Affinage

HCN1

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 · UniProt O60741

Length
890 aa
Mass
98.8 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCN1 encodes a hyperpolarization-activated cation channel that conducts the Ih current and thereby sets the resting excitability and integrative properties of neurons and cardiac pacemaker cells (PMID:10971612, PMID:19726656, PMID:24218458). It assembles as homotetramers with characteristically fast-activating, cAMP-insensitive kinetics, and also heteromerizes with HCN2 or HCN4 to generate channels with intermediate gating and cAMP sensitivity matching native pacemaker currents in hippocampal CA1 neurons and the sinoatrial node (PMID:11331358, PMID:11133998, PMID:12702747, PMID:11680627). The channel is enriched ~60-fold in distal apical dendrites of pyramidal neurons (PMID:12389030), where this gradient is established by the auxiliary subunit TRIP8b, which binds the HCN1 C-linker/CNBD and C-terminal SNL tripeptide and, through distinct splice isoforms, both promotes dendritic surface expression and suppresses axonal misexpression (PMID:21411649, PMID:21555075). Surface levels are further tuned by filamin A, which clusters HCN1 and drives its dynamin-dependent internalization, and by Nedd4-2, which ubiquitinates HCN1 to reduce current and surface expression (PMID:15292205, PMID:24403084, PMID:24451387). Functionally, dendritic Ih constrains the integration of distal synaptic inputs and dendritic excitability, such that HCN1 loss enhances LTP, spatial learning, and dendritic spike generation (PMID:15550252, PMID:19726656, PMID:17095562); HCN1 also establishes the dorsal-ventral oscillation frequency gradient of entorhinal stellate cells, shapes photoreceptor light-response kinetics, mediates proton-gated sour taste transduction, and stabilizes sinoatrial pacemaking (PMID:19515931, PMID:19019198, PMID:11675786, PMID:24218458). Presynaptically, HCN1 colocalizes with and suppresses Cav3.2 T-type channels to limit glutamate release and vesicle exocytosis (PMID:21358644, PMID:28467171, PMID:28071723). HCN1 gating is modulated by anesthetics that act on the closed-state channel core (propofol, ketamine) and by nitric oxide and type I interferons in a cGMP-independent manner, and it is upregulated by glucocorticoid/GR/PKA signaling (PMID:17569731, PMID:19158287, PMID:25605440, PMID:23042740, PMID:35840797). De novo missense variants clustered in the transmembrane domains cause early infantile epileptic encephalopathy through loss-of-function, constitutive cation leak, or dominant-negative disruption of voltage-dependent gating (PMID:24747641, PMID:30351409, PMID:37265603, PMID:34298002).

Mechanistic history

Synthesis pass · year-by-year structured walk · 40 steps
  1. 2000 Medium

    Establishing which HCN subunit drives the fast Ih of cortical neurons was needed to assign a molecular identity to the native current; correlating single-cell mRNA with kinetics identified HCN1 as the determinant of fast-activating Ih.

    Evidence Combined single-cell RT-PCR and patch-clamp across mouse CNS neuron populations

    PMID:10971612

    Open questions at the time
    • Correlative rather than causal
    • Does not address heteromeric contributions in individual cells
  2. 2001 High

    Native CA1 Ih did not match any single homomer, so testing subunit coassembly was needed; HCN1/HCN2 heteromers were shown to produce novel intermediate gating and cAMP sensitivity matching native current.

    Evidence Heterologous expression and concatenated tandem constructs in Xenopus oocytes with cAMP dose-response and patch-clamp

    PMID:11133998 PMID:11331358

    Open questions at the time
    • Native subunit stoichiometry not resolved
    • Did not address HCN4 partnerships
  3. 2001 Medium

    Whether GPCR-cAMP signaling regulates HCN1 directly was unresolved; HCN1 was shown to be insensitive to Gi/Gs receptor-driven cAMP, distinguishing it from HCN2.

    Evidence Co-expression of HCN1/HCN2 with GPCRs in oocytes with pharmacological pathway dissection

    PMID:11680627

    Open questions at the time
    • Single expression system
    • Does not exclude regulation via other second messengers
  4. 2002 High

    How Ih is positioned for dendritic integration was unknown; quantitative immunogold revealed a 60-fold somatodendritic HCN1 gradient establishing the structural basis for dendritic Ih.

    Evidence Quantitative immunogold electron microscopy in hippocampal CA1 pyramidal cells

    PMID:12389030

    Open questions at the time
    • Mechanism generating the gradient not identified here
    • Functional consequence inferred, not tested
  5. 2002 High

    Establishing HCN1's role in vision required distinguishing native rod Ih from heteromeric currents; rod Ih matched homomeric HCN1, assigning a defined photoreceptor function.

    Evidence Immunocytochemistry, patch-clamp of isolated rods, and HEK293 expression comparison

    PMID:12096053

    Open questions at the time
    • Cone contribution not directly addressed
    • In vivo consequence not yet tested
  6. 2003 Medium

    The molecular composition of sinoatrial pacemaker channels was uncertain; HCN1/HCN4 heteromers were shown to approach native f-current kinetics.

    Evidence HEK293 tandem-construct expression and patch-clamp

    PMID:12702747

    Open questions at the time
    • Native current not fully recapitulated
    • Single lab
  7. 2004 High

    HCN1 surface organization and gating control were unexplained; filamin A was identified as an HCN1-specific scaffold clustering channels and modulating gating.

    Evidence Yeast two-hybrid, Co-IP from bovine brain, imaging in filamin+/- cells, electrophysiology

    PMID:15292205

    Open questions at the time
    • Did not establish endocytic mechanism (later shown)
    • Physiological consequence in neurons not tested here
  8. 2004 High

    The in vivo function of dendritic HCN1 was unknown; forebrain knockout showed HCN1 constrains distal dendritic integration, LTP, and spatial memory.

    Evidence Global and forebrain-restricted HCN1 KO mice with behavior, EEG, and LTP recordings

    PMID:15550252

    Open questions at the time
    • Did not distinguish presynaptic vs postsynaptic contributions
    • Compensatory mechanisms not addressed here
  9. 2007 High

    How anesthetics act on HCN1 was unclear; propofol was shown to inhibit HCN1 by binding the closed-state membrane-embedded core independent of cAMP.

    Evidence Patch-clamp with kinetic modeling and second-messenger uncoupling

    PMID:17569731

    Open questions at the time
    • No structural binding site defined
    • In vivo behavioral link established by later anesthetic studies
  10. 2007 High

    Whether HCN1 has presynaptic functions and how this changes developmentally was unknown; presynaptic HCN1 in immature perforant path was shown to modulate synaptic efficacy and to be regulated by network activity.

    Evidence Immunohistochemistry, EM, electrophysiology, and activity-blockade in rat hippocampal slices

    PMID:17460082

    Open questions at the time
    • Trafficking machinery not identified here
    • Adult presynaptic role addressed later
  11. 2008 High

    Whether HCN1 contributes to retinal light-response timing was unresolved; HCN1 KO prolonged ERG responses, showing HCN1 shortens photoreceptor light responses across rod and cone pathways.

