# Post-Translational Crosstalk in Cardiac Sodium Channels and Arrhythmogenesis

> **NIH NIH F30** · UNIVERSITY OF IOWA · 2020 · $45,547

## Abstract

PROJECT SUMMARY

Sudden Cardiac Death (SCD) is a major health problem in the United States and globally, accounting
for 15%-20% of all deaths. Reduction of sodium current (INa) through the main cardiac voltage-gated
sodium channel (Nav1.5) has been identified as a contributor to arrhythmias leading to SCD in many
acquired and inherited cardiomyopathies. Two post-translational modifications (PTMs) in the
cytoplasmic III-IV linking domain of Nav1.5, acetylation at K1479 and phosphorylation at S1503, have
been found to decrease INa by reducing cell surface abundance of Nav1.5. Notably, both of these
PTMs are reversed by increased intracellular NAD+ levels, providing a therapeutic strategy to
increase INa. Preliminary studies found that Nicotinamide Riboside (NR), a NAD+ precursor, increases
INa in vitro. However, it remains unknown how these Nav1.5 PTMs modulated by NAD+ and
Nicotinamide Riboside can coordinate channel localization and influence cardiac electrophysiology in
vivo.
An additional PTM, ubiquination, is an established regulator in the internalization and trafficking of
Nav1.5 and other sodium channels. Recent studies suggest ubiquination may be facilitated by other
PTMs, a process known as ‘PTM crosstalk’. The objective of my application is to determine if and
how these PTMs on Nav1.5 regulate channel localization and to determine if these processes may be
manipulated to affect arrhythmic risk in vivo. The overall hypothesis is that modulation of PTMs by
Nicotinamide Riboside, an NAD+ precursor, disrupts crosstalk with ubiquination-endocytic processes,
thereby increasing cell surface localization of Nav1.5 and modifying the arrhythmic risk. To test this
hypothesis, two mouse models of Nav1.5 dysfunction will be utilized, in addition to cellular
approaches. These studies will test the hypothesis through two specific aims:
Aim 1: Determine the mechanism(s) driving Nav1.5 surface localization in response to increasing
NAD+ content by examining post-translational modifications and endocytic processes in vitro.
Aim 2: Determine if Nicotinamide Riboside supplementation can modify cardiac electrical activity in
mouse models of Nav1.5 dysfunction.

## Key facts

- **NIH application ID:** 9981003
- **Project number:** 5F30HL137272-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Daniel Stevens Matasic
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,547
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981003

## Citation

> US National Institutes of Health, RePORTER application 9981003, Post-Translational Crosstalk in Cardiac Sodium Channels and Arrhythmogenesis (5F30HL137272-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9981003. Licensed CC0.

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