Details for: HCN2

Gene ID: 610

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HCN2

Ensembl ID: ENSG00000099822

Description: hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • cerebral cortex neuron CL0010012
    CSI 3.94
    rCSI 16.06%
    PRS 75.59
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 3.04
    rCSI 5.37%
    PRS 66.24
  • inhibitory interneuron CL0000498
    CSI 1.99
    rCSI 4.6%
    PRS 72.13
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 1.92
    rCSI 2.39%
    PRS 64.6
  • rod bipolar cell CL0000751
    CSI 1.9
    rCSI 3.41%
    PRS 77.31
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 1.69
    rCSI 6.09%
    PRS 64.62
  • retinal ganglion cell CL0000740
    CSI 1.51
    rCSI 3.35%
    PRS 70.2
  • retinal bipolar neuron CL0000748
    CSI 1.29
    rCSI 2.41%
    PRS 72.7
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.17
    rCSI 4.41%
    PRS 67.21
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.05
    rCSI 2.55%
    PRS 64.6
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.48
    rCSI 2.82%
    PRS 67.22

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HCN2](/details-gene/610) (hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2) is a protein-coding gene located on chromosome 19p13.3. It encodes a crucial ion channel that functions as a voltage-gated cation channel, permeable to both potassium and sodium ions. The channel's activity is uniquely modulated by hyperpolarization of the plasma membrane and by the binding of intracellular cyclic nucleotides, particularly cAMP ([GO:0030552](https://www.ebi.ac.uk/QuickGO/term/GO:0030552)). Its expression profile indicates a highly specialized role within the nervous system, with its highest significance observed in various neuronal populations, including [cerebral cortex neuron](/details-cell/CL0010012) and multiple types of interneurons. Functionally, [HCN2](/details-gene/610) is a key component of the "pacemaker" current (Ih), which is critical for regulating neuronal excitability, rhythmicity, and membrane potential. Mutations in [HCN2](/details-gene/610) have been clinically associated with forms of genetic epilepsy ([602477](https://omim.org/entry/602477), [602781](https://omim.org/entry/602781)). ## Cellular Roles and Expression Landscape The expression pattern of [HCN2](/details-gene/610) firmly establishes it as a gene with a central role in the central nervous system. **Overall**, the gene shows the highest significance in a diverse array of neuronal subtypes. It is a particularly strong marker for [cerebral cortex neuron](/details-cell/CL0010012) (CSI: 3.94), highlighting its importance in cortical function. The gene's significance is also pronounced in specific interneuron populations, such as [caudal ganglionic eminence derived cortical interneuron](/details-cell/CL4023064) (CSI: 3.04), general [inhibitory interneuron](/details-cell/CL0000498) (CSI: 1.99), and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 1.92), suggesting a key role in regulating inhibitory circuits within the cortex. Beyond the cortex, [HCN2](/details-gene/610) is also a significant marker in retinal neurons, including [rod bipolar cell](/details-cell/CL0000751) (CSI: 1.90), [retinal ganglion cell](/details-cell/CL0000740) (CSI: 1.51), and [retinal bipolar neuron](/details-cell/CL0000748) (CSI: 1.29). This pattern suggests that [HCN2](/details-gene/610)-mediated pacemaker currents are fundamental not only to cortical processing but also to the initial stages of visual signal transduction and processing in the retina. Its consistent high significance across both excitatory (e.g., [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041)) and inhibitory neurons underscores its fundamental role in maintaining neuronal homeostasis and excitability across the nervous system. ## Pathways and Molecular Function The molecular functions and biological pathways associated with [HCN2](/details-gene/610) are consistent with its role as a neuronal pacemaker channel. Its primary molecular function is described as `Intracellularly camp-activated cation channel activity` ([GO:0005222](https://www.ebi.ac.uk/QuickGO/term/GO:0005222)), `Voltage-gated potassium channel activity` ([GO:0005249](https://www.ebi.ac.uk/QuickGO/term/GO:0005249)), and `Voltage-gated sodium channel activity` ([GO:0005248](https://www.ebi.ac.uk/QuickGO/term/GO:0005248)). This dual ion permeability is a hallmark of HCN channels. The gene product is a core component of the `Hcn channel complex` ([GO:0098855](https://www.ebi.ac.uk/QuickGO/term/GO:0098855)), which is localized to the `Plasma membrane` ([GO:0005886](https://www.ebi.ac.uk/QuickGO/term/GO:0005886)) of neuronal compartments like the `Axon` ([GO:0030424](https://www.ebi.ac.uk/QuickGO/term/GO:0030424)) and `Dendrite` ([GO:0030425](https://www.ebi.ac.uk/QuickGO/term/GO:0030425)). At the process level, [HCN2](/details-gene/610) is integral to the `Regulation of membrane potential` ([GO:0042391](https://www.ebi.ac.uk/QuickGO/term/GO:0042391)) and is involved in both `Potassium ion transmembrane transport` ([GO:0071805](https://www.ebi.ac.uk/QuickGO/term/GO:0071805)) and `Sodium ion transmembrane transport` ([GO:0035725](https://www.ebi.ac.uk/QuickGO/term/GO:0035725)). Its function is tightly linked to `Cellular response to camp` ([GO:0071320](https://www.ebi.ac.uk/QuickGO/term/GO:0071320)), which modulates channel gating. These functions are contextualized within the broader `Neuronal system` ([R-HSA-112316](https://reactome.org/content/detail/R-HSA-112316)) and are a specific instance of `Potassium channels` ([R-HSA-1296071](https://reactome.org/content/detail/R-HSA-1296071)) as annotated by Reactome. Several studies have confirmed its pacemaker function in both the brain and heart ([Link](https://doi.org/10.1016/s0092-8674(00)81434-8), [Link](https://doi.org/10.1016/s0167-4781(99)00092-5)). ## Research Directions The association of [HCN2](/details-gene/610) with neurological disorders, particularly epilepsy, presents a clear path for future investigation. Published research demonstrates that both loss-of-function and gain-of-function mutations can lead to different forms of epilepsy by disrupting neuronal excitability ([Link](https://doi.org/10.1523/jneurosci.3727-11.2011), [Link](https://doi.org/10.1002/humu.23357)). This suggests that the precise level of [HCN2](/details-gene/610) activity is critical for maintaining the delicate balance of excitation and inhibition in cortical circuits. Understanding how specific mutations alter channel kinetics and how these changes manifest in the context of different neuronal subtypes remains a key challenge. Based on the available data, several testable hypotheses can be proposed: 1. Dysregulation of [HCN2](/details-gene/610) expression or function specifically within [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) populations is a key mechanism for cortical circuit disinhibition, directly contributing to the pathogenesis of certain genetic epilepsies. 2. The high significance of [HCN2](/details-gene/610) in retinal cells like [rod bipolar cell](/details-cell/CL0000751) implies a critical role in temporal filtering of visual signals; therefore, variants in [HCN2](/details-gene/610) may be associated with subtle visual processing deficits that have not yet been clinically characterized. To test the first hypothesis, a specific experimental approach could be employed. A conditional knockout mouse model could be generated (e.g., *Pvalb-Cre;Hcn2-flox/flox*) to selectively delete [HCN2](/details-gene/610) in parvalbumin-positive interneurons. *Ex vivo* brain slice electrophysiology could then be used to measure changes in the intrinsic properties of these interneurons and the resulting inhibitory postsynaptic currents onto pyramidal neurons. Concurrently, *in vivo* electroencephalography (EEG) could be performed to assess the susceptibility of these mice to pharmacologically-induced seizures, directly linking the cell-specific gene deletion to a network-level epilepsy phenotype. From a therapeutic perspective, [HCN2](/details-gene/610) is a promising, albeit challenging, drug target. As an ion channel, it is amenable to small molecule modulation. For epilepsies caused by gain-of-function mutations, a strategy involving specific channel inhibitors or negative allosteric modulators would be appropriate. Conversely, for loss-of-function variants, channel activators or potentiators would be required. The primary challenge is the widespread expression of [HCN2](/details-gene/610) throughout the CNS and in the heart, which raises the potential for significant off-target effects. Therefore, the development of subtype-specific or mutation-specific modulators, or novel targeted delivery systems, will be critical for realizing its therapeutic potential.