    Evidence Electroretinography in HCN1 KO mice with immunohistochemistry and patch-clamp

    PMID:19019198

    Open questions at the time
    • Cone-specific mechanism not isolated
    • Downstream visual processing not assessed
  12. 2008 High

    An HCN1-specific N-terminal interaction was uncharacterized; HCN1 was shown to bind protocadherin 15 CD3 in a Ca2+-dependent manner competing with HCN1 self-assembly.

    Evidence Yeast two-hybrid, pull-downs, SPR with Ca2+ titration, hair-cell immunolocalization

    PMID:19008224

    Open questions at the time
    • Functional role in hearing not established here
    • In vivo relevance of competition untested
  13. 2009 High

    How dendritic Ih loss alters network excitability was unknown; entorhinal HCN1 deletion increased dendritic excitability and disrupted excitatory-inhibitory balance despite hyperpolarized resting potentials.

    Evidence Whole-cell recordings in adult HCN1 null brain slices

    PMID:19726656

    Open questions at the time
    • Behavioral consequence not directly measured here
    • Homeostatic compensation addressed separately
  14. 2009 High

    The molecular basis of the entorhinal oscillation frequency gradient was unknown; HCN1 KO flattened the dorsal-ventral resonance gradient, identifying HCN1 as its substrate.

    Evidence Whole-cell recordings from control and HCN1 KO stellate cells

    PMID:19515931

    Open questions at the time
    • Link to grid-cell coding inferred, not directly tested
    • Subunit heteromer contribution not addressed
  15. 2009 High

    Whether HCN1 is a molecular target for ketamine hypnosis was unresolved; HCN1 was identified as a substrate, with KO mice resistant to ketamine-induced loss of righting.

    Evidence Patch-clamp of recombinant and native channels, HCN1 KO mice, behavioral assay

    PMID:19158287

    Open questions at the time
    • Binding site not mapped
    • Neural locus refined in later conditional-KO work
  16. 2010 High

    Whether loss of dendritic Ih is compensated was unknown; HCN1 KO neurons were shown to upregulate GABA-A alpha5 tonic current to restore synaptic summation, revealing homeostatic regulation.

    Evidence Patch-clamp, pharmacology, computational modeling, Western blot in HCN1 KO mice

    PMID:20164346

    Open questions at the time
    • Signaling pathway linking Ih loss to GABA-A upregulation unknown
    • Generality across regions untested
  17. 2011 High

    How TRIP8b controls HCN1 was undefined; two distinct C-terminal interaction sites were mapped, one inhibiting opening and one optimizing trafficking.

    Evidence Deletion mutagenesis, Co-IP, electrophysiology, trafficking assays

    PMID:21411649

    Open questions at the time
    • Structural detail of the complex not resolved
    • Isoform-specific roles addressed separately
  18. 2011 High

    Whether TRIP8b directs HCN1 subcellular targeting in vivo was unknown; TRIP8b isoforms were shown to cooperatively enrich HCN1 in dendrites and suppress axonal misexpression.

    Evidence TRIP8b KO and isoform-specific mutant mice with immunohistochemistry and electrophysiology

    PMID:21358644 PMID:21555075

    Open questions at the time
    • Mechanism of compartment selectivity at molecular level incomplete
    • Does not explain TRIP8b-independent presynaptic targeting
  19. 2011 High

    How presynaptic HCN1 regulates transmitter release was unclear; HCN1 was shown to colocalize with and suppress Cav3.2 to inhibit glutamate release at active zones.

    Evidence EM immunolocalization, patch-clamp, and pharmacology in WT and HCN1 KO mice

    PMID:21358644

    Open questions at the time
    • Direct physical HCN1-Cav3.2 interaction shown later
    • Quantitative release impact addressed in subsequent work
  20. 2012 High

    Whether presynaptic HCN1 trafficking uses the same machinery as dendritic HCN1 was unknown; presynaptic HCN1 was shown to traffic independently of TRIP8b, revealing compartment-selective targeting.

    Evidence EM, electrophysiology in TRIP8b-null mice, kainate seizure model

    PMID:22363812 PMID:23077068

    Open questions at the time
    • Presynaptic targeting machinery unidentified
    • Mechanism of seizure-induced plasticity unknown
  21. 2012 High

    Whether reducing HCN1 has therapeutic-relevant behavioral effects was unknown; CA1 HCN1 knockdown produced antidepressant/anxiolytic phenotypes linked to BDNF-mTOR signaling.

    Evidence Lentiviral shRNA in rat CA1, patch-clamp, behavior, Western blot

    PMID:22884333

    Open questions at the time
    • Causal link between BDNF-mTOR and behavior not isolated
    • Off-target effects of knockdown not fully excluded
  22. 2012 Medium

    Whether type I interferons modulate neuronal excitability via HCN1 was unknown; IFN-alpha/beta were shown to specifically inhibit HCN1 Ih and alter cortical oscillations in vivo.

    Evidence Patch-clamp with IFN treatment, IFNAR KO and HCN1 KO mice, in vivo EEG

    PMID:23042740

    Open questions at the time
    • Intracellular signaling from IFNAR to HCN1 unresolved
    • Single lab
  23. 2012 Medium

    The composition of HCN1 complexes in hair cells was undefined; HCN1 was shown to form a ternary complex with protocadherin 15 CD3 and filamin A via an HCN1-specific N-terminus that also binds PIP3/PIP2.

    Evidence Co-IP from organ of Corti, confocal/EM immunogold, qPCR

    PMID:22948144

    Open questions at the time
    • Functional consequence for hearing not established
    • Single lab
  24. 2013 High

    The neural locus of HCN1-mediated ketamine hypnosis was unresolved; forebrain-selective KO localized the relevant substrate to cortical principal cells.

    Evidence Conditional forebrain HCN1 KO with electrophysiology and behavior

    PMID:23377220

    Open questions at the time
    • Molecular binding site for ketamine still unmapped
    • Other anesthetics addressed separately
  25. 2013 High

    HCN1's role in cardiac pacemaking was undefined; HCN1-deficient mice developed congenital sick sinus syndrome, establishing HCN1 as a stabilizer of the leading pacemaker region.

    Evidence Immunohistochemistry, SAN cell patch-clamp, telemetric ECG, in vivo electrophysiology in HCN1-deficient mice

    PMID:24218458

    Open questions at the time
    • Relative HCN1 vs HCN4 contribution to native f-current not fully quantified
    • Human cardiac relevance not directly tested
  26. 2013 High

    Whether HCN1 has cell-autonomous roles in cerebellar learning was unknown; Purkinje-cell-specific KO showed HCN1 promotes late-stage motor learning and constrains inhibitory response duration.

