Affinage

HCN4

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 · UniProt Q9Y3Q4

Length
1203 aa
Mass
129.0 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCN4 is the principal pore-forming subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that generate the cardiac pacemaker current (If/Ih), and it is essential for sinoatrial node automaticity, atrioventricular conduction, and autonomic heart rate regulation. HCN4 forms homotetramers or heterotetramers with HCN1 or proteolytically processed HCN2, is gated by membrane hyperpolarization with kinetics determined by S1–S2 transmembrane residues (notably L272), and is potentiated by direct cAMP binding to its C-terminal CNBD—whose isoform-specific sensitivity is set by the β4–β5 loop—while PKA phosphorylation at ≥13 sites and Src kinase phosphorylation at Tyr531 provide additional sympathetic modulation (PMID:20829353, PMID:20713547, PMID:17977941, PMID:12813043). Channel surface expression requires a caveolin-binding domain (Y259/F262) that targets HCN4 to caveolae, and is further regulated by protein partners including β2-adrenergic receptors (via the N-terminal tail), LRMP, IRAG, and Shugoshin-1, while transcription is controlled by MEF2, NRSF, Sp1, BMAL1 (circadian rhythmicity), HDAC4, miR-1, and miR-423-5p (PMID:22659290, PMID:22613709, PMID:32647060, PMID:33953173, PMID:19477969, PMID:33278629, PMID:28821541). Loss-of-function mutations (e.g., D553N, G480R) cause familial sinus bradycardia and sick sinus syndrome, while the gain-of-function V240M mutation causes inappropriate sinus tachycardia treatable with ivabradine, which blocks the open pore at Y507/I511 on S6 as revealed by cryo-EM (PMID:15123648, PMID:17646576, PMID:38032931, PMID:38917012).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2001 High

    Demonstrating that HCN4 channels in taste receptor cells are gated by extracellular protons expanded HCN4 function beyond cardiac pacemaking to sensory transduction.

    Evidence Patch-clamp on taste cells with pH manipulation, in situ hybridization and immunohistochemistry

    PMID:11675786

    Open questions at the time
    • Whether HCN4 is required for sour taste in vivo was not tested
    • Contribution relative to other acid-sensing channels in taste cells unknown
  2. 2003 High

    Establishing that HCN4 co-assembles with HCN1 into heteromeric channels with intermediate kinetics resolved how native If properties differ from any single HCN isoform.

    Evidence Tandem concatenated HCN4-HCN1 constructs and co-transfection in HEK293 cells with patch-clamp

    PMID:12702747

    Open questions at the time
    • Stoichiometry of native heteromeric channels in SAN not determined
    • Whether other HCN isoforms participate in native complexes unclear
  3. 2003 High

    Chimeric HCN2/HCN4 analysis identified L272 in S1 and I308 in S2 as determinants of HCN4's characteristically slow activation and cAMP-dependent kinetic modulation, localizing gating control to the voltage-sensor domain.

    Evidence Systematic chimera and point-mutant electrophysiology in heterologous cells

    PMID:12813043

    Open questions at the time
    • Structural basis of how L272 slows gating not resolved
    • Interaction between S1-S2 region and C-linker/CNBD gating not addressed
  4. 2003 High

    Identifying KCNE2 as a specific auxiliary subunit of HCN4 that enhances current amplitude and slows kinetics revealed a β-subunit modulation mechanism for pacemaker channels.

    Evidence Co-expression in oocytes and CHO cells, yeast two-hybrid mapping interaction to C-terminal tails

    PMID:12856183

    Open questions at the time
    • In vivo relevance of KCNE2-HCN4 interaction in SAN not demonstrated
    • Whether KCNE2 participates in native heteromeric HCN4/HCN1 channels unknown
  5. 2004 High

    The D553N mutation was initially shown to cause dominant-negative trafficking failure, establishing the first disease mechanism for HCN4 channelopathy causing sinus node dysfunction.

    Evidence Trafficking and electrophysiology assays in HEK293 cells with WT/mutant co-expression

    PMID:15123648

    Open questions at the time
    • Later work (PMID:23075627) revised the mechanism to a gating defect rather than trafficking failure
    • No in vivo knock-in model
  6. 2006 Medium

    Discovery that NRSF binds the HCN4 promoter NRSE motif explained the developmental silencing of HCN4 after birth and its pathological re-expression during cardiac hypertrophy.

    Evidence EMSA and luciferase reporter assays with NRSE mutations in neonatal rat cardiomyocytes

    PMID:17173866

    Open questions at the time
    • No ChIP confirmation of NRSF binding in vivo
    • Mechanism of NRSF de-repression in hypertrophy not fully defined
  7. 2006 Medium

    Src kinase was identified as a direct modulator of HCN4, forming a protein complex and enhancing channel activity, adding tyrosine kinase signaling to the regulatory repertoire of pacemaker channels.

    Evidence Co-immunoprecipitation and patch-clamp in HEK293 cells and rat ventricular myocytes with constitutively active Src

    PMID:16680072

    Open questions at the time
    • Specific phosphorylation sites not identified in this study
    • Physiological stimulus activating Src-HCN4 pathway in SAN not established
  8. 2007 High

    Mapping Tyr531 as the critical Src phosphosite for voltage-dependent modulation of HCN4, and separately showing G480R causes familial bradycardia via pore-domain trafficking and gating defects, established residue-level mechanisms for kinase regulation and a second disease-causing mutation.

