HCN2 Gene

HGNC Family	Ion channels
Name	hyperpolarization activated cyclic nucleotide gated potassium channel 2
Description	The protein encoded by this gene is a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and in the brain. The encoded protein is activated by cAMP and can produce a fast, large current. Defects in this gene were noted as a possible cause of some forms of epilepsy. [provided by RefSeq, Jan 2017]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hyperpolarization‐activated cyclic nucleotide–gated channel 2 (HCN2) is a key mediator of the depolarizing “pacemaker” current that underlies rhythmic activity in a variety of excitable tissues, including the heart and central as well as peripheral neurons. HCN2 channels are activated upon hyperpolarization and their voltage‐dependent gating is finely tuned by intracellular messengers such as cyclic AMP and cyclic GMP. For instance, phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P₂) and direct cAMP binding shift HCN2 activation curves toward more depolarized potentials, while cGMP‐dependent protein kinase II phosphorylation can counteract this effect by shifting activation to more negative potentials."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " In addition to mediating a mixed sodium/potassium current, HCN2 channels also permit calcium influx, thus broadening their role in intracellular signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Dysregulation or genetic variants of HCN2 have been implicated in neurological disorders such as epilepsy, where alterations in the slope of the conductance–voltage relationship may contribute to epileptogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and in cardiac conditions including atrial fibrillation and ventricular hypertrophy, where aberrant HCN2 expression can disturb repolarization reserve."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In sensory systems, HCN2 is differentially expressed—such as in retinal bipolar cells, where it contributes to dim light responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and in dorsal root ganglion neurons, influencing neuronal excitability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Accessory proteins like TRIP8b interact with the C-terminal domain of HCN2 to regulate its trafficking and surface expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Moreover, targeted applications of HCN2—such as its gene transfer into mesenchymal stem cells to generate functional pacemaker currents—highlight its therapeutic potential in managing arrhythmias"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", while inhibition of HCN2 in other pathological settings, including breast cancer, suggests broader clinical implications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Collectively, these studies underscore the multifaceted role of HCN2 in modulating membrane excitability and rhythmogenesis as well as its emerging relevance as a target for therapeutic intervention in both cardiac and neurological disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Phillip Pian, Annalisa Bucchi, Richard B Robinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gen Physiol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1085/jgp.200609648"}], "href": "https://doi.org/10.1085/jgp.200609648"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17074978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17074978"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Verena Hammelmann, Xiangang Zong, Franz Hofmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cGMP-dependent protein kinase II Is an inhibitory modulator of the hyperpolarization-activated HCN2 channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0017078"}], "href": "https://doi.org/10.1371/journal.pone.0017078"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21347269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21347269"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Claudia P Alvarez-Baron, Vadim A Klenchin, Baron Chanda "}, {"type": "b", "children": [{"type": "t", "text": "Minimal molecular determinants of isoform-specific differences in efficacy in the HCN channel family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gen Physiol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1085/jgp.201812031"}], "href": "https://doi.org/10.1085/jgp.201812031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29980633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29980633"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "A Moroni, A Barbuti, C Altomare, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic and ionic properties of the human HCN2 pacemaker channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pflugers Arch (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s004249900225"}], "href": "https://doi.org/10.1007/s004249900225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10764222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10764222"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "T Vaccari, A Moroni, M Rocchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human gene coding for HCN2, a pacemaker channel of the heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0167-4781(99)00092-5"}], "href": "https://doi.org/10.1016/s0167-4781(99"}, {"type": "t", "text": "00092-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10524219"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10524219"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Guido Michels, Mathias C Brandt, Naufal Zagidullin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvn032"}], "href": "https://doi.org/10.1093/cvr/cvn032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18252758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18252758"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Bin Tang, Thomas Sander, Kimberley B Craven, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Dis (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nbd.2007.08.006"}], "href": "https://doi.org/10.1016/j.nbd.2007.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17931874"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17931874"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yao-Dong Li, Yi-Fan Hong, Yueerguli Yusufuaji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2015.3831"}], "href": "https://doi.org/10.3892/mmr.2015.3831"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26005035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26005035"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Florian Hofmann, Larissa Fabritz, Juliane Stieber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvs184"}], "href": "https://doi.org/10.1093/cvr/cvs184"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22652004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22652004"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Luca Della Santina, Ilaria Piano, Lorenzo Cangiano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Processing of retinal signals in normal and HCN deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0029812"}], "href": "https://doi.org/10.1371/journal.pone.0029812"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22279546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22279546"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Huiyin Tu, Lunbin Deng, Qian Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.20109"}], "href": "https://doi.org/10.1002/jnr.20109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15139030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15139030"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "John R Bankston, Stacey S Camp, Frank DiMaio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1201997109"}], "href": "https://doi.org/10.1073/pnas.1201997109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22550182"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22550182"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Hong-xia Li, Xiang-jun Yang, Xin Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Pacemaker current gene expression of rat mesenchymal stem cells and identification of mesenchymal stem cells expressing human pacemaker current gene (hHCN2)]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Xin Xue Guan Bing Za Zhi (2006)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17217722"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17217722"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ka-Chun Mok, Ho Tsoi, Ellen Ps Man, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Transl Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ctm2.578"}], "href": "https://doi.org/10.1002/ctm2.578"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34841695"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34841695"}]}]}]}
Synonyms	BCNG2, BCNG-2, HAC-1
Proteins	HCN2_HUMAN
NCBI Gene ID	610
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HCN2 has 5,288 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 116 datasets.

Click the + buttons to view associations for HCN2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HCN2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HCN2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of HCN2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of HCN2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of HCN2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of HCN2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HCN2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of HCN2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HCN2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HCN2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of HCN2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HCN2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of HCN2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HCN2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HCN2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HCN2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of HCN2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with HCN2 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of HCN2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HCN2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HCN2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HCN2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with HCN2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HCN2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HCN2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HCN2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by HCN2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving HCN2 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HCN2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with HCN2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with HCN2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HCN2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for HCN2 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at HCN2 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HCN2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HCN2 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing HCN2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with HCN2 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with HCN2 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of HCN2 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with HCN2 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.