# Signaling in Inherited and Acquired Sodium Channel Gain of Function

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $667,013

## Abstract

PROJECT SUMMARY
Gain-of-function mutations in the genes encoding or age related modifications of the cardiac isoform of the
voltage-gated sodium channel have been associated with the Long-QT Syndrome Type 3 (LQT3) and heart
failure. The genetic form of sodium channel gain of function disease LQT3 represents an exemplar for elucidating
the role sodium channels play in sudden death independent of systemic remodeling.
The principal issue that will be addressed in this application is the role intercellular coupling plays in translating
a cellular pathologic response into a tissue level response that causes sudden cardiac death. In short, if cells
electrically communicate only by gap junctional coupling, then statistically the chance of sudden death should
be low and only occur after substantial gap junction loss of function. However, if cells can also communicate via
electric fields generated in very narrow spaces between cells (ephaptic coupling), then pathologic activity should
manifest during substantial ephaptic remodeling.
Additionally, symptoms of LQT3 do not manifest until sometime during or after puberty, suggesting that young
organisms are protected against life-threatening cardiac events by some type of age related remodeling. Since
gap junctions redistribute around cells, but do not necessarily decrease expression, the gap junction coupling
hypothesis remains speculative at best. However, since the determinants of cellular excitability and ephaptic
coupling change with age, the hypothesis that ephaptic coupling modulates sudden death during gain-of-sodium
function requires investigation.
Upon successful completion of these aims, we will produce new theoretical underpinnings of LQT3 and heart
failure that will help design new early detection tests and suggest new treatments during disease progression.

## Key facts

- **NIH application ID:** 10201723
- **Project number:** 5R01HL138003-04
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Steven Poelzing
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $667,013
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201723

## Citation

> US National Institutes of Health, RePORTER application 10201723, Signaling in Inherited and Acquired Sodium Channel Gain of Function (5R01HL138003-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201723. Licensed CC0.

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