    Evidence Y531F mutagenesis with PP2 inhibitor and patch-clamp (PMID:17977941); G480R biotinylation and electrophysiology in oocytes/HEK cells (PMID:17646576)

    PMID:17646576 PMID:17977941

    Open questions at the time
    • Whether Src phosphorylation of Y531 occurs in native SAN pacemaker cells not confirmed
    • Structural consequence of G480R on pore architecture unknown
  9. 2008 Medium

    Identifying miR-1 as a direct post-transcriptional repressor of HCN4 linked microRNA dysregulation to arrhythmogenic HCN4 overexpression in cardiac hypertrophy.

    Evidence miR-1 mimic transfection preventing HCN4 protein increase in hypertrophic neonatal cardiomyocytes

    PMID:18458081

    Open questions at the time
    • Direct 3′-UTR targeting by miR-1 not validated by reporter assay in this study
    • In vivo rescue with miR-1 not performed
  10. 2009 High

    Three discoveries converged to define transcriptional and heterotetrameric control: MEF2 directly activates HCN4 transcription via the CNS13 enhancer, Sp1 drives pathological HCN4 re-expression in hypertrophy, and proteolytically processed HCN2 co-assembles with HCN4 providing the cAMP sensor in native cardiac If.

    Evidence ChIP/EMSA/dominant-negative MEF2 in cardiomyocytes (PMID:19477969); Sp1 siRNA in hypertrophic cardiomyocytes (PMID:19471099); Co-IP from native heart tissue + reconstituted truncated-HCN2/HCN4 heteromers (PMID:19574228)

    PMID:19471099 PMID:19477969 PMID:19574228

    Open questions at the time
    • Whether HCN2 proteolysis occurs in human heart not shown
    • Integration of MEF2 and Sp1 transcriptional pathways not defined
  11. 2010 High

    The crystal structure of the HCN4 C-linker/CNBD revealed that the β4–β5 loop accounts for HCN4's reduced cAMP sensitivity relative to HCN2, while PKA phosphoproteomics identified ≥13 sites including a distal C-terminal site required for β-adrenergic If modulation, establishing dual (direct cAMP + PKA phosphorylation) sympathetic control.

    Evidence 2.4 Å X-ray crystallography with mutagenesis (PMID:20829353); in vitro phosphorylation/MS + SAN patch-clamp with PKA inhibition (PMID:20713547)

    PMID:20713547 PMID:20829353

    Open questions at the time
    • Full-length HCN4 structure not available at this time
    • How PKA phosphorylation and cAMP binding interact allosterically within the tetramer not resolved
  12. 2011 High

    Cardiac-specific HCN4 knockout proved the channel is essential for normal impulse generation, causing ~50% rate reduction, AV block, and lethality, definitively establishing HCN4 as the dominant If contributor in the adult heart.

    Evidence Inducible cardiac-specific KO mice with SAN patch-clamp and ECG

    PMID:21220308

    Open questions at the time
    • Relative contributions of HCN4 loss-of-function to SAN arrest versus AV block not fully dissected
    • Whether residual If in KO reflects HCN1 or HCN2 contribution not determined
  13. 2012 High

    Multiple discoveries defined the macromolecular signaling complex: HCN4 localizes to caveolae via Y259/F262, β2-adrenergic receptors bind the HCN4 N-terminal tail to enable local adrenergic modulation, and Mef2c/HDAC-dependent enhancer regulation controls tissue-specific HCN4 expression.

    Evidence Caveolin-binding domain mutagenesis + Co-IP (PMID:22659290); β2AR-HCN4 Co-IP + peptide disruption (PMID:22613709); transgenic enhancer mice + HDAC inhibitor (PMID:23085412)

    PMID:22613709 PMID:22659290 PMID:23085412

    Open questions at the time
    • Whether β2AR-HCN4 complex exists in native SAN tissue not shown by Co-IP from tissue
    • HDAC isoform specificity in enhancer regulation not fully resolved
  14. 2012 Medium

    The D553N mechanism was revised from trafficking defect to C-linker gating defect, and the K530N C-linker mutation was linked to tachycardia-bradycardia syndrome, establishing the C-linker as a critical disease-relevant gating element.

    Evidence Surface expression assays showing normal D553N trafficking (PMID:23075627); heteromeric WT+K530N electrophysiology and pedigree (PMID:23178648)

    PMID:23075627 PMID:23178648

    Open questions at the time
    • No structural data on how D553N or K530N alter C-linker conformation
    • K530N heteromeric mechanism based on single-family pedigree
  15. 2017 High

    miR-423-5p was identified as a physiological repressor of HCN4 in the SAN, mediating exercise-induced bradycardia through an Nkx2.5-driven pathway, with in vivo anti-miR rescue restoring HCN4 and heart rate.

    Evidence 3′-UTR reporter + anti-miR in swim-trained mice + ChIP for Nkx2.5 + patch-clamp

    PMID:28821541

    Open questions at the time
    • Long-term effects of anti-miR-423-5p on cardiac function not assessed
    • Whether this pathway operates in human athletes unknown
  16. 2018 High

    Bidirectional transgenic experiments showed HCN4 primarily buffers parasympathetic (vagal) slowing of heart rate rather than mediating sympathetic acceleration, reframing the physiological role of If in autonomic regulation.

    Evidence Inducible HCN4 overexpression/knockdown mice with vagus nerve stimulation and telemetric ECG

    PMID:29315578

    Open questions at the time
    • Whether vagal buffering is the dominant in vivo role during all physiological states not tested
    • Contribution of other ion channels to this vagal buffering not excluded
  17. 2019 High

    The Trx2-ROS-HDAC4-MEF2 axis was identified as a redox-sensitive pathway controlling HCN4 transcription: mitochondrial ROS elevation activates HDAC4 to suppress MEF2-dependent HCN4 enhancer, causing sick sinus syndrome.

