Affinage

HCN2

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 · UniProt Q9UL51

Length
889 aa
Mass
97.0 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCN2 is a hyperpolarization-activated, cyclic-nucleotide-modulated cation channel that generates the Ih/If current underlying pacemaking and excitability control across the heart, peripheral nociceptors, and central neurons (PMID:10524219, PMID:17687049). Voltage sensing resides in S4, whose basic residues contribute differentially to gating versus folding/trafficking (PMID:10962006), while determinants in S1/S2 set the channel's characteristic fast activation kinetics relative to HCN4 (PMID:12813043). cAMP binding to the C-terminal CNBD shifts voltage-dependent activation positive: full activation requires only two of four bound ligands, binding and gating are reciprocally coupled, and ligand binding proceeds through an intermediate "flip" state before pore opening (PMID:20624593, PMID:26636938, PMID:29565972). This coupling is transmitted through C-linker rearrangements; intra- and intersubunit C-linker salt bridges stabilize the closed state and must break during opening even with the CNBD ligand-bound (PMID:15572346), and movements near the S6 activation gate reciprocally tune cAMP-binding affinity (PMID:22689828). HCN2 assembles into heteromers with HCN1 to produce currents matching native neuronal Ih (PMID:11331358, PMID:11133998), and its activity is governed by multiple inputs: Gi/Gs-coupled receptors acting through adenylyl cyclase and cAMP (PMID:11680627), Ca2+-activated AC1 conferring Ca2+ sensitivity (PMID:22484253), inhibitory cGKII phosphorylation at S641 (PMID:21347269), PI3K/Akt phosphorylation at S861 (PMID:33240105), the KCNE2/MiRP1 beta subunit (PMID:15292247), and transcriptional/post-transcriptional control by Sp1 and miR-1/miR-133 (PMID:18458081, PMID:19471099). In the heart, HCN2 is proteolytically processed to a C-terminally truncated form that co-assembles with HCN4 to form functional If (PMID:19574228). In nociceptive and trigeminal neurons, HCN2 is the PKA/cAMP effector required for inflammatory mechanical hyperalgesia and migraine-like pain via cyclic-nucleotide-dependent gating shifts (PMID:28767511, PMID:24525276, PMID:36658457), and in central circuits it stabilizes firing and constrains excitability, with loss- and gain-of-function variants causing epilepsy and altered neuronal excitability (PMID:17687049, PMID:19150498, PMID:22131395, PMID:29064616, PMID:37746765, PMID:40468825). Beyond its canonical channel role, HCN2 acts as a regulatory protein, binding the L-type Ca2+ channel α1C IQ motif to induce inactivation (PMID:20164379) and influencing APP processing (PMID:28017718).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 Medium

    Established that the human HCN2 gene encodes a hyperpolarization-activated, cAMP-modulated cation channel resembling the cardiac pacemaker If current, defining its core identity.

    Evidence Chromosomal mapping and functional heterologous expression with electrophysiology

    PMID:10524219

    Open questions at the time
    • Native tissue stoichiometry not addressed
    • Did not resolve subunit composition of native If
  2. 2001 High

    Determined that HCN1 and HCN2 form heteromeric channels with emergent biophysical properties matching native neuronal Ih, explaining the diversity of native currents beyond homomeric channels.

    Evidence Coexpression and concatenated dimer constructs in Xenopus oocytes with two-electrode voltage clamp and cell-free cAMP application

    PMID:11133998 PMID:11331358

    Open questions at the time
    • Native heteromer stoichiometry in specific neuronal populations not defined
    • In vivo assembly preferences unknown
  3. 2003 High

    Identified the specific transmembrane residues that set HCN2's faster activation kinetics and that distinguish voltage-sensing from folding/trafficking roles of S4 charges.

    Evidence HCN2/HCN4 chimeras, charge-neutralization mutagenesis, voltage clamp, and surface expression assays in oocytes

    PMID:10962006 PMID:12813043

    Open questions at the time
    • Structural basis of S4 charge pairing inferred, not directly visualized
    • Coupling to pore not resolved
  4. 2004 High

    Defined how cAMP signaling is mechanically transmitted to the gate, showing C-linker salt bridges stabilize the closed state and that beta-subunit MiRP1 tunes conductance and kinetics.

    Evidence Site-directed mutagenesis with functional rescue compared to crystal structure; reciprocal co-IP and patch clamp in cardiac myocytes

    PMID:15292247 PMID:15572346

    Open questions at the time
    • Dynamic C-linker motion inferred from static structure plus function
    • Physiological role of MiRP1 association in vivo not established
  5. 2010 High

    Resolved the allosteric logic of ligand gating by directly measuring binding and activation simultaneously, establishing reciprocal coupling and partial-occupancy activation.

    Evidence Patch-clamp fluorometry with fluorescent cAMP and kinetic modeling; S6 alanine scanning with biochemical CNBD-binding assay

    PMID:20624593 PMID:22689828

    Open questions at the time
    • Atomic pathway connecting gate to CNBD not visualized
    • Whether identical coupling holds in heteromers untested
  6. 2009 High

    Showed that cardiac HCN2 is proteolytically truncated to lose its CNBD and co-assembles with HCN4 to form native-like If, reassigning cAMP regulation of cardiac If to the HCN4 partner.

    Evidence N-/C-terminal antibody Western blots and co-IP from adult mouse heart; heterologous co-expression and patch clamp

    PMID:19574228

    Open questions at the time
    • Identity of the responsible protease unknown
    • Functional consequence of truncation in vivo not quantified
  7. 2008 High

    Connected HCN2 loss-of-function to absence epilepsy and identified its transcriptional and post-transcriptional regulators, linking channel abundance to disease and remodeling.

