ArticleNature chemical biology2014
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
Article in Nature chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 56 citations in OpenAlex.
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- L-Type CaCirculation research · 2026Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.eLife · 2024Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.bioRxiv : the preprint server for biology · 2024Article
- Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model.The journal of headache and pain · 2023Article
- Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.Nature structural & molecular biology · 2023Article
- Propofol, an Anesthetic Agent, Inhibits HCN Channels through the Allosteric Modulation of the cAMP-Dependent Gating Mechanism.Biomolecules · 2022Article
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Review: HCN Channels in the Heart.Current cardiology reviews · 2022Review
- Sinoatrial node pacemaker cells share dominant biological properties with glutamatergic neurons.Protein & cell · 2021Article
- Cyclic-di-GMP Induces STING-Dependent ILC2 to ILC1 Shift During Innate Type 2 Lung Inflammation.Frontiers in immunology · 2021Article
- The STING-IFN-β-Dependent Axis Is Markedly Low in Patients with Relapsing-Remitting Multiple Sclerosis.International journal of molecular sciences · 2020Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4.Frontiers in physiology · 2020Review
- Biofilm formation - what we can learn from recent developments.Journal of internal medicine · 2018Article
- HCN Channels: New Therapeutic Targets for Pain Treatment.Molecules (Basel, Switzerland) · 2018Review
- Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel.The Journal of biological chemistry · 2018Article
- A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction.Heart and vessels · 2018Article
- Versatile modes of cellular regulation via cyclic dinucleotides.Nature chemical biology · 2017Review
- Investigating cyclic nucleotide and cyclic dinucleotide binding to HCN channels by surface plasmon resonance.PloS one · 2017Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder β-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system.
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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.