ArticlePflugers Archiv : European journal of physiology2009
Sensitivity of HCN channel deactivation to cAMP is amplified by an S4 mutation combined with activation mode shift.
Article in Pflugers Archiv : European journal of physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- HCN1 is a primary HCN Pacemaker Channel in Neurons.Nature communications · 2026Article
- The proximal N-terminus of IRAG is required for potentiation of HCN4 channels.bioRxiv : the preprint server for biology · 2026Article
- Subunit-specific conductance of single homomeric and heteromeric HCN pacemaker channels at femtosiemens resolution.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The HCN domain is required for HCN channel cell-surface expression and couples voltage- and cAMP-dependent gating mechanisms.The Journal of biological chemistry · 2020Article
- Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.The Journal of membrane biology · 2020Article
- HCN Channel C-Terminal Region Speeds Activation Rates Independently of Autoinhibition.The Journal of membrane biology · 2015Article
- Sequence of gating charge movement and pore gating in HERG activation and deactivation pathways.Biophysical journal · 2015Article
- Will the real single HCN channel please stand up?Biophysical journal · 2013Article
- 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
- Tissue-specific N terminus of the HCN4 channel affects channel activation.The Journal of biological chemistry · 2011Article
- Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperpolarisation-activation of HCN ion channels relies on the movement of a charged S4 transmembrane helix, preferentially stabilising the open conformation of the ion pore gate. The open state is additionally stabilised, (a) when cyclic AMP (cAMP) is bound to a cytoplasmic C-terminal domain or (b) when the "mode I" open state formed initially by gate opening undergoes a "mode shift" into a "mode II" open state with a new S4 conformation. We isolated a mutation (lysine 381 to glutamate) in S4 of mouse HCN4; patch-clamp of homomeric channels in excised inside-out membranes revealed a conditional phenotype. When cAMP-liganded K381E channels are previously activated by hyperpolarisation, tens of seconds are required for complete deactivation at a weakly depolarised potential; this "ultra-sustained activation" is not observed without cAMP. Whilst cAMP slows deactivation of wild-type channels, the K381E mutation amplifies this effect to enable extraordinary kinetic stabilisation of the open state. K381E channels retain S4-gate coupling, with strong voltage dependence of the rate-limiting step for deactivation of mode II channels near -40 mV. At these voltages, the mode I deactivation pathway shows a different rate-limiting step, lacking strong voltage or cAMP dependence. Ultra-sustained activation thus reflects stabilisation of the mode II open state by the K381E mutation in synergistic combination with cAMP binding. Thus, the voltage-sensing domain is subject to strong functional coupling not only to the pore domain but also to the cytoplasmic cAMP-sensing domain in a manner specific to the voltage sensor conformation.
Indexed as
Identifiers
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.