# Investigating the interactions of auxillary subunits with the Nav1.5 channel

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary/Abstract
 Within the years 2013 to 2016, 6.2 million patients were diagnosed with heart failure in the United
States. Heart failure has multiple causes, and many fatal cases include patients being predisposed to
arrhythmias. One mechanism for triggering a pro-arrhythmic state are changes cardiac action potential such as
the prolongation of the depolarization. The main contributor of this rapid depolarization is the ionic current
supplied by the Nav1.5 voltage gated sodium channel within the human heart. In addition, there are multiple
subunits that interact with the channel in a physiological setting including the subunits of intracellular fibroblast
growth factor (FGF) 12A, FGF12B, and calmodulin (CaM). In preliminary data, it has been shown that FGF12A
is upregulated in the left ventricle in failing hearts and that FGF12B is the most prevalent FGF isoform in the
human heart. Both FGF12A, FGF12B and CaM have shown to alter the inactivation of the Nav1.5 channel
through modulation of the DIII and DIV voltage sensing domains (VSD). However, there is no research as to
the combined effects of these subunits and their potential to synergistically modulate the Nav1.5 VSDs. As the
DIII and DIV VSDs are modulated by these proposed subunits, it can be hypothesized that the efficacy of class
1b anti-arrhythmic drugs are also affected by the proposed subunits. These preliminary findings confer to the
two hypotheses: (1) combinations of modulating subunits bound to Nav1.5 can collectively alter gating to
disrupt activation and inactivaiton and (2) the subunits of FGF12A, FGF12B, and CaM will alter the interaction
of efficacy of class 1b anti-arrhythmic drugs. To support these hypotheses, three aims were created. Aim 1 will
focus on determining the biophysical changes the combined subunits have on the Nav1.5 VSDs. The aim will
be accomplished with the use of voltage clamp fluorometry to examine the changes in the activation of the
individual VSDs. Aim 2 will develop a machine learning model to decipher how alterations to the VSD
activations change the overall ionic current. Aim 3 will conclude the proposal by looking at changes in the
effectiveness of the class 1b anti-arrhythmic drugs lidocaine, mexiletine, and ranolazine in response to varying
levels of each subunit. This proposal has implications that stretch both at the biophysical understanding of the
Nav1.5 channel to the clinical application in the use of specific anti-arrhythmic drugs. The overall application
will provide rigorous and exemplary training for the applicant to successfully become a translation research
scientist.

## Key facts

- **NIH application ID:** 10988220
- **Project number:** 5F31HL164080-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Lucy Summer Woodbury
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988220

## Citation

> US National Institutes of Health, RePORTER application 10988220, Investigating the interactions of auxillary subunits with the Nav1.5 channel (5F31HL164080-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10988220. Licensed CC0.

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