    Evidence Conduction system-specific Trx2 KO mice, ChIP, MitoTEMPO rescue, ECG telemetry

    PMID:31751569

    Open questions at the time
    • Whether this redox pathway operates in human SAN disease not established
    • Direct HDAC4 phosphorylation/activation mechanism by ROS not defined
  18. 2020 High

    LRMP and IRAG were identified as ER-tethered, isoform-specific modulators of HCN4—LRMP inhibiting cAMP-dependent gating and IRAG causing ligand-independent voltage shift—while BMAL1 was shown to directly drive circadian HCN4 transcription in the SAN.

    Evidence Co-IP + patch-clamp for LRMP/IRAG (PMID:32647060); ChIP + Bmal1 cardiomyocyte-KO + promoter bioluminescence (PMID:33278629)

    PMID:32647060 PMID:33278629

    Open questions at the time
    • How ER-resident LRMP/IRAG access plasma membrane HCN4 mechanistically unclear
    • Whether BMAL1 rhythmicity is disrupted in human SAN disease not tested
  19. 2020 High

    Ectopic HCN4 expression driven by mTOR hyperactivation was shown sufficient to cause epileptic seizures in cortical malformation neurons, establishing a pathogenic neuronal role for HCN4 outside the heart.

    Evidence Mouse FCM model with HCN4 blockade preventing seizures, validated in resected human tissue

    PMID:33208499

    Open questions at the time
    • Whether HCN4-selective blockers would be effective anti-epileptic drugs in humans not tested
    • Mechanism of mTOR-driven HCN4 transcription not defined
  20. 2021 High

    Shugoshin-1 was identified as a trafficking partner of HCN4, with the CAID syndrome mutation impairing this interaction and reducing If in patient iPSC-cardiomyocytes, linking a mitotic regulator to pacemaker channel surface expression.

    Evidence Co-IP, surface expression assay, patch-clamp in iPSC-CMs carrying the SGO1 K23E mutation

    PMID:33953173

    Open questions at the time
    • Structural basis of SGO1-HCN4 interaction unknown
    • Whether SGO1 regulates HCN4 in SAN tissue in vivo not shown
  21. 2023 High

    Single-channel recordings of the V240M gain-of-function mutation showed increased conductance and open probability causing inappropriate sinus tachycardia, the first HCN4 gain-of-function mechanism resolved at single-channel level, with ivabradine providing clinical rescue.

    Evidence Single-channel and macroscopic patch-clamp, computer simulations, clinical ivabradine treatment

    PMID:38032931

    Open questions at the time
    • Structural mechanism by which V240M in the HCN domain increases conductance unknown
    • Long-term outcomes of ivabradine in HCN4 gain-of-function patients not reported
  22. 2024 High

    The 3 Å cryo-EM structure of HCN4 bound to ivabradine revealed the drug's open-pore binding site at Y507/I511 on S6 and the role of C479 in block kinetics, providing the first near-atomic view of HCN4 pharmacological inhibition.

    Evidence Cryo-EM structure determination, molecular dynamics simulations, electrophysiology with pore mutants

    PMID:38917012

    Open questions at the time
    • Structure in the closed or cAMP-free state not yet reported
    • Whether ivabradine binding differs in heteromeric HCN4/HCN1 channels unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length, state-resolved structural model of HCN4 in its resting, open, and cAMP-bound conformations—particularly in heteromeric complexes with HCN1—remains unavailable, limiting mechanistic understanding of voltage-dependent gating, hysteresis, and allosteric coupling between the CNBD, C-linker, and voltage sensor.
  • No full-length structure of HCN4 in the closed/resting state
  • Heteromeric HCN4/HCN1 channel architecture not structurally resolved
  • Integration of PKA phosphorylation, Src phosphorylation, and cAMP binding within the native tetramer not mechanistically modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 8
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 2
Partners
ADRB2CAV1CAV3HCN1HCN2KCNE2LRMPSGO1
Complex memberships
HCN4-β2AR signaling complexHCN4/HCN1 heterotetramerHCN4/HCN2 heterotetramer