    Evidence Purkinje-cell-selective HCN1 KO with VOR testing, rotarod, and slice electrophysiology

    PMID:24000178

    Open questions at the time
    • Circuit-level mechanism not fully resolved
    • Link to specific synaptic inputs incomplete
  27. 2014 High

    Whether HCN1 mutations cause human disease was unknown; de novo missense variants were shown to cause early infantile epileptic encephalopathy with divergent gain- and loss-of-function effects.

    Evidence Exome sequencing with patch-clamp of WT and mutant channels

    PMID:24747641

    Open questions at the time
    • Genotype-phenotype rules not yet defined
    • Common pathogenic mechanism clarified by later work
  28. 2014 High

    How HCN1 surface levels are negatively regulated was incompletely understood; filamin A was shown to drive dynamin-dependent HCN1 internalization, and Nedd4-2 to ubiquitinate HCN1 and reduce surface expression.

    Evidence Mutagenesis, endocytosis pharmacology, imaging, decoy peptides, Co-IP from native brain, ubiquitination and surface assays

    PMID:24403084 PMID:24451387

    Open questions at the time
    • Physiological triggers of internalization unknown
    • Interplay with TRIP8b trafficking not fully resolved
  29. 2014 Medium

    Whether secretory-pathway checkpoints control HCN1 trafficking was unknown; a di-arginine ER retention signal in the C-terminus was identified as a surface-expression checkpoint.

    Evidence Transgenic Xenopus photoreceptor and HEK293 trafficking assays with mutagenesis

    PMID:25142030

    Open questions at the time
    • Regulation of the retention signal unknown
    • Single lab
  30. 2014 Medium

    Whether TRIP8b directs HCN1 localization universally was unresolved; in retina TRIP8b was shown to stabilize total HCN1 protein rather than direct surface trafficking, revealing tissue-specific roles.

    Evidence TRIP8b KO mice with immunohistochemistry, Western blot, isoform analysis

    PMID:24409334

    Open questions at the time
    • Mechanism of protein stabilization undefined
    • Single lab
  31. 2015 High

    Whether NO modulates HCN1 distinctly from HCN2 was unknown; NO was shown to suppress HCN1 Ih in a cGMP-independent manner while enhancing HCN2 via cGMP.

    Evidence Patch-clamp in superior olivary neurons, WT vs HCN1 KO, pharmacology

    PMID:25605440

    Open questions at the time
    • Molecular target of cGMP-independent NO action unidentified
    • Single physiological system
  32. 2015 High

    Whether forebrain HCN1 mediates volatile anesthetic effects was unresolved; forebrain KO dissociated HCN1's contribution to hypnosis/amnesia from immobility.

    Evidence Global and forebrain-selective KO mice, MAC determination, fear-potentiated startle

    PMID:26287296

    Open questions at the time
    • Direct anesthetic binding to HCN1 not shown here
    • Circuit basis of amnesia incomplete
  33. 2017 Medium

    Whether HCN1 physically regulates Cav3.2 was unresolved; HCN1 was shown to bind Cav3.2 N-terminus and reduce Ca2+ influx, providing a molecular basis for presynaptic suppression.

    Evidence Co-IP from mouse brain and tsA-201 cells with co-expression patch-clamp

    PMID:28467171

    Open questions at the time
    • Stoichiometry and in vivo complex undefined
    • Single lab
  34. 2017 High

    How presynaptic HCN1 controls release was incompletely quantified; HCN1 was shown to reduce the rate of vesicle exocytosis from entorhinal terminals.

    Evidence Two-photon FM1-43 imaging and electrophysiology in forebrain and global HCN1 KO mice

    PMID:28071723

    Open questions at the time
    • Molecular coupling to release machinery beyond Cav3.2 unclear
    • Terminal subtype selectivity not fully defined
  35. 2018 High

    The structural distribution and functional spectrum of HCN1 variants was unclear; transmembrane variants were linked to severe encephalopathy with a range from loss-of-function to pore-block, supported by MD simulation.

    Evidence Patch-clamp of 12 variants, MD simulation, exome/targeted sequencing

    PMID:30351409

    Open questions at the time
    • Unifying pathogenic mechanism not yet identified
    • Heterotetramer behavior partially modeled
  36. 2018 Medium

    Whether stress hormones regulate HCN1 was unknown; GR activation was shown to upregulate TRIP8b and HCN1 via PKA in dorsal CA1, reducing excitability.

    Evidence Corticosterone/GR antagonist/PKA inhibitor pharmacology with patch-clamp and Western blot in dorsal vs ventral CA1

    PMID:35840797

    Open questions at the time
    • Transcriptional vs post-translational mechanism not fully separated
    • Single lab
  37. 2019 Medium

    Whether additional auxiliary proteins regulate HCN1 surface expression was unknown; TMEM74 was identified as an HCN1-interacting partner enhancing surface Ih in amygdala neurons.

    Evidence Co-IP, patch-clamp, surface assays, Tmem74 KO and rescue, lentiviral overexpression

    PMID:30886335

    Open questions at the time
    • Mechanism of surface stabilization undefined
    • Single lab
  38. 2021 High

    How specific pathogenic variants disrupt gating was unresolved; the M305L variant was shown to abolish voltage-dependent gating via loss of a sulphur-aromatic VSD-pore coupling, acting dominant-negatively in heterotetramers.

    Evidence Two-electrode voltage clamp at varying WT:mutant ratios and MD simulation

    PMID:34298002

    Open questions at the time
    • Generalizability to other variants partial
    • In vivo phenotype not tested here
  39. 2022 High

    How transmembrane variants cause seizures in vivo was unknown; G391D knock-in disrupted HCN1 targeting to interneuron axon terminals and produced seizures worsened paradoxically by sodium channel blockers.

    Evidence Knock-in mouse models, protein distribution analysis, EEG, pharmacological challenge

    PMID:35972069

    Open questions at the time
    • Mechanism linking mistargeting to interneuron dysfunction incomplete
    • Therapeutic implications preliminary
  40. 2023 High

    Whether a unifying pathogenic mechanism underlies transmembrane HCN1 encephalopathy was unresolved; cation leak (large instantaneous current) was identified as a convergent mechanism across seven variants.

