epilepsies as well as autism. These gain-of-function mutations produce a 3-20-fold increase in K+ current and
all result in very severe intellectual disability. In a mouse model of epilepsy expressing the Slack-R455H
mutation, KNa currents are increased in both excitatory and inhibitory cortical neurons. The characteristics of
the increased KNa current are, however, different in the two types of cells, and the firing of excitatory neurons is
increased while that of GABAergic interneurons is suppressed. This proposal will test the hypothesis that
excitatory and inhibitory cortical neurons preferentially express either Slack-A or Slack-B splice isoforms, which
differ substantially in their activation properties. In situ hybridization and immunolocalization experiments,
coupled with the use of antisense oligonucleotides, will localize and suppress the expression of each isoform.
The second part of the proposal will investigate the finding that, in addition to increased KNa currents, cortical
neurons in Slack mutant mice have greatly increased Na+ currents and levels of NaV subunits. Because both
physiological and pathophysiological (Slack mutant) activation of Slack channels triggers increased translation
of mRNAs for β-actin and for mRNA translation reporter constructs, we will test whether this mechanism
contributes to increased synthesis of NaV channel subunits. The ability of Slack channels to stimulate
translation will be tested using reporter constructs containing 5’ and 3’ UTR domains of NaV genes, as well as
assays of the rate of synthesis of nascent NaV peptides in cortical neurons. Finally, experiments will determine
if specific domains in the cytoplasmic C-terminal domain of Slack channels, or K+ flux through the channels,
are required for stimulation of mRNA reporter constructs or increased Na+ channel synthesis. The findings will
provide essential information on the major unsolved question of how neurons coordinate expression of Na+ and
K+ channels to regulate intrinsic excitability, and on how disruption of this process leads to abnormal firing and
severe intellectual disability.

## Key facts

- **NIH application ID:** 10584753
- **Project number:** 2R01NS102239-06
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** LEONARD K KACZMAREK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $430,696
- **Award type:** 2
- **Project period:** 2018-03-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10584753

## Citation

> US National Institutes of Health, RePORTER application 10584753, Cellular Regulation of Sodium-activated Potassium Channels (2R01NS102239-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10584753. Licensed CC0.

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