Ion Channels in Cardiac Non-Excitable Cells: From Single-Cell Atlases to Disease
- 1Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- 2Bob and Corrine Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Abstract
Cardiovascular disease is shaped not only by cardiomyocyte excitability but also by electrophysiological and membrane-signaling programs in cardiac fibroblasts, endothelial cells, mural cells, immune cells, and adipocytes. Recent single-cell RNA sequencing, spatial transcriptomic, and disease-atlas studies have revealed broad expression of ion-channel transcripts across these non-excitable cardiac cell populations. However, transcript detection alone does not establish functional channel activity, cell-state specificity, or therapeutic relevance. This narrative Review therefore focuses on mechanistically supported channel–cell–disease axes rather than providing an exhaustive catalogue of ion channels detected in cardiac non-myocytes. We synthesize evidence for mechanosensitive channels, transient receptor potential channels, calcium-entry pathways, acid-sensing channels, and potassium, sodium, and chloride channels, as well as connexin hemichannels and pannexin channels. We emphasize studies in which omics-based channel nomination is supported by functional validation through electrophysiology, Ca2+ imaging, mechanostimulation, pharmacological intervention, or cell-selective genetic perturbation. Particular attention is given to mechanisms linking mechanical stress, Ca2+ entry, membrane potential, cell-volume regulation, ATP release, immune activation, vascular tone, fibrosis, and metabolic dysfunction. We also identify key evidence gaps where expression-based observations require direct functional testing in human tissues and disease-relevant cardiac models. By distinguishing atlas-level association from causal channel function, this Review provides a framework for prioritizing non-myocyte ion-channel mechanisms as therapeutic targets in cardiovascular diseases.
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BibTeX
@article{chen2026channels,
title = {{Ion Channels in Cardiac Non-Excitable Cells: From Single-Cell Atlases to Disease}},
author = {Weixuan Chen and Ashlyn A. Fitzgerald and Brett Bardallis and Anu Priya Bharathi Rajan and Pengfei Liang},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191790},
url = {https://www.mdpi.com/2073-4409/15/19/1790},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ion Channels in Cardiac Non-Excitable Cells: From Single-Cell Atlases to Disease
AU - Weixuan Chen
AU - Ashlyn A. Fitzgerald
AU - Brett Bardallis
AU - Anu Priya Bharathi Rajan
AU - Pengfei Liang
PY - 2026
DA - 2026/09/30
JO - Cells
DO - 10.3390/cells15191790
UR - https://www.mdpi.com/2073-4409/15/19/1790
AB - Cardiovascular disease is shaped not only by cardiomyocyte excitability but also by electrophysiological and membrane-signaling programs in cardiac fibroblasts, endothelial cells, mural cells, immune cells, and adipocytes. Recent single-cell RNA sequencing, spatial transcriptomic, and disease-atlas studies have revealed broad expression of ion-channel transcripts across these non-excitable cardiac cell populations. However, transcript detection alone does not establish functional channel activity, cell-state specificity, or therapeutic relevance. This narrative Review therefore focuses on mechanistically supported channel–cell–disease axes rather than providing an exhaustive catalogue of ion channels detected in cardiac non-myocytes. We synthesize evidence for mechanosensitive channels, transient receptor potential channels, calcium-entry pathways, acid-sensing channels, and potassium, sodium, and chloride channels, as well as connexin hemichannels and pannexin channels. We emphasize studies in which omics-based channel nomination is supported by functional validation through electrophysiology, Ca2+ imaging, mechanostimulation, pharmacological intervention, or cell-selective genetic perturbation. Particular attention is given to mechanisms linking mechanical stress, Ca2+ entry, membrane potential, cell-volume regulation, ATP release, immune activation, vascular tone, fibrosis, and metabolic dysfunction. We also identify key evidence gaps where expression-based observations require direct functional testing in human tissues and disease-relevant cardiac models. By distinguishing atlas-level association from causal channel function, this Review provides a framework for prioritizing non-myocyte ion-channel mechanisms as therapeutic targets in cardiovascular diseases.
SN - 2073-4409
ER -