    Evidence Two-electrode voltage clamp of 7 variants with clinical correlation

    PMID:37265603

    Open questions at the time
    • Structural basis of cation leak not fully resolved
    • Therapeutic targeting of leak untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular binding sites for anesthetics and the cGMP-independent NO/IFN modulators on HCN1, and the compartment-selective trafficking machinery for presynaptic HCN1, remain undefined.
  • No structural binding site mapped for propofol/ketamine on HCN1
  • Presynaptic axonal targeting machinery unidentified
  • Molecular targets of cGMP-independent NO and IFN modulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 3 R-HSA-9609507 Protein localization 3 R-HSA-397014 Muscle contraction 1
Partners
CACNA1HFLNAHCN2HCN4NEDD4LPCDH15TMEM74TRIP8B
Complex memberships
HCN1-protocadherin 15 CD3-filamin A ternary complexHCN1/HCN2 heterotetramerHCN1/HCN4 heterotetramer

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 HCN1 protein shows a 60-fold increase in immunogold density from somatic to distal apical dendritic membranes of hippocampal CA1 pyramidal cells, with distal dendritic shafts having 16 times more HCN1 than proximal dendrites of similar diameter; density is also higher in dendritic shafts than in spines at equivalent distances from the soma. High-resolution immunolocalization (light microscopy and quantitative immunogold electron microscopy) Nature neuroscience High 12389030
2001 HCN1 and HCN2 subunits coassemble into heteromeric channels with novel biophysical properties (intermediate activation kinetics, voltage dependence, and large cAMP sensitivity of +14 mV) that cannot be explained by independent populations of homomers; these heteromeric properties closely match native Ih in hippocampal CA1 pyramidal neurons that co-express both subunits. Heterologous expression in Xenopus oocytes, cell-free patch recordings, cAMP dose-response analysis The Journal of general physiology High 11133998 11331358
2000 HCN1 and HCN2 form functional heteromeric channels demonstrated using concatenated (tandem) cDNA constructs; heteromeric channels activate faster than HCN2, have voltage dependence similar to HCN2, and intermediate cAMP sensitivity, resembling native pacemaker current in CA1 pyramidal neurons. Concatenated cDNA constructs expressed in Xenopus oocytes, patch-clamp recordings The Journal of biological chemistry High 11133998
2003 HCN1 and HCN4 co-assemble into heteromeric channels in cardiac sinoatrial node; HCN4-HCN1 tandem constructs in HEK293 cells show activation kinetics approaching native sinoatrial f-current, indicating both isoforms contribute to native pacemaker channel properties. Heterologous expression in HEK293 cells, concatenated tandem constructs, patch-clamp recordings The Journal of physiology Medium 12702747
2001 HCN1 and HCN4 are expressed in rat taste cells and mediate a hyperpolarization-activated current enhanced by sour (low pH) stimulation; lowering extracellular pH causes a dose-dependent flattening of the HCN activation curve and a positive shift in half-maximal activation voltage, indicating HCN channels are gated by extracellular protons. In situ hybridization, immunohistochemistry, patch-clamp recordings in taste cell slices with pH manipulation Nature High 11675786
2004 Filamin A (a cytoplasmic actin-binding scaffold protein) interacts specifically with HCN1 (but not HCN2 or HCN4) via a 22-amino acid region downstream of the cyclic nucleotide-binding domain in the HCN1 C-terminus; in filamin A-expressing cells HCN1 channels localize in hot spots on the membrane, whereas in filamin-deficient cells they distribute evenly and show strongly accelerated gating kinetics. Yeast two-hybrid, co-immunoprecipitation from bovine brain, immunofluorescence in filamin+ vs. filamin− cell lines, electrophysiology The Journal of biological chemistry High 15292205
2004 Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent spatial learning and memory, augments theta oscillation power, and enhances LTP specifically at the distal perforant path inputs to CA1 pyramidal dendrites but not at proximal Schaffer collateral inputs, establishing HCN1 as a constraint on dendritic integration of distal synaptic inputs. Global and forebrain-restricted HCN1 knockout mice, behavioral testing (Morris water maze), EEG, LTP electrophysiology Cell High 15550252
2009 HCN1 channel subunits are a molecular substrate for the hypnotic action of ketamine: ketamine inhibits HCN1-containing channels at clinically relevant concentrations in a subunit-specific manner (S-(+)-ketamine more potent than racemate); in cortical pyramidal neurons ketamine induces membrane hyperpolarization and enhances dendritosomatic synaptic coupling in wild-type but not HCN1 knockout mice; HCN1 knockout mice show strongly reduced sensitivity to ketamine-induced loss-of-righting reflex. Patch-clamp recordings of recombinant and native channels, global HCN1 knockout mice, loss-of-righting reflex behavioral assay The Journal of neuroscience High 19158287
2011 TRIP8b interacts with HCN1 at two distinct C-terminal sites: (1) an upstream site where the C-linker/cyclic nucleotide-binding domain of HCN1 interacts with an 80-aa conserved core domain of TRIP8b, necessary and sufficient for inhibiting channel opening; and (2) a downstream site where the C-terminal SNL tripeptide of HCN1 interacts with the TRIP8b tetratricopeptide repeat domain, which stabilizes the complex and optimizes trafficking effects. Deletion mutagenesis, co-immunoprecipitation, electrophysiology, trafficking assays in neurons and heterologous cells The Journal of neuroscience High 21411649
2011 TRIP8b is required for proper subcellular targeting of HCN1 to distal apical dendrites of CA1 pyramidal neurons; isoform-wide disruption of the TRIP8b/HCN1 interaction causes HCN1 mistargeting throughout somatodendritic compartments; TRIP8b(1a-4) promotes HCN1 surface expression in dendrites while TRIP8b(1a) suppresses HCN1 misexpression in axons. TRIP8b knockout and mutant mice, immunohistochemistry, electrophysiology Neuron High 21555075
2011 Presynaptic HCN1 channels co-localize with Cav3.2 T-type calcium channels at active zones of mature asymmetric synaptic terminals targeting entorhinal cortical layer III pyramidal neurons; HCN channels inhibit glutamate release by suppressing Cav3.2 activity, providing a presynaptic mechanism for regulating synaptic strength. Electron microscopy immunolocalization, patch-clamp electrophysiology, pharmacology in wild-type and HCN1 KO mice Nature neuroscience High 21358644
2007 Presynaptic HCN1 channels are present in axon terminals of the perforant path in immature rats and modulate synaptic efficacy; with maturation, presynaptic expression disappears due to altered channel transport to axons (not reduced expression in entorhinal cortex soma); blocking action potential firing in vitro increases presynaptic HCN1 expression, indicating network activity controls this axonal transport. Immunohistochemistry, electron microscopy, electrophysiology, activity-blockade experiments in rat hippocampal slices The Journal of neuroscience High 17460082
2014 Filamin A (FLNa) promotes dynamin-dependent internalization of HCN1 channels in HEK293 cells and hippocampal neurons, redistributing channels to endosomal compartments and reducing Ih density; dominant-negative FLNa enhances native HCN1 expression; decoy peptides mimicking the FLNa-binding domain of HCN1 abolish punctate HCN1 distribution, augment endogenous Ih, and enhance membrane voltage-sag responses. Mutational analysis, pharmacological endocytosis inhibition, live imaging, dominant-negative constructs, decoy peptides, patch-clamp in HEK293 cells and hippocampal neurons The Journal of biological chemistry High 24403084
