# Sodium Channels and Cardiac Arrhythmias

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $535,251

## Abstract

Project Summary
Evolutionarily, voltage-gated sodium channels are fundamental to the organization of most complex excitable
tissues where they are crucial to ensure the sharp initiation dynamics and proper propagation of the action
potential and are at the center of cellular excitability. Hence, mutations in voltage-gated sodium channel genes
have been linked to a whole host of diseases including cardiac arrhythmias. Modification in Na+ current (INa) is
known to contribute to both cardiac arrhythmias from acquired heart diseases and inherited cardiac arrhythmias.
Since the original cloning of the genes encoding for voltage-gated sodium channels and the recording of its
function by patch-clamping over 30 years ago, the -subunit of the sodium channel was thought to be a
monomer. However, during the previous funding period our studies of mutations found in SCN5A linked to
several different arrhythmic syndromes led us to question the traditional idea of the sodium channel forming a
monomer. In fact, we and others have shown that several Brugada Syndrome (BrS) mutations display dominant-
negative effects (DN-effect), which could only be attributed to interaction between -subunits within multimeric
complexes. Similarly, we have shown that the defects of several BrS or LQT3 SCN5A mutations could be
rescued by different SCN5A polymorphisms expressed on a separate construct, again supporting the idea of an
subunit interaction. Finally, we also reported the presence of atypical BrS mutations that do not present
defects when expressed alone but lead to reduced current amplitudes when co-expressed with WT, again
supporting an interaction of the subunits. Therefore, multiple lines of evidence challenged the conventional
wisdom that sodium channels exist in complexes containing a single subunit. We thus sought to investigate
the stoichiometry of sodium channel subunits. We demonstrated using different experimental approaches that
sodium channels form functional dimers. We also identified the region modulating the dimerization and found
that this physical dimerization results in coupled gating of the sodium channels and involves 14-3-3. Our findings
shifted conventional paradigms in regards to sodium channel assembly, structure, and function. Our overall
hypothesis for this renewal is that the physical dimerization of sodium channels leads to dimerization-dependent
channel activity (i.e. channel gating and trafficking) with implication for normal physiology and for cardiac
pathologies linked to dysregulation of the sodium current. In aim 1 we will study the biophysical coupling and
determine if this is dynamically modulated. In aim 2 we will explore trafficking of the sodium channel and the
involvement of 14-3-3. Finally in aim 3 we will determine the role of posttranslational modification in the
dimerization of sodium channels. Understanding of the mechanisms involved in channel dimerization, trafficking
and functional biophysical coupling could op...

## Key facts

- **NIH application ID:** 10458504
- **Project number:** 5R01HL094450-09
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Isabelle Deschenes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,251
- **Award type:** 5
- **Project period:** 2010-03-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458504

## Citation

> US National Institutes of Health, RePORTER application 10458504, Sodium Channels and Cardiac Arrhythmias (5R01HL094450-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10458504. Licensed CC0.

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