    Evidence Spontaneous mutant mouse with EEG and molecular characterization; miRNA reporter/forced-expression and Sp1 siRNA in hypertrophy models

    PMID:18458081 PMID:19150498 PMID:19471099

    Open questions at the time
    • Cellular circuit mechanism of spike-wave discharge not fully mapped in ap/ap mouse
    • Sp1 evidence is single-laboratory
  8. 2007 High

    Established HCN2 as the primary Ih isoform in reticular thalamic neurons, demonstrating its role in stabilizing firing and constraining circuit excitability.

    Evidence HCN2 knockout mice with whole-cell patch clamp, pharmacology, and immunohistochemistry in thalamic circuits

    PMID:17687049

    Open questions at the time
    • Contribution of HCN1/HCN2 heteromers in RTN not separated
    • Behavioral consequences not assessed here
  9. 2011 High

    Linked specific HCN2 mutations and signaling inputs to excitability, showing a recessive C-linker variant raises neuronal excitability and that cGKII phosphorylation at S641 inhibits gating.

    Evidence Mutation screening with heterologous and native neuron electrophysiology; co-IP, immunohistochemistry, and S641A mutagenesis

    PMID:21347269 PMID:22131395

    Open questions at the time
    • Heteromer behavior of E515K masks effect, complicating in vivo interpretation
    • In vivo relevance of cGKII phosphorylation not directly tested
  10. 2017 High

    Identified HCN2 as the PKA/cAMP effector required for inflammatory pain sensitization and resolved gain-of-function epilepsy variants, distinguishing pathogenic from benign variants.

    Evidence Conditional knockout of HCN2/PKA in nociceptors with behavioral and calcium imaging; oscyte voltage clamp on GGE patient variants

    PMID:28767511 PMID:29064616

    Open questions at the time
    • Direct PKA phosphorylation site on HCN2 in nociceptors not mapped here
    • GGE variant work is single-laboratory functional assay
  11. 2018 High

    Dissected peripheral versus central HCN2 contributions to chronic pain, showing peripheral HCN2 drives mechanical and central HCN2 drives thermal hyperalgesia.

    Evidence Tissue-specific and inducible global HCN2 knockouts with behavioral tests and single-fiber skin-nerve recordings

    PMID:24525276

    Open questions at the time
    • Molecular trigger for activity-dependent HCN2 upregulation not defined
    • Central site mediating thermal effect not localized
  12. 2019 Medium

    Extended HCN2's role to mood and pacemaking control, showing it regulates tonic firing of accumbal cholinergic interneurons and depressive-like behavior.

    Evidence Chronic stress models with AAV HCN2 overexpression, electrophysiology, and behavior

    PMID:30638901

    Open questions at the time
    • Single-laboratory finding
    • Upstream cause of HCN2 downregulation in depression unknown
  13. 2022 High

    Established trigeminal and thalamocortical HCN2 as drivers of migraine-like pain and allodynia, linking NO/cGMP signaling to HCN2-mediated hyperexcitability.

    Evidence Pharmacology and targeted deletion across migraine models with C-FOS, in vivo electrophysiology, and cGMP measurement; in vivo calcium imaging with VPL knockdown

    PMID:36658457 PMID:36846300

    Open questions at the time
    • VPL allodynia mechanism is single-laboratory
    • Whether cGMP acts via CNBD or cGKII in TG neurons not separated
  14. 2020 Medium

    Identified PI3K/Akt phosphorylation at S861 as an additional regulatory input controlling HCN2 activation voltage and current magnitude.

    Evidence PI3K/Akt inhibitors, PIP3 and active-Akt rescue, and S861A mutagenesis with electrophysiology in HEK293

    PMID:33240105

    Open questions at the time
    • Single-laboratory result
    • Physiological context where Akt regulates HCN2 in vivo not defined
  15. 2025 High

    Catalogued the spectrum of pathogenic HCN2 variants, mechanistically separating dominant-negative trafficking defects, silent loss-of-function, and gain-of-function and extending HCN2 to Alzheimer's-related hippocampal hyperexcitability.

    Evidence Oocyte/HEK electrophysiology, trafficking imaging, and structural analysis across variants; AAV bidirectional manipulation in dCA1 with electrophysiology and memory tests

    PMID:37746765 PMID:40016780 PMID:40468825

    Open questions at the time
    • Genotype-phenotype rules for variant class still incomplete
    • AD finding is single-laboratory

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HCN2's many regulatory inputs (cAMP/cGMP, PKA, cGKII, Akt, SUMOylation, beta subunits, Ca2+/AC1) are integrated at a single channel in vivo, and whether its non-channel roles (LTCC inactivation, APP processing) operate physiologically, remain unresolved.
  • No unified structural model of multi-input regulation
  • SUMOylation writer/eraser unidentified (single-method PLA)
  • Physiological significance of non-channel scaffolding interactions untested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
ADCY1AKT1CACNA1CHCN1HCN4KCNE2PRKG2
Complex memberships
HCN1-HCN2 heteromeric channelHCN2-HCN4 cardiac If channel