2007 Propofol inhibits HCN1 channels by preferentially associating with the membrane-embedded channel core at closed-resting and closed-activated states; inhibition is independent of cAMP and internal protons; kinetic modeling reveals that channel gating is best described by models where closed and open states communicate via a voltage-independent reaction. Patch-clamp electrophysiology, kinetic modeling, second-messenger uncoupling, in vitro pharmacology The Journal of physiology High 17569731
2014 De novo missense mutations in HCN1 cause early infantile epileptic encephalopathy; patch-clamp recordings of mutant channels reveal striking but divergent effects on Ih, including shifts in voltage dependence and altered kinetics, demonstrating that gain- and loss-of-function mechanisms both occur. Exome sequencing, patch-clamp recordings of wild-type and mutant HCN1 in heterologous cells Nature genetics High 24747641
2018 Pathogenic HCN1 variants cluster within or near transmembrane domains for severe epileptic encephalopathy, while milder phenotype variants are located in N- and C-terminal intracellular regions; functional analysis of 12 variants ranged from complete loss-of-function to shifts in activation kinetics/voltage dependence; molecular dynamics of G391D showed the channel pore blocked by cation(s) complexed to the Asp residue in homotetramers, while heterotetramers showed an instantaneous current possibly linked to pore deformation. Patch-clamp (whole-cell), molecular dynamics simulation, exome/targeted sequencing Brain High 30351409
2012 Knockdown of HCN1 in dorsal hippocampal CA1 region increases cellular excitability (consistent with Ih reduction) and produces antidepressant- and anxiolytic-like behaviors associated with upregulation of BDNF-mTOR signaling pathways. Lentiviral shRNA knockdown in rat dorsal hippocampal CA1, whole-cell patch-clamp, behavioral testing, Western blotting Neuron High 22884333
2009 HCN1 deletion from entorhinal cortex dendrites ablates dendritic Ih, making dendrites more excitable despite hyperpolarized resting membrane potentials; at resting membrane potential, 50 Hz EPSP trains produce action potentials in HCN1−/− neurons; enhanced pyramidal cell excitability increases spontaneous EPSC frequency onto HCN1−/− neurons, disrupting excitatory-inhibitory balance. Whole-cell recordings in brain slices from adult HCN1 null mice, pharmacology The Journal of neuroscience High 19726656
2006 In a genetic rat model of absence epilepsy (WAG/Rij), HCN1 channel expression declines primarily in apical dendrites of layer 5 cortical pyramidal neurons prior to seizure onset; this loss causes a spatially uniform 2-fold reduction in dendritic Ih, increases somatodendritic coupling, lowers the threshold for dendritic Ca2+ spike generation by backpropagating action potentials, and promotes intrinsic burst firing. Dual soma-dendrite whole-cell recordings, computational modeling, immunohistochemistry in WAG/Rij and control rats The Journal of physiology High 17095562
2013 HCN1 is highly expressed in the sinoatrial node co-localized with HCN4; HCN1-deficient mice display congenital sick sinus syndrome characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses, establishing HCN1 as a stabilizer of the leading pacemaker region. Immunohistochemistry, patch-clamp of isolated SAN cells, telemetric ECG, echocardiography, in vivo electrophysiology in HCN1-deficient mice Circulation High 24218458
2009 HCN1 channel knockout flattens the dorsal-ventral gradient of membrane potential oscillation frequency and resonant frequency in medial entorhinal cortex layer II stellate cells, establishing HCN1 as the molecular substrate for the dorsal-ventral frequency gradient that scales with grid cell field size. Whole-cell patch recordings from adult control and HCN1 global KO mice brain slices The Journal of neuroscience High 19515931
2010 In cortical pyramidal neurons from HCN1 knockout mice, loss of dendritic Ih is compensated by upregulation of GABA-A alpha5 subunit-mediated tonic current, which quantitatively restores baseline sublinear synaptic summation; this identifies dendritosomatic synaptic efficacy as a controlled variable for homeostatic regulation of cortical excitability in vivo. Whole-cell patch-clamp, pharmacology (bicuculline, L-655,708), computational modeling, Western blotting in HCN1 KO mice The Journal of neuroscience High 20164346
2002 HCN1 is expressed in the inner segment and cell body of rabbit retinal rod photoreceptors; Ih can only be recorded from these HCN1-expressing regions; the biophysical properties of rod Ih (half-activation ~-75 mV, fast kinetics, minimal cAMP shift of +2.3 mV) match homomeric HCN1 channels expressed in HEK293 cells, indicating rods express homomeric HCN1. Immunocytochemistry, patch-clamp in isolated rods, heterologous expression in HEK293 cells The Journal of physiology High 12096053
2014 Nedd4-2 ubiquitin ligase interacts with HCN1 via a PY motif in the HCN1 C-terminus; co-expression of Nedd4-2 with HCN1 increases HCN1 ubiquitination, drastically reduces HCN1-mediated current amplitude (85-92% in oocytes), and reduces surface expression (34%) in HEK293 cells, opposing the trafficking-promoting effect of TRIP8b(1a-4). Co-immunoprecipitation from rat hippocampus/neocortex/cerebellum and HEK293 cells, ubiquitination assays, Xenopus oocyte electrophysiology, surface expression assays FASEB journal High 24451387
2012 TRIP8b splice forms act cooperatively to regulate HCN1 subcellular localization in CA1 pyramidal neurons; TRIP8b(1a-4) promotes HCN1 surface expression in dendrites while TRIP8b(1a) suppresses HCN1 misexpression in axons; both isoforms are needed for correct distal dendritic enrichment of HCN1. TRIP8b isoform-specific knockout mice, immunohistochemistry, electrophysiology Neuron High 21555075
2012 Axonal HCN1 trafficking in entorhinal cortex perforant path is regulated by specific TRIP8b isoforms; in adult TRIP8b-null mice, axonal HCN1 is significantly increased in the perforant path; overexpression of TRIP8b(1a) (but not TRIP8b(1a-4)) in cultured entorhinal neurons promotes somatodendritic and reduces axonal HCN1 expression. TRIP8b knockout and isoform-specific mutant mice, overexpression in cultured neurons, immunohistochemistry PloS one Medium 22363812
2012 Presynaptic HCN1 channels in adult cortical synaptic terminals are trafficked independently of TRIP8b (expression and function comparable in TRIP8b-null mice and wild-type); seizure-induced plasticity of presynaptic HCN channel function is also TRIP8b-independent, indicating compartment-selective molecular mechanisms for HCN subunit targeting. Electron microscopy, electrophysiology, TRIP8b-null mice, kainic acid seizure model The Journal of neuroscience High 23077068
2008 HCN1 knockout mice show prolonged ERG response duration (both scotopic and photopic) without altered b-wave amplitude under scotopic conditions, demonstrating HCN1 channels shorten and shape light responses at the photoreceptor level in both rod and cone pathways. Electroretinography in HCN1 KO mice, immunohistochemistry, patch-clamp The European journal of neuroscience High 19019198
2015 Nitric oxide (NO) selectively suppresses HCN1-mediated Ih (shifting half-activation to more hyperpolarized potentials and slowing kinetics) while enhancing HCN2-mediated Ih in a cGMP-dependent manner; NO modulation of HCN1 currents is cGMP-independent and absent in HCN1 knockout mice. Patch-clamp in neurons of superior olivary complex, comparison in wild-type and HCN1 KO mice, pharmacology The Journal of physiology High 25605440
2014 A di-arginine ER retention signal in the intrinsically disordered region of the HCN1 C-terminus retains channels in the early secretory pathway; mutation of this signal increases surface expression in HEK293 cells, identifying a post-translational trafficking checkpoint for HCN1. Transgenic Xenopus photoreceptor trafficking assay with deletion constructs, HEK293 cell surface expression assays, mutagenesis Cellular and molecular life sciences Medium 25142030
