# Molecular Mechanisms of Epilepsy-Causing Mutations in IKM channels: Anti-epileptic effect of Lipophilic compounds.

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $38,696

## Abstract

PROJECT SUMMARY
Abnormal neuronal activity in the brain leads to epileptic seizures that, when repeated or prolonged, can cause
neuronal damage resulting in delayed psychomotor development and intellectual disability. Most genetic
variants associated with epilepsy are in genes encoding ion channels, including potassium channels that
regulate neuronal excitability such as IKM channels. Inherited mutations in the IKM channel cause a wide
spectrum of early-onset epileptic disorders. The long-term goal of this research program is to understand the
mechanisms by which the wt IKM channel work, how epilepsy-causing mutations lead to dysfunction of IKM
channels and to design drugs that correct IKM dysfunction. The objective of this application is to determine how
epilepsy-inducing mutations in the IKM subunits KCNQ2 and KCNQ3 cause channel malfunction. Because
polyunsaturated fatty acids (PUFAs) have been shown to alleviate the symptoms of intractable epileptic
seizures, we will investigate the mechanisms by which these compounds reverse channel malfunction and
therefore improve neuronal function. The overarching hypothesis is that that epilepsy-causing mutations in
KCNQ channels affect voltage sensor movement and that PUFAs can restore normal voltage dependence of
voltage sensor movement in mutated KCNQ channels. The rationale for the proposed research is that
understanding the molecular basis by which different mutations in the IKM channel are linked to epilepsy will not
only help explain epilepsy pathogenesis but also provide clues for intervention strategies. Guided by
preliminary data, we will test our hypothesis by pursuing three specific aims: (1) determine the mechanisms by
which epilepsy-causing mutations affect IKM channels function. (2) determine how PUFAs affect voltage sensor
and gate movements of IKM channels bearing epilepsy-associated mutations and to identify which PUFA
variants restores channel function, and (3) determine whether PUFAs reduce hyperexcitability on neurons
bearing epilepsy-causing mutations in IKM channels. Under the first Aim, we will combine cysteine accessibility
and VCF approaches to simultaneously measure voltage sensor movement and gate opening in the wt IKM and
a set of epilepsy-associated mutants. This will allow us to determine how mutations affect the movement of the
voltage sensor and the activation gate in KCNQ2 and KCNQ3 channels. We will also incorporate unnatural
amino acids (UUAs) into mutated channels (UUAs mutagenesis) to further map the molecular determinants of
channel dysfunction. Under Aim 2, we will test PUFA variants with different chain lengths, different acyl chains
and different types of polar head groups to determine the molecular mechanism of PUFA’s effects on these
mutations. Under the third Aim, we will test PUFA variants that can correct channel function and restore activity
in iPSC-derived cortical neurons bearing epilepsy-associated mutations in KCNQ2 and/or KCNQ3. The
proposed research i...

## Key facts

- **NIH application ID:** 10399187
- **Project number:** 3R01NS110847-02S1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Rene Barro-Soria
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,696
- **Award type:** 3
- **Project period:** 2021-05-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399187

## Citation

> US National Institutes of Health, RePORTER application 10399187, Molecular Mechanisms of Epilepsy-Causing Mutations in IKM channels: Anti-epileptic effect of Lipophilic compounds. (3R01NS110847-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399187. Licensed CC0.

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