# The sodium channel ecosystem in the adult ventricular myocyte

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $583,453

## Abstract

PROJECT SUMMARY
The voltage-gated sodium channel (Na-channel) is a central component of cardiac electrogenesis. Its
dysfunction can lead to arrhythmias that cause sudden cardiac death both in acquired (ischemia; heart failure),
and genetic disorders. Rare and common genetic variants in SCN5A, encoding the pore-forming Na-channel
subunit NaV1.5, are strongly associated with life-threatening arrhythmias and with structural heart disease. Yet,
insight into Na-channel function beyond electrogenesis, is limited.
Na-channels form macromolecular complexes that, in adult ventricular myocytes, cluster at specific subcellular
domains (or “pools”). A key emerging concept is that certain Na-channel partners localize only to one
subcellular domain, endowing the functional complex with region-specific properties that, if disrupted, facilitate
arrhythmias. Here, we propose the existence of a major Na-channel subpopulation that clusters with subjacent
mitochondria to create an anatomical substrate for electro-metabolic coupling. We further propose that in this
subdomain regulation is reciprocal: mitochondria regulate Na-channels and Na-channels regulate
mitochondrial function. As such, this hub can be a key node in the genesis of cardiomyopathies associated
with Na-channel variants. Based on published as well as preliminary data we propose the following SPECIFIC
AIMS:
Aim 1. To characterize the molecular composition and function of the Na-channel-mitochondrial hub.
Hypothesis: We postulate that the mitochondrial reticulum in the adult cardiac myocyte presents distinct,
functionally active hubs that contact the cell membrane at positions enriched for Na-channel proteins. We
propose that at these hubs, Na-channel composition/activity can affect mitochondrial structure and function.
Aim 2. To define the molecular network that constitutes the SCN5A/NaV1.5 interactome.
Hypothesis: We postulate that proteomic approaches will lead to the discovery of yet-unidentified molecules
that are a part of the Na-channel/mitochondrial hub, and that knowledge on their identity and nanoscale
localization will give new information as to the function of this hub in health and disease. We further speculate
that expression and sequence integrity of SCN5A is coupled, directly or indirectly, to a transcriptional
regulatory network that modulates cell energy and metabolism.
This proposal advances the concept that electro-metabolic coupling is a two-way process where electrical and
metabolic activity reach a mutual equilibrium. Successful accomplishment of these experiments will amend
basic concepts that are fundamental to our understanding of the electrical and metabolic cell homeostasis.

## Key facts

- **NIH application ID:** 9841997
- **Project number:** 5R01HL145911-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Mario Delmar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,453
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841997

## Citation

> US National Institutes of Health, RePORTER application 9841997, The sodium channel ecosystem in the adult ventricular myocyte (5R01HL145911-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841997. Licensed CC0.

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