2008 HCN1 N-terminus binds the C-terminus of protocadherin 15 CD3 (a hair cell tip link protein) in a calcium-dependent manner (K_D shifts from 239 nM without Ca2+ to 52.6 nM at 61 μM Ca2+); amino-terminus binding of HCN1 to itself (for channel assembly) is also Ca2+-dependent but at a lower effective [Ca2+], suggesting competition between HCN1-protocadherin 15 and HCN1-HCN1 interactions in vivo. Yeast two-hybrid, pull-down assays, surface plasmon resonance with Ca2+ titration, immunolocalization in hair cells The Journal of biological chemistry High 19008224
2012 HCN1 forms a ternary complex with protocadherin 15 CD3 and filamin A in cochlear hair cells (immunoprecipitation); alternatively, HCN1 can interact with HCN2 forming a complex that excludes protocadherin 15 CD3; HCN1-specific N-terminal sequence (not conserved in HCN2/HCN4) mediates Ca2+-dependent protocadherin 15 CD3 binding and also binds PIP3 and PIP2. Co-immunoprecipitation from organ of Corti, confocal and EM immunogold microscopy, quantitative PCR The Journal of biological chemistry Medium 22948144
2017 HCN1 co-immunoprecipitates with Cav3.2 T-type channels from mouse brain and tsA-201 cells via HCN1 N-terminus to Cav3.2 N-terminus interaction; HCN1 expression decreases Cav3.2 Ba2+ influx and shifts Cav3.2 activation gating in a depolarizing direction; reciprocal regulation of HCN1 by Cav3.2 was not observed. Co-immunoprecipitation from mouse brain and tsA-201 cells, patch-clamp electrophysiology, co-expression in heterologous cells Channels Medium 28467171
2019 TMEM74 physically interacts with HCN1 channels in basolateral amygdaloid nucleus (BLA) pyramidal neurons; TMEM74 deletion reduces HCN1 surface expression and Ih; TMEM74 overexpression restores HCN1 surface expression and reduces neuronal excitability; TM1 domain of TMEM74 is required for its membrane localization and Ih-enhancing function. Co-immunoprecipitation, whole-cell patch-clamp, surface expression assays, Tmem74 KO and rescue in mice, lentiviral overexpression Molecular psychiatry Medium 30886335
2013 Forebrain-selective HCN1 knockout abolishes ketamine-induced membrane hyperpolarization and enhancement of synaptic coupling in cortical pyramidal neurons and shifts the EC50 for ketamine-induced loss-of-righting reflex by ~31%, localizing the relevant neural substrate for HCN1-mediated ketamine hypnosis to forebrain principal cells. Conditional (forebrain-selective) HCN1 KO mice, patch-clamp electrophysiology, loss-of-righting reflex behavioral assay Anesthesiology High 23377220
2015 Forebrain HCN1 channels contribute to hypnotic and amnestic effects of volatile anesthetics (isoflurane, sevoflurane) but are not involved in their immobilizing actions; forebrain-selective HCN1 KO significantly increases MAC of hypnosis and reduces amnestic effects without altering MAC of immobility. Global and forebrain-selective HCN1 KO mice, minimum alveolar concentration determination, fear-potentiated startle amnesia test Anesthesia and analgesia High 26287296
2021 The HCN1 M305L/M294L pathogenic variant (located in S5 domain) lacks voltage-dependent activation and deactivation but maintains normal cation selectivity; molecular dynamics simulations identify a sulphur-aromatic interaction between M305 and F389 that couples the voltage-sensing domain to the pore domain; a single mutated subunit in heterotetramers is sufficient to significantly disrupt voltage-dependent activation. Patch-clamp (two-electrode voltage clamp in Xenopus oocytes with varying WT:mutant ratios), molecular dynamics simulation of wild-type and mutant homotetramers Progress in biophysics and molecular biology High 34298002
2023 Seven HCN1 pathogenic variants located in transmembrane domains all produce a significantly larger instantaneous current (cation leak) in addition to variable effects on voltage dependence and kinetics; cation leak is identified as a common pathogenic mechanism in HCN1 developmental and epileptic encephalopathy. Two-electrode voltage-clamp recordings in Xenopus oocytes for 7 variants, clinical correlation in 11 patients Brain communications High 37265603
2018 Glucocorticoid receptor (GR) activation by corticosterone increases TRIP8b and HCN1 protein expression and elevates Ih specifically in dorsal (not ventral) CA1 neurons via a PKA-dependent (not CaMKII-dependent) pathway, reducing neuronal excitability; chronic social defeat stress phenocopies this effect in susceptible mice. Corticosterone bath application, GR antagonist, PKA inhibitors, whole-cell patch-clamp, Western blotting in dorsal vs. ventral CA1 Molecular psychiatry Medium 35840797
2012 Type I interferons (IFN-α/β) specifically inhibit HCN1-mediated Ih in cortical pyramidal neurons via intact IFNAR signaling; IFN treatment hyperpolarizes resting membrane potential, shifts resonance frequency, and increases membrane impedance; in vivo IFN-β application reduces EEG power of higher frequencies only in HCN1-expressing (not HCN1 KO) mice. Patch-clamp in rodent brain slices with IFN treatment, IFNAR KO mice, HCN1 KO mice, in vivo EEG Cerebral cortex Medium 23042740
2013 HCN1 channels in cerebellar Purkinje cells promote late stages of motor learning (vestibulo-ocular reflex adaptation) and constrain the duration of inhibitory synaptic responses; deletion of HCN1 from Purkinje cells selectively impairs late-stage motor learning without affecting early learning or responses to excitatory inputs in the absence of membrane hyperpolarization. Purkinje cell-selective HCN1 KO mice, vestibulo-ocular reflex testing, rotarod, whole-cell patch-clamp in cerebellar slices The Journal of physiology High 24000178
2022 The HCN1 G391D knock-in variant disrupts HCN1 protein targeting to the axon terminals of basket cell interneurons in mice; both G391D and M153I variants produce spontaneous generalized tonic-clonic seizures; sodium channel blockers (lamotrigine, phenytoin) paradoxically induce seizures in both knock-in lines, consistent with impaired inhibitory neuron function. Knock-in mouse models, immunohistochemistry/protein distribution analysis, EEG seizure monitoring, pharmacological challenge with antiepileptic drugs eLife High 35972069
2017 HCN1 channels reduce the rate of synaptic vesicle exocytosis from a subset of entorhinal cortex synaptic terminals; forebrain HCN1-deficient mice show increased FM1-43 dye release from EC synaptic terminals, and HCN1 absence enhances both non-action potential-dependent and action potential-dependent spontaneous release as well as synchronous evoked release. Two-photon FM1-43 exocytosis imaging, electrophysiology, pharmacology in forebrain HCN1 KO and global HCN1 KO mice Scientific reports High 28071723
2000 Single-cell RT-PCR combined with patch-clamp demonstrates that HCN1 mRNA expression in individual neocortical and hippocampal pyramidal neurons (at least 8-fold higher than subcortical neurons) correlates with significantly faster Ih activation kinetics, establishing HCN1 as a molecular determinant of fast-activating Ih in cortical neurons. Combined patch-clamp and single-cell RT-multiplex PCR (RT-mPCR) in four mouse CNS neuron populations The European journal of neuroscience Medium 10971612
2001 Gi- and Gs-coupled receptor activation upregulates cAMP to modulate HCN2 but not HCN1; the insensitivity of HCN1 to cAMP-mediated receptor signaling is confirmed by the absence of changes in activation rate, deactivation rate, or amplitude in response to mu-opioid or 5-HT4(a) receptor activation in Xenopus oocytes. Co-expression of HCN1 or HCN2 with GPCRs in Xenopus oocytes, patch-clamp, pharmacological dissection (SQ22536, PKA/PKC inhibitors) Pflügers Archiv Medium 11680627
2014 TRIP8b is required for maximal total expression of HCN1 in the mouse retina; in TRIP8b KO mice, HCN1 surface trafficking in retinal neurons is unaffected, but total HCN1 protein is dramatically reduced, indicating a role for TRIP8b in stabilizing or maintaining HCN1 protein levels rather than directing retinal localization. TRIP8b KO mice, immunohistochemistry, Western blotting, isoform expression analysis PloS one Medium 24409334

