ArticlePloS one2013
Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 67 citations in OpenAlex.
- Aging Disrupts L-type CaCirculation research · 2026Article
- Intracellular CaInternational journal of molecular sciences · 2026Article
- Regulation of Pacemaker Current in the Sinoatrial Node by Zonula Occludens-1.bioRxiv : the preprint server for biology · 2026Article
- Regulation of Na/Ca exchange by cytoplasmic protons modifies intracellular calcium dynamics and the cardiac response to ischemia.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Aging and sinus node dysfunction: mechanisms and future directions.Clinical science (London, England : 1979) · 2025Review
- Structure-Function Relationship of the Ryanodine Receptor Cluster Network in Sinoatrial Node Cells.Cells · 2024Article
- Pacemaker Channels and the Chronotropic Response in Health and Disease.Circulation research · 2024Review
- Article
- Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal CaPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Local tissue mechanics control cardiac pacemaker cell embryonic patterning.Life science alliance · 2023Article
- Emergent activity, heterogeneity, and robustness in a calcium feedback model of the sinoatrial node.Biophysical journal · 2023Article
- Sinus node dysfunction: current understanding and future directions.American journal of physiology. Heart and circulatory physiology · 2023Review
- cAMP-PKA signaling modulates the automaticity of human iPSC-derived cardiomyocytes.The Journal of general physiology · 2023Article
- Animal Models to Study Cardiac Arrhythmias.Circulation research · 2022Review
- Simultaneous imaging of calcium and contraction in the beating heart of zebrafish larvae.Theranostics · 2022Article
- Bidirectional flow of the funny current (IProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Intracellular NaInternational journal of molecular sciences · 2021Article
- Genetic Complexity of Sinoatrial Node Dysfunction.Frontiers in genetics · 2021Review
- Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity.British journal of pharmacology · 2020Article
- Distinct features of calcium handling and β-adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction.The Journal of physiology · 2020Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.