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Cardiac-specific inducible knockout of HCN4 in adult mice causes ~70% reduction in If current and ~60% reduction in spontaneous sinoatrial node rate, leading to severe bradycardia (~50% rate reduction), AV block, and death, demonstrating that HCN4 channels are essential for normal cardiac impulse generation and conduction. Inducible cardiac-specific knockout mouse model, patch-clamp electrophysiology on isolated SAN myocytes, immunofluorescence, Western blot Proceedings of the National Academy of Sciences of the United States of America High 21220308
2003 HCN4 and HCN1 co-assemble into heteromeric channels in the rabbit sinoatrial node; HCN4-HCN1 tandem constructs show intermediate activation kinetics between the two homomeric channels, suggesting native If reflects heteromeric HCN4/HCN1 channels with properties distinct from either isoform alone. Heterologous expression in HEK293 cells, patch-clamp electrophysiology, concatenated tandem constructs, co-transfection The Journal of physiology High 12702747
2001 HCN1 and HCN4 are expressed in a subset of taste receptor cells; lowering extracellular pH causes a dose-dependent depolarizing shift in the activation curve of HCN channels, indicating that HCN4 channels are gated by extracellular protons and may function as sour taste receptors. In situ hybridization, immunohistochemistry, patch-clamp electrophysiology on taste cells, pH dose-response Nature High 11675786
2004 The D553N missense mutation in HCN4 causes a trafficking defect that reduces membrane expression of the channel in a dominant-negative manner, resulting in decreased If current and sinus node dysfunction. Heterologous expression in HEK293 cells, patch-clamp electrophysiology, Western blot, trafficking assay The Journal of biological chemistry High 15123648
2003 KCNE2 specifically co-assembles with HCN4 (but not other KCNE family members) via interaction of its C-terminal tail with the C-terminal tail of HCN4, enhancing current amplitude and slowing activation kinetics of HCN4 channels. Heterologous expression in Xenopus oocytes and CHO cells, two-electrode voltage-clamp, patch-clamp, yeast two-hybrid assay Pflugers Archiv : European journal of physiology High 12856183
2010 The crystal structure of the C-terminal fragment of human HCN4 (C-linker + CNBD) at 2.4 Å reveals high overall similarity to mouse HCN2 but shows a ~3-fold reduced response to cAMP; residues in the β4-β5 loop region account for isoform differences in cAMP sensitivity. Upon cAMP binding, hHCN4 C-terminal protein exerts a prolonged effect on channel deactivation. X-ray crystallography, biochemistry, patch-clamp electrophysiology, mutagenesis The Journal of biological chemistry High 20829353
2010 PKA directly phosphorylates HCN4 at ≥13 sites (identified by in vitro phosphorylation and mass spectrometry), including a regulatory site in the distal C-terminus required for PKA-mediated shift of voltage dependence. PKA inhibition reduces β-adrenergic modulation of If in sinoatrial myocytes, indicating PKA phosphorylation contributes independently to sympathetic regulation of heart rate. In vitro phosphorylation assay, mass spectrometry, patch-clamp on isolated sinoatrial myocytes, HCN4 truncation and alanine-substitution mutants in HEK cells The Journal of general physiology High 20713547
2007 The G480R mutation in the HCN4 pore domain causes familial sinus bradycardia by activating channels at more negative voltages and reducing channel synthesis and plasma membrane trafficking, demonstrated by biotinylation and Western blot. Expression in Xenopus oocytes and HEK293 cells, patch-clamp, biotinylation assay, Western blot Circulation High 17646576
2003 Residues in transmembrane segments S1, the S1-S2 linker, and S2 of HCN4 determine its slow activation kinetics relative to HCN2; L272 in S1 is the dominant determinant, and I308M in S2 abolishes cAMP-dependent acceleration of activation kinetics. Chimeric channel analysis (HCN2/4 chimeras and point mutants), patch-clamp electrophysiology The Journal of biological chemistry High 12813043
2006 Constitutively active Src tyrosine kinase enhances HCN4 activity (positive voltage shift, accelerated kinetics, increased conductance) and forms a direct protein complex with HCN4, as shown by co-immunoprecipitation in HEK293 cells and rat ventricular myocytes. Co-transfection in HEK293 cells, whole-cell patch-clamp, co-immunoprecipitation Journal of cardiovascular pharmacology Medium 16680072
2007 Src tyrosine kinase modulates HCN4 gating primarily through Tyr531; the Y531F mutation abolishes Src-mediated positive voltage shift and conductance increase of HCN4 channels. Tyr554 mediates Src-dependent kinetic changes but not voltage dependence. Selective Src inhibitor (PP2), site-directed mutagenesis, whole-cell patch-clamp in HEK293 cells and HL-1 cardiomyocytes, in vivo mouse heart rate measurement American journal of physiology. Cell physiology High 17977941
2012 HCN4 contains a conserved caveolin-binding domain (CBD) composed of aromatic residues Y259 and F262 at the N-terminus; disruption of the CBD reduces HCN4 current density, weakens HCN4-caveolin-1 interaction, causes cytoplasmic channel accumulation, and abolishes sensitivity to cholesterol depletion-induced caveolar disorganization. Mutagenesis (Y259S, F262V, Y259F, F262Y), patch-clamp in CHO cells and caveolin-1-free fibroblasts, co-immunoprecipitation Journal of molecular and cellular cardiology High 22659290
2012 β2-adrenergic receptors form a direct protein complex with HCN4 channels; the binding site is located at a proximal region of the HCN4 N-terminal tail. A synthetic peptide from this region disrupts the HCN4-β2AR complex and prevents adrenergic augmentation of If and spontaneous contraction rate, but does not affect adrenergic regulation of voltage-gated calcium currents. Co-immunoprecipitation, synthetic peptide competition, patch-clamp electrophysiology, spontaneous contraction rate measurement The Journal of biological chemistry High 22613709