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HCN1 and HCN2 subunits coassemble to form heteromultimeric channels with novel biophysical properties (intermediate activation kinetics and voltage dependence, large cAMP shift of +14 mV) that cannot be reproduced by a linear sum of independent homomeric HCN1 and HCN2 populations; basal cAMP levels in intact oocytes modulate channel properties. Two-electrode voltage clamp in Xenopus oocytes (homomeric and coexpressed subunits); cell-free patch recordings with cAMP application The Journal of general physiology High 11133998 11331358
2000 HCN1 and HCN2 form functional heteromeric channels when expressed as concatenated (covalently linked) dimeric constructs; the heteromer activates faster than HCN2 homomers, has voltage dependence closer to HCN2, and intermediate cAMP sensitivity, closely resembling native Ih in CA1 pyramidal neurons. Concatenated cDNA construct expressed in Xenopus oocytes; two-electrode voltage clamp The Journal of biological chemistry High 11133998
2004 Two salt bridges in the C-linker region of HCN2—an intersubunit salt bridge between neighboring C-linkers and an intrasubunit salt bridge between the C-linker and CNBD—stabilize a closed channel conformation; breaking these salt bridges (by mutation) increases the favorability of channel opening, and swapping positive/negative residues restores wild-type behavior. This indicates that during channel opening the C-linker regions rearrange (disrupting these salt bridges) even when the CNBD is ligand-bound. Site-directed mutagenesis of HCN2 and CNGA1 channels; electrophysiology in Xenopus oocytes; comparison with HCN2 C-terminal crystal structure The Journal of general physiology High 15572346
2000 Charged residues in S4 of HCN2 contribute differently to voltage-dependent gating versus protein folding/trafficking: Lys-291, Arg-294, Arg-297, and Arg-300 affect voltage dependence of gating; Lys-303 and Ser-306 are essential for gating but not folding; Arg-312 is important for folding but not gating; Arg-309, Arg-315, and Arg-318 are crucial for normal folding/trafficking and likely charge-pair with Asp residues in S2/S3. Individual charge-neutralization mutagenesis (to Gln) of S2, S3, S4 residues; two-microelectrode voltage clamp in Xenopus oocytes; surface expression measured by HA-epitope chemiluminescence The Journal of biological chemistry High 10962006
2003 Single amino acid differences in transmembrane segments S1 and S2 and the S1-S2 linker determine the faster activation kinetics of HCN2 versus HCN4: replacing Phe-221 in S1 of HCN2 with Leu (the HCN4 residue) slows activation ~3-fold; mutation I308M in S2 of HCN4 abolishes the cAMP-dependent acceleration of activation kinetics and also prevents the acceleration caused by deletion of the C-terminal cAMP-binding domain. HCN2/HCN4 chimeras and point mutants expressed in Xenopus oocytes; two-electrode voltage clamp The Journal of biological chemistry High 12813043
2004 MiRP1 (KCNE2) co-assembles with HCN2 in neonatal rat ventricular myocytes (demonstrated by co-immunoprecipitation of both overexpressed HA-MiRP1/HCN2 and endogenous proteins), acting as a beta subunit that increases maximal HCN2 conductance ~4-fold and accelerates activation/deactivation kinetics at physiological voltages without affecting voltage dependence of activation. Adenoviral overexpression in neonatal rat ventricular myocytes; co-immunoprecipitation; patch-clamp electrophysiology The Journal of biological chemistry High 15292247
2010 Using patch-clamp fluorometry with a fluorescent cAMP analog, full ligand-induced activation of HCN2 appears with only two ligands bound to the tetrameric channel. Kinetic analysis reveals direct interaction between the voltage sensor and the CNBD (bypassing the pore), and demonstrates reciprocity: channel activation increases cAMP binding affinity, while binding increases the free energy of activation. Patch-clamp fluorometry with fluorescent cAMP analog (fcAMP); kinetic modeling of activation and binding Neuron High 20624593
2009 The inner activation gate region of HCN2 (S6 segment) contributes to state-dependent cAMP binding affinity: ZD7288 (an open-channel blocker acting at the inner pore) reduces activity-dependent increases in cAMP binding. Alanine scanning of S6 residues T426–A435 identifies T426, M430, and H434 as enhancing cAMP binding when mutated, while F431A and I432A dampen the response, demonstrating that movements near the activation gate directly affect ligand binding affinity. Patch-clamp fluorometry; ZD7288 block; alanine-scanning mutagenesis of S6; independent biochemical CNBD-binding assay The Journal of general physiology High 22689828
2009 In the myocardium, HCN2 undergoes proteolytic processing: the full-length 105 kDa HCN2 protein present in brain and transfected HEK-293 cells is truncated to a ~60 kDa form in adult mouse heart that lacks the C-terminus containing the cAMP-binding domain. The truncated myocardial HCN2 co-assembles with HCN4 to form heteromeric channels that activate faster than either homomer and resemble endogenous myocardial If; the HCN4 subunit is proposed to underlie cAMP-mediated regulation of cardiac If. Western blot with N- and C-terminal antibodies; co-immunoprecipitation from adult mouse heart; heterologous co-expression and patch clamp in HEK-293 cells The Journal of biological chemistry High 19574228
2001 Gi-coupled (µ-opioid) and Gs-coupled (5-HT4a) receptors both enhance HCN2 but not HCN1 currents via the cAMP pathway; the effect involves Gβγ-activation of adenylyl cyclase (for µ-opioid receptor) or direct Gαs-activation (for 5-HT4a receptor), is blocked by adenylyl cyclase inhibitor SQ22536, is independent of PKA/PKC, and causes a ~15 mV positive shift in voltage dependence of HCN2 activation. Two-electrode voltage clamp in Xenopus oocytes co-expressing HCN channels with GPCRs; pharmacological dissection of G-protein pathway Pflugers Archiv : European journal of physiology High 11680627