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 398 15550252
2002 Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nature neuroscience 367 12389030
2001 Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. The Journal of general physiology 336 11331358
2009 HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. The Journal of neuroscience : the official journal of the Society for Neuroscience 213 19158287
2003 Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. The Journal of physiology 179 12702747
2014 De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nature genetics 178 24747641
2000 Functional heteromerization of HCN1 and HCN2 pacemaker channels. The Journal of biological chemistry 175 11133998
2001 Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 173 11675786
2007 HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 152 18003822
2009 Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 150 19726656
2004 HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 146 15525777
2011 Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nature neuroscience 139 21358644
2006 Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model. The Journal of physiology 135 17095562
2012 Enhancement of dorsal hippocampal activity by knockdown of HCN1 channels leads to anxiolytic- and antidepressant-like behaviors. Neuron 129 22884333
2000 Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarization-activated cyclic nucleotide-gated ion channels (Ih) in central neurons. The European journal of neuroscience 111 10971612
2018 HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain : a journal of neurology 107 30351409
2009 Knock-out of HCN1 subunit flattens dorsal-ventral frequency gradient of medial entorhinal neurons in adult mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 91 19515931
2004 Interaction of the pacemaker channel HCN1 with filamin A. The Journal of biological chemistry 87 15292205
2013 Sick sinus syndrome in HCN1-deficient mice. Circulation 77 24218458
2010 Increased seizure severity and seizure-related death in mice lacking HCN1 channels. Epilepsia 72 20384728
2011 TRIP8b regulates HCN1 channel trafficking and gating through two distinct C-terminal interaction sites. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 21411649
2012 HCN1 and HCN2 in Rat DRG neurons: levels in nociceptors and non-nociceptors, NT3-dependence and influence of CFA-induced skin inflammation on HCN2 and NT3 expression. PloS one 69 23236374
2007 Localization of HCN1 channels to presynaptic compartments: novel plasticity that may contribute to hippocampal maturation. The Journal of neuroscience : the official journal of the Society for Neuroscience 67 17460082
2013 Forebrain HCN1 channels contribute to hypnotic actions of ketamine. Anesthesiology 64 23377220
2011 TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 63 21555075
2011 Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. Neuron 62 22099465
2013 HCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain. The Journal of pharmacology and experimental therapeutics 61 23549867
2018 Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy. Neuropharmacology 59 29339292
2005 Preferential localization of the hyperpolarization-activated cyclic nucleotide-gated cation channel subunit HCN1 in basket cell terminals of the rat cerebellum. The European journal of neuroscience 58 15869503
2010 Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 20164346
2007 Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy. Neurobiology of disease 53 17931874
2002 Functional characterisation and subcellular localisation of HCN1 channels in rabbit retinal rod photoreceptors. The Journal of physiology 53 12096053
2018 Selective Blockade of HCN1/HCN2 Channels as a Potential Pharmacological Strategy Against Pain. Frontiers in pharmacology 52 30467478
2008 Light responses in the mouse retina are prolonged upon targeted deletion of the HCN1 channel gene. The European journal of neuroscience 49 19019198
2008 In the ventral cochlear nucleus Kv1.1 and subunits of HCN1 are colocalized at surfaces of neurons that have low-voltage-activated and hyperpolarization-activated conductances. Neuroscience 47 18424000
2020 The potential role of the HCN1 ion channel and BDNF-mTOR signaling pathways and synaptic transmission in the alleviation of PTSD. Translational psychiatry 46 32198387
2004 Characterization of the human HCN1 channel and its inhibition by capsazepine. British journal of pharmacology 46 15351778
2018 A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability. Neurobiology of disease 43 29936235
2006 HCN1 ion channel immunoreactivity in spinal cord and medulla oblongata. Brain research 43 16503331
2018 Applying ketamine to alleviate the PTSD-like effects by regulating the HCN1-related BDNF. Progress in neuro-psychopharmacology & biological psychiatry 40 29596995
2014 Activation of GABAB receptors ameliorates cognitive impairment via restoring the balance of HCN1/HCN2 surface expression in the hippocampal CA1 area in rats with chronic cerebral hypoperfusion. Molecular neurobiology 39 24838625
2015 HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics. Anesthesia and analgesia 37 26287296
2003 Cell type-dependent expression of HCN1 in the main olfactory bulb. The European journal of neuroscience 36 12887416
2007 Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core. The Journal of physiology 34 17569731
2012 TRIP8b-independent trafficking and plasticity of adult cortical presynaptic HCN1 channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 23077068
2022 Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons. Molecular psychiatry 29 35840797
2021 Effect of ketamine on mood dysfunction and spatial cognition deficits in PTSD mouse models via HCN1-BDNF signaling. Journal of affective disorders 28 33752039
2014 Filamin A promotes dynamin-dependent internalization of hyperpolarization-activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons. The Journal of biological chemistry 28 24403084
2015 Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region. Neurobiology of learning and memory 27 26021557
2012 HCN1 and HCN2 proteins are expressed in cochlear hair cells: HCN1 can form a ternary complex with protocadherin 15 CD3 and F-actin-binding filamin A or can interact with HCN2. The Journal of biological chemistry 27 22948144
2015 Nitric oxide selectively suppresses IH currents mediated by HCN1-containing channels. The Journal of physiology 26 25605440
2016 Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia. Human molecular genetics 25 26740549
2014 Imbalance of HCN1 and HCN2 expression in hippocampal CA1 area impairs spatial learning and memory in rats with chronic morphine exposure. Progress in neuro-psychopharmacology & biological psychiatry 24 25301101