2012 HCN4 K530N mutation in the C-linker causes tachycardia-bradycardia syndrome and atrial fibrillation; in heteromeric channels (WT+mutant), but not homomeric mutant channels, there is a significant hyperpolarizing shift in half-maximal activation voltage, attributed to altered C-linker oligomerization equilibrium between nucleotide-free and ligand-bound tetrameric states. Patch-clamp electrophysiology in HEK293 cells (homomeric and heteromeric co-expression), pedigree analysis European heart journal Medium 23178648
2009 Cardiac myocardial HCN2 undergoes proteolytic processing in adult mouse heart, losing its C-terminal cAMP-binding domain to yield a ~60 kDa fragment; this C-terminally truncated HCN2 co-assembles with HCN4 to form heteromeric channels that activate faster than homomeric HCN2 or HCN4 and display properties similar to endogenous myocardial If. HCN4 provides the cAMP sensitivity in these complexes. Western blot, co-immunoprecipitation with isoform-specific antibodies from adult mouse heart, heterologous expression of truncated HCN2+HCN4, patch-clamp The Journal of biological chemistry High 19574228
2009 MEF2 (myocyte enhancer factor-2) and AP1 transcription factors directly bind to the CNS13 enhancer in the Hcn4 genomic locus; dominant-negative MEF2 inhibits enhancer activity, reduces Hcn4 mRNA expression, and decreases Ih amplitude in embryonic heart inflow tract myocytes, establishing Hcn4 as a direct MEF2 transcriptional target. Luciferase reporter assay, EMSA, chromatin immunoprecipitation, dominant-negative MEF2 overexpression, patch-clamp in primary neonatal rat cardiomyocytes Cardiovascular research High 19477969
2006 The NRSE motif in the HCN4 gene promoter binds NRSF (neuron-restrictive silencing factor), and this interaction mediates the developmental silencing of HCN4 after birth and its reactivation during cardiac hypertrophy; mutant NRSE constructs fail to recapitulate developmental expression changes. Promoter-luciferase reporter assay, EMSA confirming NRSF binding, mutation analysis in primary neonatal rat cardiomyocytes Biochemical and biophysical research communications Medium 17173866
2008 HCN4 is a direct target of miR-1 in cardiomyocytes; down-regulation of miR-1 in hypertrophied rat hearts contributes to increased HCN4 protein levels, and forced miR-1 expression prevents HCN4 overexpression in hypertrophic cardiomyocytes. Western blot, RT-PCR, transfection of miR-1 mimics in primary neonatal cardiomyocytes, rat cardiac hypertrophy model The Journal of biological chemistry Medium 18458081
2017 miR-423-5p targets the HCN4 3'-UTR and suppresses HCN4 expression; knockdown of miR-423-5p rescues HCN4 expression and If, reversing training-induced bradycardia in swim-trained mice. The upregulation of miR-423-5p and its host gene NSRP1 in the sinus node is driven by increased Nkx2.5. Luciferase 3'-UTR reporter assay, anti-miR knockdown in vivo, next-generation sequencing, qRT-PCR, Western blot, patch-clamp, chromatin immunoprecipitation Circulation research High 28821541
2020 The circadian clock transcription factor BMAL1 directly binds to the Hcn4 promoter in sinoatrial node cells, driving 24-hour rhythmicity of HCN4 expression and If. Cardiomyocyte-specific knockout of Bmal1 abolishes the day-night difference in Hcn4 mRNA expression and intrinsic heart rate. Chromatin immunoprecipitation, cardiomyocyte-specific Bmal1 KO transgenic mice, patch-clamp, qRT-PCR, Western blot, telemetric ECG, HCN4 promoter reporter bioluminescence Heart rhythm High 33278629
2012 Mef2C directly activates an Hcn4 enhancer in non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo; HDAC inhibition expands Hcn4 enhancer activity to working myocardium, and cardiac hypertrophy-induced HDAC nuclear export causes ectopic Hcn4 enhancer activation in working myocardium. Transgenic reporter mice, in vivo cis-regulatory analysis, HDAC inhibitor treatment of transgenic embryos, transverse aortic constriction model Developmental biology Medium 23085412
2019 Mitochondrial thioredoxin-2 (Trx2) maintains HCN4 expression in sinoatrial node cells; its deletion increases mitochondrial ROS, which elevates HDAC4, reduces histone acetylation at the MEF2 binding site of the HCN4 enhancer, and decreases HCN4 transcription, causing sick sinus syndrome. Cardiac conduction system-specific Trx2 KO (Hcn4-CreERT2), chromatin immunoprecipitation, histological analysis, mitochondria-specific ROS scavenger (MitoTEMPO) rescue, ECG telemetry Journal of molecular and cellular cardiology High 31751569
2020 Ectopic HCN4 expression in cortical FCM neurons (driven by mTOR hyperactivation) is sufficient to cause epileptic seizures; increasing intracellular cAMP (which preferentially enhances HCN4 gating) drives repetitive firing selectively in FCM neurons, and blocking HCN4 prevents epilepsy in the mouse model. Mouse FCM model (TSC/FCDII), patch-clamp, cAMP manipulation, HCN4 channel blockade, immunohistochemistry in human resected tissue Science translational medicine High 33208499
2012 HCN4 cAMP sensitivity and basal voltage dependence are controlled by multiple channel domains, including the distal C-terminus (residues 719-1012); in CHO cells, ligand-independent relief of autoinhibition occurs for HCN4 but not HCN2, mediated by membrane-associated intracellular factors acting on the distal C-terminus. Patch-clamp in CHO and HEK cells, excised patch recordings, truncation mutants, isoform comparison The Journal of general physiology Medium 23109717
2020 LRMP (Jaw1) and IRAG (Mrvi1/Jaw1L) are ER transmembrane proteins that associate with and modulate HCN4 in an isoform-specific manner: LRMP inhibits cAMP-dependent activation of HCN4 while IRAG causes ligand-independent depolarization of basal voltage dependence. IRAG is highly expressed in mouse sinoatrial node and computer modeling predicts it increases HCN4 current. Co-immunoprecipitation, patch-clamp in HEK and CHO cells, computer modeling, mouse sinoatrial node expression analysis Proceedings of the National Academy of Sciences of the United States of America High 32647060
2021 Shugoshin-1 directly interacts with HCN4 to promote cell-surface expression and function; the clinical CAID syndrome mutation p.Lys23Glu impairs this interaction, reducing funny-current and causing dysrhythmia in patient-derived iPSC-cardiomyocytes. Co-immunoprecipitation, patch-clamp in neonatal rat ventricular myocytes and iPSC-cardiomyocytes, surface expression assay Nature communications High 33953173
2011 HCN4 channels contain two tissue-specific N-terminal variants arising from different transcription start sites; the brain expresses only one variant while heart expresses both. Three positively charged residues (Arg9, Lys10, Lys22) in the N-terminus contribute to differential channel activation kinetics between variants. Identification of mRNA variants, patch-clamp in HEK293H cells, N-terminal mutagenesis The Journal of biological chemistry Medium 21372143
2010 Human HCN4 exhibits voltage-dependent hysteresis: the activation curve shifts to more depolarized voltages with more hyperpolarized holding potentials. cAMP enhances If and modifies this intrinsic hysteresis. HCN4 accounts for 75% of HCN transcripts in human sinoatrial node. Patch-clamp in HEK293 cells stably expressing hHCN4 (triangular ramp and action potential clamp protocols), qRT-PCR of human SAN tissue Sheng li xue bao : [Acta physiologica Sinica] Medium 20179882
2018 HCN4 pacemaker channels attenuate parasympathetic (vagal) responses of the sinoatrial node: HCN4 knockdown enhances parasympathetic-induced sinus pause, while HCN4 overexpression attenuates bradycardia induced by vagus nerve stimulation during β-adrenergic stimulation. β-adrenergic response of the SAN is preserved regardless of HCN4 expression level. Tetracycline-inducible HCN4 overexpression/knockdown transgenic mice, telemetric ECG, vagus nerve stimulation, patch-clamp on isolated pacemaker cells The Journal of physiology High 29315578
2024 Cryo-EM structure of HCN4 in complex with ivabradine at 3 Å resolution shows ivabradine bound inside the open pore; Y507 and I511 on S6 are the key molecular determinants of ivabradine binding to the inner cavity, F510 indirectly contributes by controlling Y507 orientation, and Cys479 in the selectivity filter accelerates the kinetics of block. Molecular dynamics simulations show ivabradine blocks ion permeation by electrostatic repulsion at the selectivity filter. Cryo-EM structure determination, molecular dynamics simulations, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 38917012
2012 The HCN4 D553N mutation in the C-linker causes a gating defect rather than a primary trafficking defect: D553N channels reach the plasma membrane normally but generate currents with reduced amplitude, likely due to stabilization of a salt bridge important for C-linker gating. cAMP regulation is altered but not sufficient to account for the full loss-of-function. Fluorescence microscopy, FACS surface expression assay, two-electrode voltage-clamp in Xenopus oocytes, patch-clamp in mammalian cells Cellular physiology and biochemistry Medium 23075627
2009 Sp1 is a common transactivator of HCN4 gene transcription; siRNA silencing of Sp1 prevents overexpression of HCN4 in hypertrophic cardiomyocytes, and upregulation of Sp1 underlies pathological re-expression of HCN4 in ventricular hypertrophy. 5'-RACE, luciferase reporter assay, qRT-PCR, Western blot, Sp1 siRNA knockdown in primary neonatal rat cardiomyocytes Cellular physiology and biochemistry Medium 19471099
2013 HCN4 co-localizes and co-immunoprecipitates with caveolin-3 in adult human atrial and ventricular cardiomyocytes; caveolae disruption shifts the voltage dependence of If toward more positive (immature) values in adult cardiomyocytes but not in fetal cardiomyocytes where HCN4-Cav3 co-localization is absent. Co-immunoprecipitation, immunohistochemistry in hESC-CMs and adult/fetal human cardiomyocytes, patch-clamp with caveolae-disrupting agents Stem cells and development Medium 23311301
2012 Thy1 (a GPI-anchored protein) co-localizes and co-immunoprecipitates with HCN4 in rat retinal ganglion cells, representing the first reported association of Thy1 with a membrane-spanning ion channel subunit. Co-immunoprecipitation with anti-Thy1 and anti-HCN4 antibodies, immunohistochemistry, confocal imaging, patch-clamp on immunopanned cells Investigative ophthalmology & visual science Medium 22281825
2023 A gain-of-function HCN4 mutation V240M located in the N-terminal HCN domain increases single-channel conductance, opening frequency, and opening probability without altering cAMP sensitivity or membrane expression, causing inappropriate sinus tachycardia. Computer simulations confirm increased If and beating rate. Treatment with ivabradine reversed IST and cardiomyopathy. Macroscopic and single-channel patch-clamp in cells expressing WT and/or V240M HCN4, computer simulations, clinical ivabradine treatment Proceedings of the National Academy of Sciences of the United States of America High 38032931
2022 CVB3 (Coxsackievirus B3) reduces HCN4 plasma membrane density in hiPSC-derived pacemaker cells by triggering increased autophagosomal insertion of HCN4; CVB3 non-structural proteins 2C and 3A have the most robust effect on HCN4 activity. Inhibition of Rab7-directed autophagosome transport (with CID 106770) recovers cytoplasmic HCN4 accumulation. hiPSC-derived pacemaker cells with inducible CVB3 expression, HCN4 trafficking immunofluorescence, patch-clamp, HEK cell HCN4 expression system, Rab7 and CVB3-3A inhibitors Cellular and molecular life sciences : CMLS Medium 35864219
2021 LncRNA RCPCD suppresses HCN4 expression by increasing methylation of the HCN4 promoter through DNMT1, DNMT2, and DNMT3; overexpression of RCPCD inhibits differentiation of embryonic stem cells into pacemaker-like cells, an effect rescued by HCN4 co-expression. Methylation-specific PCR, chromatin immunoprecipitation, RNA immunoprecipitation, luciferase reporter, adenoviral overexpression/knockdown, rescue experiments Cell death & disease Medium 34215719
2013 Testosterone recruits the androgen receptor (AR) directly to regulatory regions of the HCN4 gene (and MEF2C), increasing histone acetylation and upregulating HCN4 expression and cardiomyogenesis in stem cells. Chromatin immunoprecipitation, AR knockdown/antagonist, dose-response, qRT-PCR, Western blot in mES and P19 cells Journal of molecular and cellular cardiology Medium 23598283

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proceedings of the National Academy of Sciences of the United States of America 228 21220308
2013 HCN4 dynamically marks the first heart field and conduction system precursors. Circulation research 178 23743334
2003 Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. The Journal of physiology 178 12702747
2001 Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 172 11675786
2004 Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. The Journal of biological chemistry 162 15123648
2007 Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4. Journal of cellular physiology 149 17516552
2013 A HCN4+ cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells. Nature cell biology 148 23974038
2008 Down-regulation of miR-1/miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart. The Journal of biological chemistry 147 18458081
2014 HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. Journal of the American College of Cardiology 145 25145517
2007 Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 121 17646576
2014 The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. Journal of the American College of Cardiology 112 25145518
2006 Extended atrial conduction system characterised by the expression of the HCN4 channel and connexin45. Cardiovascular research 90 16989793
2003 Expression of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 during mouse heart development. Gene expression patterns : GEP 89 14643687
2003 KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Pflugers Archiv : European journal of physiology 85 12856183
2015 Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. International journal of molecular sciences 83 25642760
2010 Structural basis for the cAMP-dependent gating in the human HCN4 channel. The Journal of biological chemistry 81 20829353
2010 Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node. The Journal of general physiology 80 20713547
2012 Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. European heart journal 76 23178648
2017 Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia. Circulation research 71 28821541
2009 Role of HCN4 channel in preventing ventricular arrhythmia. Journal of human genetics 66 19165230
2009 Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node. Journal of molecular and cellular cardiology 65 19394343
2020 A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate. Heart rhythm 62 33278629
2015 Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4. Journal of molecular and cellular cardiology 57 25986146
2014 A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation. Heart rhythm 55 24607718
2010 A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. Journal of cardiovascular electrophysiology 53 20662977
2012 A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins. Journal of molecular and cellular cardiology 50 22659290
2003 Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4. The Journal of biological chemistry 48 12813043
2015 HCN4, Sinus Bradycardia and Atrial Fibrillation. Arrhythmia & electrophysiology review 46 26835093
2013 HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus. Neuroscience 46 23357121
2020 Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice. Science translational medicine 42 33208499
2007 Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531. American journal of physiology. Cell physiology 39 17977941
2011 Funny current channel HCN4 delineates the developing cardiac conduction system in chicken heart. Heart rhythm 38 21421080
2017 Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction. Heart rhythm 37 28104484
2006 Constitutively active Src tyrosine kinase changes gating of HCN4 channels through direct binding to the channel proteins. Journal of cardiovascular pharmacology 37 16680072
2014 Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 36 24569893
2009 The cardiac pacemaker-specific channel Hcn4 is a direct transcriptional target of MEF2. Cardiovascular research 36 19477969
2006 NRSF regulates the developmental and hypertrophic changes of HCN4 transcription in rat cardiac myocytes. Biochemical and biophysical research communications 35 17173866
2015 Enhancement of Spontaneous Activity by HCN4 Overexpression in Mouse Embryonic Stem Cell-Derived Cardiomyocytes - A Possible Biological Pacemaker. PloS one 34 26384234
2013 Molecular and functional evidence of HCN4 and caveolin-3 interaction during cardiomyocyte differentiation from human embryonic stem cells. Stem cells and development 34 23311301
2018 A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability. Frontiers in molecular neuroscience 32 30127718
2018 HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node. The Journal of physiology 31 29315578
2017 Gabapentin Modulates HCN4 Channel Voltage-Dependence. Frontiers in pharmacology 28 28871229
2008 Engineering physiologically controlled pacemaker cells with lentiviral HCN4 gene transfer. The journal of gene medicine 28 18383475
2007 Adenoviral gene transfer of HCN4 creates a genetic pacemaker in pigs with complete atrioventricular block. Life sciences 28 17382969
2012 Spatiotemporal regulation of an Hcn4 enhancer defines a role for Mef2c and HDACs in cardiac electrical patterning. Developmental biology 26 23085412
2017 Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia open 25 29588962
2010 Dynamic changes in HCN2, HCN4, KCNE1, and KCNE2 expression in ventricular cells from acute myocardial infarction rat hearts. Biochemical and biophysical research communications 25 20381460
2016 Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function. Pflugers Archiv : European journal of physiology 24 27553229
2014 Insights into cardiac conduction system formation provided by HCN4 expression. Trends in cardiovascular medicine 24 25442735
2009 Hyperpolarization-activated cyclic-nucleotide gated 4 (HCN4) protein is expressed in a subset of rat dorsal root and trigeminal ganglion neurons. Cell and tissue research 24 19820968
2019 HCN4 knockdown in dorsal hippocampus promotes anxiety-like behavior in mice. Genes, brain, and behavior 23 30585408
2013 Testosterone enhances cardiomyogenesis in stem cells and recruits the androgen receptor to the MEF2C and HCN4 genes. Journal of molecular and cellular cardiology 22 23598283
2010 Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking. Sheng li xue bao : [Acta physiologica Sinica] 21 20179882
2009 Proteolytic processing of HCN2 and co-assembly with HCN4 in the generation of cardiac pacemaker channels. The Journal of biological chemistry 21 19574228
2014 A novel HCN4 mutation, G1097W, is associated with atrioventricular block. Circulation journal : official journal of the Japanese Circulation Society 20 24492017
2011 Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder. Neuroscience letters 20 21529705
2009 Transcriptional control of pacemaker channel genes HCN2 and HCN4 by Sp1 and implications in re-expression of these genes in hypertrophied myocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20 19471099
2012 Cellular context and multiple channel domains determine cAMP sensitivity of HCN4 channels: ligand-independent relief of autoinhibition in HCN4. The Journal of general physiology 19 23109717
2020 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 18 32647060
2019 Using a Multiplex Nucleic Acid in situ Hybridization Technique to Determine HCN4 mRNA Expression in the Adult Rodent Brain. Frontiers in molecular neuroscience 18 31555092
2012 Adrenergic regulation of HCN4 channel requires protein association with β2-adrenergic receptor. The Journal of biological chemistry 18 22613709
2023 A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family. Proceedings of the National Academy of Sciences of the United States of America 17 38032931
2019 Mitochondrial thioredoxin-2 maintains HCN4 expression and prevents oxidative stress-mediated sick sinus syndrome. Journal of molecular and cellular cardiology 17 31751569
2009 Identification, isolation and characterization of HCN4-positive pacemaking cells derived from murine embryonic stem cells during cardiac differentiation. Pacing and clinical electrophysiology : PACE 17 19895411
2020 Gastrointestinal Neurons Expressing HCN4 Regulate Retrograde Peristalsis. Cell reports 16 32130893
2015 HCN4 mutation as a molecular explanation on patients with bradycardia and non-compaction cardiomyopathy. European journal of medical genetics 16 26206080
2022 Paradigm shift: new concepts for HCN4 function in cardiac pacemaking. Pflugers Archiv : European journal of physiology 15 35556164
2018 A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction. Heart and vessels 15 29349559
2022 Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying HCN4 Pathogenic Variants. Genes 14 35328031
2019 The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease. Biochemical and biophysical research communications 14 31481236
2018 HCN4 Gene Polymorphisms Are Associated With Occurrence of Tachycardia-Induced Cardiomyopathy in Patients With Atrial Fibrillation. Circulation. Genomic and precision medicine 14 29987112
2021 Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel. Nature communications 13 33953173
2018 In Vitro Analyses of Novel HCN4 Gene Mutations. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 30196304
2013 In situ investigation of allografted mouse HCN4 gene-transfected rat bone marrow mesenchymal stromal cells with the use of patch-clamp recording of ventricular slices. Cytotherapy 13 23768927
2012 Hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4) involvement in Tourette's syndrome autoimmunity. Journal of neuroimmunology 13 22683190
2017 A novel 'splice site' HCN4 Gene mutation, c.1737+1 G>T, causes familial bradycardia, reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability. International journal of cardiology 12 28465117
2013 Inducible gene deletion in the entire cardiac conduction system using Hcn4-CreERT2 BAC transgenic mice. Genesis (New York, N.Y. : 2000) 12 24281837
2020 Notch1-mediated histone demethylation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia. Toxicology letters 11 32234357
2018 HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia. International heart journal 11 29628472
2022 Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system. Cellular and molecular life sciences : CMLS 10 35864219
2021 Downregulated lncRNA RCPCD promotes differentiation of embryonic stem cells into cardiac pacemaker-like cells by suppressing HCN4 promoter methylation. Cell death & disease 10 34215719
2019 Pacemaker cell characteristics of differentiated and HCN4-transduced human mesenchymal stem cells. Life sciences 10 31291594
2012 Thy1 associates with the cation channel subunit HCN4 in adult rat retina. Investigative ophthalmology & visual science 10 22281825
2008 HCN4-like immunoreactivity in rat retinal ganglion cells. Visual neuroscience 10 18282314
2024 Structural determinants of ivabradine block of the open pore of HCN4. Proceedings of the National Academy of Sciences of the United States of America 9 38917012
2019 Protein and surface expression of HCN2 and HCN4 subunits in mesocorticolimbic areas after cocaine sensitization. Neurochemistry international 9 30794847
2011 Blocking effects of acehytisine on pacemaker currents (I(f)) in sinoatrial node cells and human HCN4 channels expressed in Xenopus laevis oocytes. Journal of ethnopharmacology 9 22107837
2010 Expression of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN4) is increased in hypertrophic cardiomyopathy. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 9 20207172
2023 Alkali metal cations modulate the geometry of different binding sites in HCN4 selectivity filter for permeation or block. The Journal of general physiology 8 37523352
2022 Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes. Stem cell research & therapy 8 35365232
2021 Ivabradine prevents deleterious effects of dopamine therapy in heart failure: No role for HCN4 overexpression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 33450487
2012 The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 8 23075627
2011 Tissue-specific N terminus of the HCN4 channel affects channel activation. The Journal of biological chemistry 8 21372143
2015 Morphology of mouse sinoatrial node and its expression of NF-160 and HCN4. International journal of clinical and experimental medicine 7 26550270
2023 Electroacupuncture inhibits PDK1/Akt/HCN4 pathway to improve neurogenic urinary retention in rats. Zhen ci yan jiu = Acupuncture research 6 37879946
2024 Stem cell-derived cardiomyocytes expressing a dominant negative pacemaker HCN4 channel do not reduce the risk of graft-related arrhythmias. Frontiers in cardiovascular medicine 5 39045008
2023 The Action Potential Clamp Technique as a Tool for Risk Stratification of Sinus Bradycardia Due to Loss-of-Function Mutations in HCN4: An In Silico Exploration Based on In Vitro and In Vivo Data. Biomedicines 5 37760888
2022 Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients caused by heterozygous mutations in the HCN4 gene. Stem cell research 5 36332467
2020 Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord. Molecular brain 5 32948209
2019 Correlation between HCN4 gene polymorphisms and lone atrial fibrillation risk. Artificial cells, nanomedicine, and biotechnology 5 31315459