ArticleThe EMBO journal2008
Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP.
Article in The EMBO journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 113 citations in OpenAlex.
- Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping.Journal of the American Heart Association · 2016Trial
- Effect of ivabradine-induced heart rate reduction on flow-mediated dilation measured with high-sensitivity ultrasound in patients with stable coronary heart disease.Cardiovascular ultrasound · 2014Trial
- L-Type CaCirculation research · 2026Article
- HCN4 channels sense temperature and determine heart rate responses to heat.Nature communications · 2025Article
- Combination of Autodisplay and Dynamic Pharmacophore Modeling Reveals New Insights into Cyclic Nucleotide Binding in Hyperpolarization-Activated and Cyclic Nucleotide-Gated Ion Channel 4 (HCN4).ACS pharmacology & translational science · 2024Article
- Pacemaker Channels and the Chronotropic Response in Health and Disease.Circulation research · 2024Review
- Genetics of sinoatrial node function and heart rate disorders.Disease models & mechanisms · 2023Review
- Sinus node dysfunction: current understanding and future directions.American journal of physiology. Heart and circulatory physiology · 2023Review
- The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells.The Journal of general physiology · 2022Article
- Paradigm shift: new concepts for HCN4 function in cardiac pacemaking.Pflugers Archiv : European journal of physiology · 2022Review
- Animal Models to Study Cardiac Arrhythmias.Circulation research · 2022Review
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Effect of Shenfu Injection on Differentiation of Bone Marrow Mesenchymal Stem Cells into Pacemaker-Like Cells and Improvement of Pacing Function of Sinoatrial Node.Oxidative medicine and cellular longevity · 2022Article
- Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model.Molecular genetics and metabolism reports · 2021Article
- Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function.Frontiers in physiology · 2021Review
- cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells.Nature communications · 2020Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation.Circulation research · 2020Review
- The Cardiac Pacemaker Story-Fundamental Role of the NaFrontiers in pharmacology · 2020Review
- HCN4 knockdown in dorsal hippocampus promotes anxiety-like behavior in mice.Genes, brain, and behavior · 2019Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Important targets for cAMP signalling in the heart are hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that underlie the depolarizing 'pacemaker' current, I(f). We studied the role of I(f) in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q). Homozygous HCN4(R669Q/R669Q) mice die during embryonic development. Prior to E12, homozygous and heterozygous embryos display reduced heart rates and show no or attenuated responses to catecholaminergic stimulation. Adult heterozygous mice display normal heart rates at rest and during exercise. However, following beta-adrenergic stimulation, hearts exhibit pauses and sino-atrial node block. Our results demonstrate that in the embryo, HCN4 is a true cardiac pacemaker and elevation of HCN4 channel activity by cAMP is essential for viability. In adult mice, an important function of HCN4 channels is to prevent sinus pauses during and after stress while their role as a pacemaker of the murine heart is put into question. Most importantly, our results indicate that HCN4 channels can fulfil their physiological function only when cAMP is bound.
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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.