2012 Regulation of axonal HCN1 trafficking in perforant path involves expression of specific TRIP8b isoforms. PloS one 24 22363812
2017 The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy. Oncotarget 23 27901476
2018 Loss of HCN1 subunits causes absence epilepsy in rats. Brain research 22 30408474
2015 Hcn1 is a tremorgenic genetic component in a rat model of essential tremor. PloS one 22 25970616
2012 HCN1 channels: a new therapeutic target for depressive disorders? Science signaling 22 23033536
2019 Functional coupling of Tmem74 and HCN1 channels regulates anxiety-like behavior in BLA neurons. Molecular psychiatry 21 30886335
2008 Calcium-dependent binding of HCN1 channel protein to hair cell stereociliary tip link protein protocadherin 15 CD3. The Journal of biological chemistry 21 19008224
2017 HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals. Scientific reports 20 28071723
2013 HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibition. The Journal of physiology 20 24000178
2012 Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations. Cerebral cortex (New York, N.Y. : 1991) 20 23042740
2017 Cyclophosphamide-induced HCN1 channel upregulation in interstitial Cajal-like cells leads to bladder hyperactivity in mice. Experimental & molecular medicine 19 28428632
2006 Role of Hcn1 and its phosphorylation in fission yeast anaphase-promoting complex/cyclosome function. The Journal of biological chemistry 18 16950791
2022 CREB1 transcription-activated lncRNA PVT1 promotes cardiac fibrosis via miR-145/HCN1 axis. International journal of cardiology 17 35063587
2021 Biophysical analysis of an HCN1 epilepsy variant suggests a critical role for S5 helix Met-305 in voltage sensor to pore domain coupling. Progress in biophysics and molecular biology 17 34298002
2003 Morphological analysis of the hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1) immunoreactive bipolar cells in the rabbit retina. The Journal of comparative neurology 17 14608601
2001 Gi- and Gs-coupled receptors up-regulate the cAMP cascade to modulate HCN2, but not HCN1 pacemaker channels. Pflugers Archiv : European journal of physiology 17 11680627
2022 Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. eLife 16 35972069
2020 Cerebral ischemia-reperfusion causes a down regulation of HCN1 expression via enhancing the nuclear NRSF-HDAC4 gathering that contributes to neuron damage. Brain research bulletin 16 31923455
2013 Spike-and-wave discharge mediated reduction in hippocampal HCN1 channel function associates with learning deficits in a genetic mouse model of epilepsy. Neurobiology of disease 16 24368169
2011 Selective pharmacological inhibition of the pacemaker channel isoforms (HCN1-4) as new possible therapeutical targets. Current medicinal chemistry 16 21774761
2003 Hyperpolarization-activated, cyclic AMP-gated, HCN1-like cation channel: the primary, full-length HCN isoform expressed in a saccular hair-cell layer. Neuroscience 16 12699787
2022 Novel HCN1 Mutations Associated With Epilepsy and Impacts on Neuronal Excitability. Frontiers in molecular neuroscience 15 35845605
2018 Distal Dendritic Enrichment of HCN1 Channels in Hippocampal CA1 Is Promoted by Estrogen, but Does Not Require Reelin. eNeuro 15 30406178
2017 Down-regulation of T-type Cav3.2 channels by hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1): Evidence of a signaling complex. Channels (Austin, Tex.) 14 28467171
2014 Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarization-activated cyclic nucleotide-gated (HCN)-1 channels. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 24451387
2009 HCN1 channels constrain DHPG-induced LTD at hippocampal Schaffer collateral-CA1 synapses. Learning & memory (Cold Spring Harbor, N.Y.) 14 19940037
1992 Human cortical neuronal cell line (HCN-1): further in vitro characterization and suitability for brain transplantation. Cell transplantation 13 1344290
2015 An N-terminal deletion variant of HCN1 in the epileptic WAG/Rij strain modulates HCN current densities. Frontiers in molecular neuroscience 12 26578877
2013 Genetically-engineered mesenchymal stem cells transfected with human HCN1 gene to create cardiac pacemaker cells. The Journal of international medical research 12 24097828
2009 Activity-dependent regulation of HCN1 protein in cortical neurons. Biochemical and biophysical research communications 11 19563776
2023 Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease. Cerebral cortex (New York, N.Y. : 1991) 10 37874022
2016 Use Dependent Attenuation of Rat HCN1-Mediated Ih in Intact HEK293 Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 10 27184742
2014 A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane. Cellular and molecular life sciences : CMLS 10 25142030
2023 Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy. Brain communications 9 37265603
2014 TRIP8b is required for maximal expression of HCN1 in the mouse retina. PloS one 9 24409334
2022 Ion behavior in the selectivity filter of HCN1 channels. Biophysical journal 8 35474263
2021 HCN1 channels: A versatile tool for signal processing by primary sensory neurons. Progress in biophysics and molecular biology 8 34197835
2021 Moxibustion Regulates Gastrointestinal Motility via HCN1 in Functional Dyspepsia Rats. Medical science monitor : international medical journal of experimental and clinical research 8 34845181
2015 The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp. Neuroscience 8 25659346
2023 The Impact of Altered HCN1 Expression on Brain Function and Its Relationship with Epileptogenesis. Current neuropharmacology 7 37366350
2022 Impaired Color Recognition in HCN1 Epilepsy: A Single Case Report. Frontiers in neurology 7 35359652
2022 Progressively Decreased HCN1 Channels Results in Cone Morphological Defects in Diabetic Retinopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 7 36123121
2022 Prenatal alcohol exposure enhanced alcohol preference and susceptibility to PTSD in a sex-dependent manner through the synaptic HCN1 channel. Journal of affective disorders 7 36587902
2020 Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence. Brain sciences 7 33105624
2015 Immunolocalization of hyperpolarization-activated cationic HCN1 and HCN3 channels in the rat nephron: regulation of HCN3 by potassium diets. Histochemistry and cell biology 7 26515056
2010 I(h) "run-up" in rat neocortical neurons and transiently rat or human HCN1-expressing HEK293 cells. Journal of neuroscience research 7 20806410
2023 Retinal Dysfunction in a Mouse Model of HCN1 Genetic Epilepsy. The Journal of neuroscience : the official journal of the Society for Neuroscience 6 36813574

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