Genular Protein ID: 1933186398

Symbol: HCN2_HUMAN

Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2

UniProtKB Accession Codes:

Q9UL51 O60742 O60743 O75267 Q9UBS2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 11 ChEMBL 1 ChiTaRS 1 ComplexPortal 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 3 DrugCentral 1 EMBL 13 Ensembl 1 EvolutionaryTrace 1 GO 21 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 4 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 3 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10524219

Title: The human gene coding for HCN2, a pacemaker channel of the heart.

PubMed ID: 10524219

DOI: 10.1016/s0167-4781(99)00092-5

PubMed ID: 10228147

Title: Two pacemaker channels from human heart with profoundly different activation kinetics.

PubMed ID: 10228147

DOI: 10.1093/emboj/18.9.2323

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 9630217

Title: Identification of a gene encoding a hyperpolarization-activated 'pacemaker' channel of brain.

PubMed ID: 9630217

DOI: 10.1016/s0092-8674(00)81434-8

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 22006928

Title: Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.

PubMed ID: 22006928

DOI: 10.1074/jbc.m111.297606

PubMed ID: 25197093

Title: Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.

PubMed ID: 25197093

DOI: 10.1073/pnas.1410389111

PubMed ID: 26546007

Title: The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contain multiple S-palmitoylation sites.

PubMed ID: 26546007

DOI: 10.1007/s12576-015-0420-5

PubMed ID: 22131395

Title: Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy.

PubMed ID: 22131395

DOI: 10.1523/jneurosci.3727-11.2011

PubMed ID: 24324597

Title: Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner.

PubMed ID: 24324597

DOI: 10.1371/journal.pone.0080376

PubMed ID: 29064616

Title: Gain-of-function HCN2 variants in genetic epilepsy.

PubMed ID: 29064616

DOI: 10.1002/humu.23357

PubMed ID: 29463886

Title: A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development.

PubMed ID: 29463886

DOI: 10.1038/s41380-018-0020-x

Sequence Information:

  • Length: 889
  • Mass: 96950
  • Checksum: 4B263E0C06C2A47D
  • Sequence:
    • MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA PPQHPPRAEA 
LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG ECGRGEPQCS PAGPEGPARG 
PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL 
RMFGSQKAVE REQERVKSAG AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET 
TAPWIVFNVV SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP 
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW EEIFHMTYDL 
ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV SINGMVNHSW SELYSFALFK 
AMSHMLCIGY GRQAPESMTD IWLTMLSMIV GATCYAMFIG HATALIQSLD SSRRQYQEKY 
KQVEQYMSFH KLPADFRQKI HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA 
SMPLFANADP NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK 
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR AFETVAIDRL 
DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE MVQQAELGQR VGLFPPPPPP 
PQVTSAIATL QQAAAMSFCP QVARPLVGPL ALGSPRLVRR PPPGPAPAAA SPGPPPPASP 
PGAPASPRAP RTSPYGGLPA APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP 
ASSSTPRLGP TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL