Dissertation
Sodium current composition and remodeling in murine cardiomyocytes
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
Abstract
This thesis explores the role of voltage-gated sodium channel (VGSC) isoforms in cardiac function and pathology, with a specific focus on their contributions to electrical remodeling and arrhythmogenesis in disease states. VGSCs, particularly NaV1.5, are critical for the rapid depolarization phase of the cardiac action potential, underpinning synchronous myocardial contraction and efficient conduction. While NaV1.5 is the predominant isoform in cardiomyocytes, emerging evidence suggests that other NaV isoforms may also contribute to cardiac conduction, especially under pathological conditions like heart failure, ischemia, and inherited arrhythmias. Using a novel chemical-genetic mouse model, this study identifies and quantifies the contributions of non-NaV1.5 isoforms in healthy and diseased cardiomyocytes. Results demonstrate that while NaV1.5 produces the majority of sodium current in healthy myocardium, other isoforms, particularly NaV1.8 and NaV1.4, are also significant contributors. Pharmacological inhibition of NaV1.5 in vivo revealed upregulation of non-cardiac isoforms, suggesting they may play a role in compensating for impaired depolarization. Additionally, this thesis addresses the limitations of existing pharmacological tools for isoform-specific modulation and highlights the therapeutic potential of isoform-targeted interventions. This work provides new insights into the molecular mechanisms underlying sodium channel dysfunction in cardiac diseases and offers a foundation for the development of safer and effective therapeutic strategies targeting VGSCs.
Details
- Title: Subtitle
- Sodium current composition and remodeling in murine cardiomyocytes
- Creators
- Colin James Clark
- Contributors
- Christopher Ahern (Advisor)Barry London (Committee Member)Robert Piper (Committee Member)Stephanie Gantz (Committee Member)Joel Geerling (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Molecular Physiology and Biophysics
- Date degree season
- Spring 2026
- Publisher
- University of Iowa
- Number of pages
- xii, 59 pages
- Copyright
- Copyright 2024 Colin James Clark
- Language
- English
- Date submitted
- 04/27/2026
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (page 52-59).
- Public Abstract (ETD)
This research focuses on understanding how proteins called voltage-gated sodium channels help the heart function properly and how changes in these channels can lead to heart problems. The heart relies on electrical signals to pump blood efficiently, and these signals are controlled by sodium channels, which act like gates that let sodium into heart cells. The main sodium channel in the heart is called NaV1.5.
In some diseases, like heart failure or inherited conditions such as Brugada syndrome, the function of sodium channels can be disrupted. This study explores not only NaV1.5 but also other sodium channels, like NaV1.8 and NaV1.4, which are typically found in nerves and skeletal muscle respectively but may play a role in the heart under certain conditions. By using a specially designed mouse model, this research reveals how these other sodium channels might contribute to heart rhythm and affect its ability to circulate blood. The findings could lead to better treatments for heart diseases by targeting specific sodium channels with new medications. This approach may help improve heart function while avoiding side effects caused by existing treatments. The study provides a step forward in understanding how the heart works and how to keep it healthy.
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9985176973502771
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