ArticleProceedings of the National Academy of Sciences of the United States of America2011
Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 34 citations in OpenAlex.
- The proximal N-terminus of IRAG is required for potentiation of HCN4 channels.bioRxiv : the preprint server for biology · 2026Article
- Predicting Binding Affinities for the Binding Domain of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Isoforms Using Free-Energy Perturbation.bioRxiv : the preprint server for biology · 2026Article
- An inter-subunit path is required for entropically-driven and negatively cooperative binding of cyclic nucleotides in the HCN2 channel.Communications biology · 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
- Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2.International journal of molecular sciences · 2023Review
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.The Journal of membrane biology · 2020Article
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- Hydrophobic alkyl chains substituted to the 8-position of cyclic nucleotides enhance activation of CNG and HCN channels by an intricate enthalpy - entropy compensation.Scientific reports · 2018Article
- Activation gating in HCN2 channels.PLoS computational biology · 2018Article
- Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia.The Journal of biological chemistry · 2017Article
- HCN Channel C-Terminal Region Speeds Activation Rates Independently of Autoinhibition.The Journal of membrane biology · 2015Article
- Cellular context and multiple channel domains determine cAMP sensitivity of HCN4 channels: ligand-independent relief of autoinhibition in HCN4.The Journal of general physiology · 2012Article
- Distinct perinatal features of the hyperpolarization-activated non-selective cation current I(h) in the rat cortical plate.Neural development · 2012Article
- Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.The Journal of biological chemistry · 2011Article
- PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Article
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5 authors at 2 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Voltage gating of hyperpolarization-activated cation (HCN) channels is potentiated by direct binding of cAMP to a cytoplasmic cAMP-sensing domain (CSD). When unliganded, the CSD inhibits hyperpolarization-dependent opening of the HCN channel gate; cAMP binding relieves this autoinhibition so that opening becomes more favorable thermodynamically. This autoinhibition-relief mechanism is conserved with that of several other cyclic nucleotide receptors using the same ligand-binding fold. Besides its thermodynamic effect, cAMP also modulates the depolarization-dependent deactivation rate by kinetically trapping channels in an open state. Here we report studies of strong open-state trapping in an HCN channel showing that the well-established autoinhibition-relief model is insufficient. Whereas deletion of the CSD mimics the thermodynamic open-state stabilization usually associated with cAMP binding, CSD deletion removes rather than mimics the kinetic effect of strong open-state trapping. Substitution of different CSD sequences leads to variation of the degree of open-state trapping in the liganded channel but not in the unliganded channel. CSD-dependent open-state trapping is observed during a voltage-dependent deactivation pathway, specific to the secondary open state that is formed by mode shift after prolonged hyperpolarization activation. This hysteretic activation-deactivation cycle is preserved by CSD substitution, but the change in deactivation kinetics of the liganded channel resulting from CSD substitution is not correlated with the change in autoinhibition properties. Thus the liganded and the unliganded forms of the CSD respectively provide the structural determinants for open-state trapping and autoinhibition, such that two distinct mechanisms for cAMP regulation can operate in one receptor.
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