2006 Molecular dynamics simulations of the HCN2 C-linker/CNBD fragment (based on crystal structure) show that cAMP binding triggers a quaternary oscillation (~10 ns timescale) not seen in the apoprotein; absence of cAMP causes conformational rearrangements within CNBDs driving them to a more flexible, disordered state that exerts an inhibitory effect on the channel. The cAMP-triggered oscillation is proposed to couple to C-linker motion that modulates gating. Molecular dynamics simulation based on HCN2 C-linker/CNBD crystal structure; comparison of cAMP-bound vs. apo states Biophysical journal Low 16500960
2004 HCN2 forms a protein assembly with three neuronal scaffold proteins—tamalin, S-SCAM, and Mint2—via distinct interaction modes: tamalin PDZ domain interacts with both the PDZ-binding motif and an internal C-terminal tail sequence of HCN2; S-SCAM PDZ domain interacts with the CNBD and CNBD-downstream sequence; Mint2 MID domain interacts with the CNBD-downstream sequence of HCN2. Co-immunoprecipitation from rat brain and heterologous cell extracts; GST pull-down assays; domain mapping with truncation constructs Genes to cells : devoted to molecular & cellular mechanisms Medium 15265006
2009 Extracellular niflumic acid (NFA) interacts with the outer region of S4 voltage-sensing domains of HCN2 to slow activation and deactivation, shift voltage dependence of activation by −24.5 mV (at 1 mM), and preferentially interacts with closed-state channels. Neutralization of any three of the four outermost basic S4 residues abolishes the NFA-induced shift, indicating that NFA acts via multiple outer S4 charges. Site-directed mutagenesis of S4 residues; two-electrode voltage clamp in Xenopus oocytes; state-dependence analysis Molecular pharmacology High 19218366
2011 cGMP-dependent protein kinase II (cGKII) physically interacts with the proximal C-terminus of HCN2, co-localizing in native mouse brain (co-IP and immunohistochemistry), and phosphorylates HCN2 at Ser-641 in the C-terminal end of the CNBD. This phosphorylation shifts the voltage-dependence of activation 2–5 mV negative (inhibitory), counteracting the stimulatory effect of cGMP on gating via the CNBD. The inhibitory effect is abolished by S641 mutation or by impairing cGKII catalytic domain, but preserved when the CNBD is unable to bind cGMP. Co-immunoprecipitation and immunohistochemistry in native mouse brain and heterologous cells; site-directed mutagenesis (S641A); electrophysiology PloS one High 21347269
2012 Ca2+-activated adenylyl cyclase AC1 (but not AC6) physically and functionally interacts with HCN2 in neonatal rat ventricular myocytes; co-expression of AC1 with HCN2 increases intracellular cAMP, shifts HCN2 activation ~10 mV positive, and makes the β-adrenergic response of HCN2 dependent on intracellular Ca2+ (abolished by BAPTA pretreatment). Co-expression of AC6 does not introduce Ca2+ sensitivity. Adenoviral co-expression in neonatal rat ventricular myocytes; patch-clamp electrophysiology; intracellular cAMP measurement; BAPTA chelation experiments Journal of molecular and cellular cardiology Medium 22484253
2017 PKA-dependent phosphorylation of HCN2 in peripheral nociceptive neurons is required for cAMP-mediated inflammatory pain sensitization: selective genetic disruption of either HCN2 or PKA in nociceptors abolished cAMP-induced sensitization and eliminated the cAMP-mediated increase in calcium transients in DRG neurons. PKA activity is required for facilitation of Ih via cAMP (a hallmark of HCN2 function). Cre/loxP conditional knockout of HCN2 or PKA in nociceptors; intradermal 8-Br-cAMP inflammatory pain assay; DRG calcium imaging Pain High 28767511
2011 HCN2 transports ammonium in the distal nephron: HCN2 cDNA is expressed in rat renal collecting duct intercalated cells and is N-glycosylated; in Xenopus oocytes, HCN2 transports K+ > NH4+ >> Na+; in microperfused outer medullary collecting duct, ZD7288 (HCN2 inhibitor) decreases NH4+ transport specifically in intercalated cells under basal conditions. Xenopus oocyte electrophysiology with ion substitution; microperfusion of rat outer medullary collecting duct; Western blot; immunolocalization Kidney international Medium 21796099
2008 Loss-of-function of HCN2 causes absence epilepsy (spike-wave discharges), ataxia, and tremor in mice: the spontaneous apathetic (ap/ap) mutant has a 4-bp insertion in Hcn2 causing ~90% reduction in mRNA and complete absence of truncated HCN2 protein from brain. Characterization of spontaneous mutant mouse; sequencing; Northern/Western blot; EEG recording Neurobiology of disease High 19150498
2007 HCN2 is the primary functional isoform underlying Ih in reticular thalamic nucleus (RTN) neurons: HCN2 knockout abolishes Ih in RTN neurons, eliminates sensitivity to 8-bromo-cAMP and lamotrigine, increases temporal summation of EPSPs, and increases GABAergic output to thalamocortical relay neurons. HCN2 is colocalized with GluR4 in dendritic spines of RTN neurons, and enhanced excitability after Ih block requires ionotropic glutamate receptor activation. HCN2 knockout mice; whole-cell patch clamp in RTN and thalamocortical relay neurons; pharmacological Ih block; immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience High 17687049
2011 A homozygous recessive loss-of-function mutation E515K in the HCN2 C-linker causes a large negative shift in activation and slowed kinetics in homomeric mutant channels but not in heteromeric WT/mutant channels; homomeric mutant HCN2 lowers action potential threshold and strongly increases excitability and firing frequency in neonatal rat cortical neurons after transfection. Mutation screening; heterologous expression and patch clamp in Xenopus oocytes; transfection into acutely isolated neonatal rat cortical neurons with electrophysiology The Journal of neuroscience : the official journal of the Society for Neuroscience High 22131395
2013 Novel HCN2 mutation p.S126L causes temperature-dependent kinetic shift: mutant channels show faster kinetics at higher temperatures (elevated temperature sensitivity) with no change in cAMP responsiveness, leading to increased availability of Ih under hyperthermic conditions that may contribute to febrile seizure susceptibility. Whole-cell patch-clamp electrophysiology at multiple temperatures in heterologous expression; cAMP dose-response analysis PloS one Medium 24324597
2017 HCN2 gain-of-function variants p.S632W and p.V246M cause a depolarizing shift in voltage dependence of activation consistent with increased channel activity; common population variants (p.E280K, p.A705T) and non-segregating variant p.R756C show no biophysical changes, establishing that specific missense variants can confer GGE susceptibility via a gain-of-function mechanism. Two-electrode voltage clamp in Xenopus oocytes; genotyping of 585 GGE patients Human mutation Medium 29064616
2016 Silencing HCN2 decreases secreted Aβ levels by altering APP maturation/processing by β-secretase (not γ-secretase directly): HCN2 knockdown and ZD7288 treatment both reduce sAPP, APP-CTF, and glycosylated APP levels. HCN2 and γ-secretase are found in close proximity by proximity ligation assay and immunoprecipitation; HCN2 was initially identified as a γ-secretase-associated protein by pull-down from rat brain. siRNA knockdown; ZD7288 pharmacological inhibition; Western blot; proximity ligation assay; co-immunoprecipitation; pull-down from rat brain Biochemical and biophysical research communications Medium 28017718
2010 HCN2 acts as a non-channel regulatory protein that modulates L-type calcium channel (LTCC) inactivation: the N-terminus of HCN2 interacts with the IQ motif of the α1C subunit of LTCC, inducing fast inactivation of α1C in the absence of auxiliary subunits. With α2δ, this inactivation is calmodulin-independent; without α2δ, HCN2-induced fast inactivation of α1C requires calmodulin. Heterologous co-expression; patch clamp; HCN2 mutant lacking N-terminus; hippocampal neuron overexpression; domain mapping American journal of physiology. Cell physiology Medium 20164379
2014 Singlet oxygen (1O2) modifies HCN2 channel function in a state-dependent manner: laser-generated 1O2 from fluorescein-conjugated cAMP or a C-terminal HCN2-SOG fusion reduces Ih amplitude (closed-state modification) and slows deactivation/enhances instantaneous current (open-state modification). Histidine H434 in S6 near the activation gate is critical for 1O2-induced slowing of deactivation and Iinst generation; H434A mutation abolishes these effects. Site-directed photodynamic generation of 1O2 using channel-tethered sensitizers; alanine mutagenesis of S6; patch-clamp recording; 1O2 scavenger controls The Journal of general physiology Medium 24733837
2005 Cell swelling activates HCN2 channels: hypoosmotic swelling (facilitated by aquaporin-1) increases HCN2 current by ~30% without altering kinetics; this effect requires an intact F-actin cytoskeleton (abolished by cytochalasin D treatment) and is not due to changes in ionic strength. Co-expression of HCN2 with aquaporin-1 in Xenopus oocytes; two-electrode voltage clamp; hypoosmotic challenge; cytochalasin D treatment; aquaporin-1 control Biophysical journal Medium 15980171
2009 Coupling of an HCN2-expressing non-myocyte (MSC, HEK293, or Cx43-transfected HeLa cell) to a ventricular myocyte via connexin43 gap junctions creates a two-cell pacemaker unit: hyperpolarization of the myocyte drives HCN2 current through the gap junction, and once junctional conductance exceeds a critical threshold, spontaneous action potentials are generated (~0.6–1.7 Hz). Both gap junction blockade (carbenoxolone) and HCN2 blockade (THA) abolish spontaneous activity. Heterologous cell co-culture with cardiac myocytes; dual whole-cell patch clamp; pharmacological blockade of gap junctions and HCN2 The Journal of physiology Medium 19736302
2020 PI3K/Akt signaling regulates HCN2 current: PI3K inhibition causes a negative shift in HCN2 activation voltage and reduces current magnitude in HEK293 cells; the same effects are seen with Akt inhibition and are reversed by PIP3 or active Akt protein. Ser-861 of mouse HCN2 is identified as a putative Akt phosphorylation site: S861A mutation mimics Akt inhibition, and Akt inhibitor has no further effect on S861A mutant. PI3K and Akt inhibitors in HEK293 cells; PIP3 rescue; active Akt protein perfusion; S861A mutagenesis; electrophysiology Frontiers in physiology Medium 33240105
2018 HCN2 channels are required for mechanical (but not heat) hyperalgesia during chronic inflammation: sensory neuron-specific HCN2 knockout reduces tactile hypersensitivity in CFA-chronic pain model but leaves heat hypersensitivity unaffected; additional disruption of central HCN2 (global knockout) also diminishes thermal hyperalgesia, indicating that thermal hyperalgesia involves central HCN2 channels. Chronic inflammation increases HCN2 expression in peripheral and spinal terminals. Conditional (sensory neuron-specific) and inducible global HCN2 knockout mice; CFA chronic inflammation model; behavioral pain tests; single-fiber recordings from skin-nerve preparations; conduction velocity measurements Pain High 24525276
2022 HCN2 channels in trigeminal ganglion neurons are required for migraine-like pain in three rodent models: pharmacological block or targeted genetic deletion of HCN2 abolishes migraine-like pain, suppresses C-FOS expression in the trigeminocervical complex, and inhibits evoked and spontaneous nociceptive TG neuron activity. The NO donor glyceryl trinitrate increases cGMP in TG in vivo and shifts HCN current voltage dependence in isolated TG neurons, directly linking cyclic nucleotide signaling to HCN2-mediated neuronal hyperexcitability. Pharmacological HCN2 block; targeted genetic deletion; in vivo C-FOS expression; in vivo electrophysiology of TG neurons; patch clamp on isolated TG neurons with GTN; cGMP measurement in vivo The Journal of neuroscience : the official journal of the Society for Neuroscience High 36658457
2019 HCN2 channels in NAc shell cholinergic interneurons control tonic firing rate and depressive-like behavior: HCN2 expression and function are decreased in ChIs of depressed mice; overexpression of HCN2 in ChIs enhances cell activity and rescues depressive phenotypes in chronic stress models. Chronic stress mouse models; AAV-mediated HCN2 overexpression in NAc ChIs; electrophysiology; behavioral tests for depression Neuron Medium 30638901
2008 miR-1 and miR-133 repress HCN2 (and HCN4) expression post-transcriptionally; forced expression of miR-1/miR-133 prevents HCN2/HCN4 overexpression in hypertrophic cardiomyocytes. Serum response factor (SRF) negatively regulates miR-1/miR-133 levels, so SRF silencing by RNAi increases miR-1/miR-133 and decreases HCN2/HCN4 protein. miRNA mimic transfection; luciferase reporter for 3'UTR targeting; Western blot of HCN2/HCN4 protein; siRNA knockdown of SRF; cardiac hypertrophy rat model The Journal of biological chemistry High 18458081
2009 Sp1 is a common transcriptional activator of HCN2 (and HCN4) genes: 5'RACE identified transcription start sites; luciferase reporter assays defined core promoter regions; Sp1 knockdown by siRNA prevents HCN2/HCN4 overexpression in hypertrophic cardiomyocytes; Sp1 levels are elevated in hypertrophic hearts. 5'RACE; luciferase reporter assay; siRNA knockdown; Western blot; cardiac hypertrophy rat model Cellular physiology and biochemistry Medium 19471099
2015 Conformational flip intermediate: using fcAMP, ligand binding to non-voltage-activated HCN2 channels triggers an intermediate conformational state (flip) prior to full activation. Kinetic analysis shows modest cooperativity among subunits during the flip, weaker than in voltage-preactivated channels. Patch-clamp fluorometry with fluorescent cAMP analog (fcAMP); global kinetic fitting Biophysical journal Medium 26636938
2018 Activation gating of homotetrameric HCN2 channels involves two separable voltage-dependent steps followed by voltage-independent pore opening. cAMP binding exerts multiple effects: stabilizes the open pore, reduces total gating charge (~8 to ~5), makes an additional closed state accessible, strongly accelerates ON-gating but not OFF-gating, and slows computed OFF-gating current of the open channel. Patch clamp; global fits of hidden Markov models to complex kinetic data; cAMP modulation analysis PLoS computational biology Medium 29565972
2025 HCN2 loss-of-function (p.G460D) causes dominant-negative effects: channels are retained intracellularly and do not reach the membrane; mutant HCN2 also reduces Ih in HCN1-HCN2 heteromers. Multiple other pathogenic HCN2 variants produce either loss-of-function (p.A363V, p.M374L dominant negative; p.L377H, p.P493L, p.G587D electrophysiologically silent with impaired membrane trafficking) or gain-of-function (p.R324H, strong conductance increase); ketogenic diet improvement is not mediated by direct effects on HCN2 activity. Patch clamp in Xenopus oocytes; confocal immunofluorescence for membrane trafficking in HEK cells; structural 3D analysis; neonatal rat cortical neuron transfection; ketogenic medium in vitro experiments Epilepsia / Annals of neurology High 37746765 40468825
2021 HCN2 SUMOylation occurs in DRG neurons and is dynamically regulated during CFA-induced inflammation: proximity ligation assays demonstrate enhanced HCN2 SUMOylation in ipsilateral L6 DRG at days 1 and 3 post-CFA, while bilateral L4/L6 HCN2 expression increases transiently at day 1. Immunohistochemistry; proximity ligation assay for SUMOylation; cryosection of lumbar DRG at multiple time points post-CFA Channels (Austin, Tex.) Low 33423595
2025 HCN2 expression is specifically reduced in hippocampal dCA1 neurons in Alzheimer's disease (hAPP-J20 mice and human AD brain); overexpression of HCN2 in dCA1 rescues HCN activity, attenuates pyramidal neuron hyperexcitability, and improves memory; knockdown of HCN2 in WT mice increases dCA1 excitability and impairs memory. AAV-mediated overexpression and knockdown; patch clamp electrophysiology; immunohistochemistry/Western blot; behavioral memory tests; calcium imaging in vivo; pharmacological HCN modulation Alzheimer's research & therapy Medium 40016780
1999 The human HCN2 gene maps to chromosome 19p13.3 and its functional expression in a human kidney cell line generates a current with properties similar to the native cardiac pacemaker f-channel (If), including hyperpolarization-activated, cAMP-modulated cation conductance. Chromosomal mapping; functional expression in HEK cells; electrophysiology Biochimica et biophysica acta Medium 10524219
2022 HCN2 upregulation in VPL thalamocortical glutamatergic neurons mediates allodynia: downregulation of HCN2 in VPLGlu neurons reduces S1HLGlu neuronal activity (measured by in vivo calcium imaging) and alleviates allodynia in chronic pain mouse models. In vivo calcium imaging; AAV-mediated HCN2 knockdown in VPLGlu neurons; optogenetic circuit manipulation; chronic pain models National science review Medium 36846300

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2000 Functional heteromerization of HCN1 and HCN2 pacemaker channels. The Journal of biological chemistry 175 11133998
1999 HAC-1, a Drosophila homolog of APAF-1 and CED-4 functions in developmental and radiation-induced apoptosis. Molecular cell 173 10619022
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
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
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
2004 Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels. The Journal of general physiology 121 15572346
2004 MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. The Journal of biological chemistry 104 15292247
2010 Interdependence of receptor activation and ligand binding in HCN2 pacemaker channels. Neuron 97 20624593
2006 Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. Journal of neurophysiology 95 16760342
2019 HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors. Neuron 90 30638901
2011 Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 22131395
2000 Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel. The Journal of biological chemistry 71 10962006
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
1999 Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-gated channel (HCN2) mRNA in the rat heart. Circulation research 68 10488052
2008 Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2. Neurobiology of disease 65 19150498
2018 HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. Nature communications 60 29519998
2014 HCN2 channels account for mechanical (but not heat) hyperalgesia during long-standing inflammation. Pain 60 24525276
1999 The human gene coding for HCN2, a pacemaker channel of the heart. Biochimica et biophysica acta 57 10524219
2007 Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy. Neurobiology of disease 53 17931874
2018 Selective Blockade of HCN1/HCN2 Channels as a Potential Pharmacological Strategy Against Pain. Frontiers in pharmacology 52 30467478
2013 HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. Journal of the American College of Cardiology 52 23395072
2007 Dendritic HCN2 channels constrain glutamate-driven excitability in reticular thalamic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 17687049
2003 Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4. The Journal of biological chemistry 48 12813043
2013 Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner. PloS one 47 24324597
2004 Hyperpolarization-activated, cyclic nucleotide-gated HCN2 cation channel forms a protein assembly with multiple neuronal scaffold proteins in distinct modes of protein-protein interaction. Genes to cells : devoted to molecular & cellular mechanisms 44 15265006
2012 Ca(2+)-stimulated adenylyl cyclase AC1 generates efficient biological pacing as single gene therapy and in combination with HCN2. Circulation 42 22753192
2015 Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats. Neuroscience 39 25813712
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
2020 HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair. Frontiers in cellular neuroscience 36 32528251
2015 The bZIP Transcription Factor HAC-1 Is Involved in the Unfolded Protein Response and Is Necessary for Growth on Cellulose in Neurospora crassa. PloS one 31 26132395
2009 Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit. The Journal of physiology 30 19736302
2018 HCN2 contributes to oxaliplatin-induced neuropathic pain through activation of the CaMKII/CREB cascade in spinal neurons. Molecular pain 28 29806529
2017 Gain-of-function HCN2 variants in genetic epilepsy. Human mutation 27 29064616
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
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
2003 Proteomic characterization of the human cortical neuronal cell line HCN-2. Journal of chemical neuroanatomy 25 14615026
2016 Baclofen ameliorates spatial working memory impairments induced by chronic cerebral hypoperfusion via up-regulation of HCN2 expression in the PFC in rats. Behavioural brain research 24 27085590
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
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
2017 Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons. Pain 23 28767511
2011 The hyperpolarization-activated cyclic nucleotide-gated HCN2 channel transports ammonium in the distal nephron. Kidney international 21 21796099
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 21 19471099
2009 Proteolytic processing of HCN2 and co-assembly with HCN4 in the generation of cardiac pacemaker channels. The Journal of biological chemistry 21 19574228
2009 Niflumic acid alters gating of HCN2 pacemaker channels by interaction with the outer region of S4 voltage sensing domains. Molecular pharmacology 20 19218366
2023 Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model. The journal of headache and pain 19 37085778
2020 Blockade of HCN2 Channels Provides Neuroprotection Against Ischemic Injury via Accelerating Autophagic Degradation in Hippocampal Neurons. Neuroscience bulletin 19 32519067
2012 Ca2+-activated adenylyl cyclase 1 introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2 current. Journal of molecular and cellular cardiology 18 22484253
2022 HCN2 channel-induced rescue of brain, eye, heart and gut teratogenesis caused by nicotine, ethanol and aberrant notch signalling. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 17 35662339
2015 Conformational Flip of Nonactivated HCN2 Channel Subunits Evoked by Cyclic Nucleotides. Biophysical journal 17 26636938
2006 cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations. Biophysical journal 17 16500960
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 PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders. Cell & bioscience 16 36104739
2018 Activation gating in HCN2 channels. PLoS computational biology 16 29565972
2012 Inner activation gate in S6 contributes to the state-dependent binding of cAMP in full-length HCN2 channel. The Journal of general physiology 16 22689828
2022 Up-regulation of HCN2 channels in a thalamocortical circuit mediates allodynia in mice. National science review 15 36846300
