ArticleProceedings of the National Academy of Sciences of the United States of America2012
Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers, 1 of them a synthesis that pooled it.
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Who cites it
117 citing papers in PubMed, 1 synthesis or guideline pooled it, 195 citations in OpenAlex.
- Co-expression of calcium and hERG potassium channels reduces the incidence of proarrhythmic events.Cardiovascular research · 2021Pooled it
- Repurposing polyamines to prevent life-threatening arrhythmias in Short QT Syndrome type 3.Nature communications · 2026Article
- Calcium Homeostatic Feedback Control Predicts Atrial Fibrillation Initiation, Remodeling, and Progression.JACC. Clinical electrophysiology · 2025Article
- A robust expression system reveals distinct gating mechanisms and calmodulin regulation of NaScience advances · 2025Article
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Alleviating the Effects of Short QT Syndrome Type 3 by Allele-Specific Suppression of theInternational journal of molecular sciences · 2024Article
- The network of cardiac KNaunyn-Schmiedeberg's archives of pharmacology · 2024Review
- X-ray Radiotherapy Impacts Cardiac Dysfunction by Modulating the Sympathetic Nervous System and Calcium Transients.International journal of molecular sciences · 2024Article
- The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.Cardiovascular research · 2024Article
- Extracellular Kir2.1Circulation research · 2024Article
- Article
- Unraveling Impacts of Chamber-Specific Differences in Intercalated Disc Ultrastructure and Molecular Organization on Cardiac Conduction.JACC. Clinical electrophysiology · 2023Article
- Pairwise biosynthesis of ion channels stabilizes excitability and mitigates arrhythmias.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.Cardiovascular research · 2023Article
- Protein networks for cardiac ion channels share protein components.Nature cardiovascular research · 2023Article
- Diversity of cells and signals in the cardiovascular system.The Journal of physiology · 2023Article
- In silico analysis of the dynamic regulation of cardiac electrophysiology by KThe Journal of physiology · 2023Article
- Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.Cardiovascular research · 2023Article
- Role of ephaptic coupling in discordant alternans domain sizes and action potential propagation in the heart.Physical review. E · 2023Article
- Cheek-Pro-Heart: What Can the Buccal Mucosa Do for Arrhythmogenic Cardiomyopathy?Biomedicines · 2023Review
57 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I(K1)-I(Na) interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I(K1)-I(Na) interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na(V)1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the post synaptic density, discs large, and zonula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na(v)1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na(v)1.5-Kir2.1 interactions. The reciprocal modulation between Na(v)1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.
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