ArticleNature communications2024
A high affinity switch for cAMP in the HCN pacemaker channels.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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The trial behind it
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
10 citing papers in PubMed, 17 citations in OpenAlex.
- Temperature dependence of HCN channel kinetics: A systematic comparison across mammalian isoforms and species.Experimental physiology · 2026Article
- Enhanced HCN-Dependent Regulation of Temporoammonic Integration and Entorhinal-Hippocampal Epileptiform Coupling Following Febrile Seizures.Neurochemical research · 2026Article
- Structure mirroring function: What's the 'matter' with the funny current?The Journal of physiology · 2026Review
- GABAExperimental physiology · 2026Article
- An inter-subunit path is required for entropically-driven and negatively cooperative binding of cyclic nucleotides in the HCN2 channel.Communications biology · 2026Article
- Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts.Journal of molecular and cellular cardiology · 2026Review
- Extracellular activation of HCN4 by a subtype-specific nanobody.Nature communications · 2025Article
- Deep Learning-Based Ion Channel Kinetics Analysis for Automated Patch Clamp Recording.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Hyperpolarization-activated cyclic nucleotide-gated channels and epilepsy: genetics, circuits, and treatments.Frontiers in neurology · 2025Review
- Similar Binding Modes of cGMP Analogues Limit Selectivity in Modulating Retinal CNG Channels via the Cyclic Nucleotide-Binding Domain.ACS chemical neuroscience · 2024Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 4 countries.
Funding
Abstract
Binding of cAMP to Hyperpolarization activated cyclic nucleotide gated (HCN) channels facilitates pore opening. It is unclear why the isolated cyclic nucleotide binding domain (CNBD) displays in vitro lower affinity for cAMP than the full-length channel in patch experiments. Here we show that HCN are endowed with an affinity switch for cAMP. Alpha helices D and E, downstream of the cyclic nucleotide binding domain (CNBD), bind to and stabilize the holo CNBD in a high affinity state. These helices increase by 30-fold cAMP efficacy and affinity measured in patch clamp and ITC, respectively. We further show that helices D and E regulate affinity by interacting with helix C of the CNBD, similarly to the regulatory protein TRIP8b. Our results uncover an intramolecular mechanism whereby changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels, adding another layer to the complex regulation of their activity.
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What OpenQuestion holds
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.