2021 Transcriptomic Analysis of HCN-2 Cells Suggests Connection among Oxidative Stress, Senescence, and Neuron Death after SARS-CoV-2 Infection. Cells 15 34571838
2016 Relevance of HCN2-expressing human mesenchymal stem cells for the generation of biological pacemakers. Stem cell research & therapy 15 27137910
2005 Hypoosmotic cell swelling as a novel mechanism for modulation of cloned HCN2 channels. Biophysical journal 15 15980171
2012 Unraveling subunit cooperativity in homotetrameric HCN2 channels. Biophysical journal 14 23199914
2006 Evaluation of HCN2 abnormalities as a cause of juvenile audiogenic seizures in Black Swiss mice. Brain research 14 16542642
2021 Changes in peripheral HCN2 channels during persistent inflammation. Channels (Austin, Tex.) 12 33423595
2015 Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats. Pharmacology, biochemistry, and behavior 12 26549214
2007 Mesenchymal stem cells transfected with HCN2 genes by LentiV can be modified to be cardiac pacemaker cells. Medical hypotheses 12 17449188
2020 HCN2 and TBX3 Reprogram Human-Induced Pluripotent Stem Cells-Derived Cardiomyocytes into Pacemaker-Like Cells. DNA and cell biology 11 31916853
2018 Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. PloS one 10 29466436
2016 Maturation and processing of the amyloid precursor protein is regulated by the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2). Biochemical and biophysical research communications 10 28017718
2015 Decreased HCN2 expression in STN contributes to abnormal high-voltage spindles in the cortex and globus pallidus of freely moving rats. Brain research 10 25998542
2011 The cGMP-dependent protein kinase II Is an inhibitory modulator of the hyperpolarization-activated HCN2 channel. PloS one 10 21347269
2021 Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy. BMC cardiovascular disorders 9 33653265
2019 Protein and surface expression of HCN2 and HCN4 subunits in mesocorticolimbic areas after cocaine sensitization. Neurochemistry international 9 30794847
2019 Decreased HCN2 channel expression attenuates neuropathic pain by inhibiting pro-inflammatory reactions and NF-κB activation in mice. International journal of clinical and experimental pathology 9 31933729
2014 State-dependent and site-directed photodynamic transformation of HCN2 channel by singlet oxygen. The Journal of general physiology 9 24733837
2024 Upregulation of HCN2 in ventral tegmental area is involved in morphine-induced conditioned place preference in rats. FEBS open bio 8 39267158
2022 HCN2 Ion Channels Drive Pain in Rodent Models of Migraine. The Journal of neuroscience : the official journal of the Society for Neuroscience 8 36658457
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
2005 Functional significance of HCN2/3-mediated I(h) in striatal cells at early developmental stages. Journal of neuroscience research 8 16175581
2002 Nicotinamide protects HCN2 cells from the free radical generating toxin, tertiary butylhydroperoxide (t-BuOOH). Neurotoxicity research 8 12709297
2023 A novel de novo HCN2 loss-of-function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet. Epilepsia 7 37746765
2022 Thyroid-stimulating hormone regulates cardiac function through modulating HCN2 via targeting microRNA-1a. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 36125044
2021 Inhibition of the pesticide rotenone-induced Ca2+ signaling, cytotoxicity and oxidative stress in HCN-2 neuronal cells by the phenolic compound hydroxytyrosol. Pesticide biochemistry and physiology 7 34802529
2013 Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? Experimental & translational stroke medicine 7 24373160
2025 HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease. Alzheimer's research & therapy 6 40016780
2021 Toward Biological Pacing by Cellular Delivery of Hcn2/SkM1. Frontiers in physiology 6 33488393
2020 Heightened reward response is associated with HCN2 overexpression in the ventral tegmental area in morphine-sensitized rats. Behavioural pharmacology 6 32040017
2020 HCN2 contributes to oxaliplatin-induced neuropathic pain by inducing spinal long-term potentiation via activation of NMDA receptor-mediated CaMKII signaling. Brain research bulletin 6 32165274
2010 Inactivation of L-type calcium channel modulated by HCN2 channel. American journal of physiology. Cell physiology 6 20164379
2025 HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models. Annals of neurology 5 40468825
2024 Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice. CNS neuroscience & therapeutics 5 38353058
2020 Regulation of HCN2 Current by PI3K/Akt Signaling. Frontiers in physiology 5 33240105
2017 The Proinflammatory Cytokine GITRL Contributes to TRAIL-mediated Neurotoxicity in the HCN-2 Human Neuronal Cell Line. Current Alzheimer research 5 28524007
2008 Age-dependent differences in the inhibition of HCN2 current in rat ventricular myocytes by the tyrosine kinase inhibitor erbstatin. Pflugers Archiv : European journal of physiology 5 18696104
2023 HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice. International journal of molecular sciences 4 37762124
2022 Gene knockdown of HCN2 ion channels in the ventral tegmental area reduces ethanol consumption in alcohol preferring rats. The American journal of drug and alcohol abuse 4 35377277
2021 Promotion of Differentiating Bone Marrow Mesenchymal Stromal Cells (BMSCs) into Cardiomyocytes via HCN2 and HCN4 Cotransfection. BioMed research international 4 34095298
2021 Loss of HCN2 in Dorsal Hippocampus of Young Adult Mice Induces Specific Apoptosis of the CA1 Pyramidal Neuron Layer. International journal of molecular sciences 4 34206649
2019 Overexpression of the medium‑conductance calcium‑activated potassium channel (SK4) and the HCN2 channel to generate a biological pacemaker. Molecular medicine reports 4 31432175
2019 Effects of HCN2 Mutations on Dendritic Excitability and Synaptic Plasticity: A Computational Study. Neuroscience 4 31682955
2013 Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) polymorphism is associated with chronic inflammatory periodontitis. A cross-sectional study. Journal of basic and clinical physiology and pharmacology 4 23907424

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