ArticlePloS one2013
Identification of the molecular site of ivabradine binding to HCN4 channels.
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 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.
- Genetic loci associated with heart rate variability and their effects on cardiac disease risk.Nature communications · 2017Pooled it
- Ivabradine could not decrease mitral regurgitation triggered atrial fibrosis and fibrillation compared with carvedilol.ESC heart failure · 2024Trial
- Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping.Journal of the American Heart Association · 2016Trial
- The HCN4 channel modulates external tufted cell burst firing.Journal of neurophysiology · 2026Article
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- Few-shot molecular property optimizationChemical science · 2026Article
- Reassessing Ivabradine: Potential Benefits and Risks in Atrial Fibrillation Therapy.Cardiovascular drugs and therapy · 2025Review
- Pharmacological Preconditioning with Diazoxide Upregulates HCN4 Channels in the Sinoatrial Node of Adult Rat Cardiomyocytes.International journal of molecular sciences · 2025Article
- Structural determinants of ivabradine block of the open pore of HCN4.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.The Journal of general physiology · 2024Article
- A Novel Flow Cytometry-Based Assay for the Identification of HCN4 CNBD Ligands.Pharmaceuticals (Basel, Switzerland) · 2023Article
- The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Article
- Two HCN4 Channels Play Functional Roles in the Zebrafish Heart.Frontiers in physiology · 2022Article
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?Journal of clinical medicine · 2021Review
- Discovery of Novel HCN4 Blockers with Unique Blocking Kinetics and Binding Properties.SLAS discovery : advancing life sciences R & D · 2021Article
- Gating movements and ion permeation in HCN4 pacemaker channels.Molecular cell · 2021Article
- Bidirectional flow of the funny current (IProceedings of the National Academy of Sciences of the United States of America · 2021Article
- The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Frontiers in pharmacology · 2021Article
- Non-canonical Molecular Targets for Novel Analgesics: Intracellular Calcium and HCN Channels.Current neuropharmacology · 2021Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ivabradine is a specific heart rate-reducing agent approved as a treatment of chronic stable angina. Its mode of action involves a selective and specific block of HCN channels, the molecular components of sinoatrial "funny" (f)-channels. Different studies suggest that the binding site of ivabradine is located in the inner vestibule of HCN channels, but the molecular details of ivabradine binding are unknown. We thus sought to investigate by mutagenesis and in silico analysis which residues of the HCN4 channel, the HCN isoform expressed in the sinoatrial node, are involved in the binding of ivabradine. Using homology modeling, we verified the presence of an inner cavity below the channel pore and identified residues lining the cavity; these residues were replaced with alanine (or valine) either alone or in combination, and WT and mutant channels were expressed in HEK293 cells. Comparison of the block efficiency of mutant vs WT channels, measured by patch-clamp, revealed that residues Y506, F509 and I510 are involved in ivabradine binding. For each mutant channel, docking simulations correctly explain the reduced block efficiency in terms of proportionally reduced affinity for ivabradine binding. In summary our study shows that ivabradine occupies a cavity below the channel pore, and identifies specific residues facing this cavity that interact and stabilize the ivabradine molecule. This study provides an interpretation of known properties of f/HCN4 channel block by ivabradine such as the "open channel block", the current-dependence of block and the property of "trapping" of drug molecules in the closed configuration.
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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.