# Post-Transcriptional Regulation of Myocardial Sodium Channels

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $571,481

## Abstract

Voltage-gated Na+ (Nav) channels play key roles in action potential generation and in controlling action
potential durations and propagation in the mammalian heart, and these channels are critical for the
maintenance of normal cardiac rhythms. Changes in Nav channel expression and properties are prevalent in
inherited and acquired cardiac diseases, and these changes can have profound pathophysiological
consequences, including increasing the risk of potentially life-threatening cardiac arrhythmias. Although it
seems generally accepted that native myocardial Nav channels function in macromolecular protein
complexes, comprising the pore-forming Nav1.5 subunit and multiple intracellular and transmembrane
accessory subunits, the physiological roles of accessory subunits in regulating Nav channel function and how
these roles are altered with myocardial disease are poorly understood. This new collaborative research
program is focused on defining the post-transcriptional mechanisms involved in the physiological regulation and
pathophysiological dysregulation of myocardial Nav1.5-encoded channels by intracellular Nav channel
accessory subunits. A multifaceted experimental strategy has been developed to define the molecular and
cellular mechanisms underlying the regulatory effects of intracellular Fibroblast Growth Factor 12B, iFGF12B,
the main iFGF variant expressed in non-diseased human heart, on the gating of Nav1.5-encoded Nav
channels (aim #1), and test the hypothesis that iFGF12A, which is upregulated in failing human heart, has
distinct effects on the biophysical and pharmacological properties of cardiac Nav1.5-encoded channels (aim
#2). Additional experiments will test the hypothesis that another intracellular accessory subunit, calmodulin,
CaM, which binds to the C terminus of Nav1.5 near the iFGF binding site, modulates iFGF12B/iFGF12A-
mediated effects on Nav1.5-encoded channel gating (aim #3). We will also create molecularly-detailed Nav
channel gating models that include Nav1.5 regulation by iFGF12A, iFGF12B and CaM and will use these models
to delineate the impact of iFGF12-mediated regulation of native Nav currents on myocyte electrophysiology.
These studies will provide fundamentally important new insights into the molecular and cellular mechanisms
underlying iFGF12-mediated regulation of myocardial Nav1.5-encoded channels and into the physiological
roles of iFGF12 in the dynamic regulation of cardiac excitability. These insights will inform efforts to explore
the potential of iFGFs and of iFGF-Nav1.5 interactions as new therapeutic targets to modulate Nav channel
functioning in inherited and acquired cardiac rhythm disorders.

## Key facts

- **NIH application ID:** 10171418
- **Project number:** 5R01HL150637-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JEANNE M. NERBONNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $571,481
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171418

## Citation

> US National Institutes of Health, RePORTER application 10171418, Post-Transcriptional Regulation of Myocardial Sodium Channels (5R01HL150637-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171418. Licensed CC0.

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