O70507 · HCN4_MOUSE

  • Protein
    Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
  • Gene
    Hcn4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Hyperpolarization-activated ion channel that are permeable to Na+ and K+ ions with very slow activation and inactivation. Exhibits higher selectivity for K+ over Na+ ions (By similarity).
Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat (PubMed:14657344, PubMed:21220308).
Contributes to the native pacemaker currents in neurons (Ih) (By similarity).
May mediate responses to sour stimuli (PubMed:11675786).

Catalytic activity

Activity regulation

Activated by cAMP, and to a lesser extent by cGMP and cCMP (PubMed:22715094).
cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Binding of cAMP removes a tonic inhibition conferred by cyclic nucleotide-binding domain (CNBD) on channel opening. Cyclic dinucleotides can modulate HCN4 channel; cyclic dinucleotides acting as potent antagonists of cAMP. Inhibited by extracellular Cs+ ions (By similarity).
Auxiliary subunits can also regulate HCN4 channel. IRAG1 causes a gain-of-function by shifting HCN4 activation to more depolarized membrane potentials in the absence of cAMP. In contrast, IRAG2 causes a loss-of-function by inhibiting cAMP-dependent potentiation of HCN4 activation (PubMed:32647060).

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site5593',5'-cyclic GMP (UniProtKB | ChEBI)
Binding site5623',5'-cyclic GMP (UniProtKB | ChEBI)
Binding site5643',5'-cyclic GMP (UniProtKB | ChEBI)
Binding site5663',5'-cyclic GMP (UniProtKB | ChEBI)
Binding site6593',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site6603',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site6623',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site6693',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site6703',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site6733',5'-cyclic AMP (UniProtKB | ChEBI)
Binding site7103',5'-cyclic AMP (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentaxon
Cellular Componentbasolateral plasma membrane
Cellular Componentdendrite
Cellular ComponentHCN channel complex
Cellular Componentneuronal cell body
Cellular Componentplasma membrane
Cellular Componentterminal bouton
Molecular FunctioncAMP binding
Molecular Functionintracellularly cAMP-activated cation channel activity
Molecular Functionsodium channel activity
Molecular Functionvoltage-gated potassium channel activity
Biological Processcellular response to cAMP
Biological Processin utero embryonic development
Biological Processmonoatomic cation transport
Biological Processpotassium ion transmembrane transport
Biological Processregulation of heart contraction
Biological Processregulation of heart rate
Biological Processregulation of membrane depolarization
Biological Processsodium ion transmembrane transport

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
  • Alternative names
    • Brain cyclic nucleotide-gated channel 3 (BCNG-3)

Gene names

    • Name
      Hcn4
    • Synonyms
      Bcng3

Organism names

  • Taxonomic identifier
  • Strain
    • C57BL/6J
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    O70507
  • Secondary accessions
    • B2RY58

Proteomes

Organism-specific databases

Subcellular Location

Features

Showing features for topological domain, transmembrane, intramembrane.

TypeIDPosition(s)Description
Topological domain1-263Cytoplasmic
Transmembrane264-286Helical; Name=Segment S1
Topological domain287-293Extracellular
Transmembrane294-314Helical; Name=Segment S2
Topological domain315-336Cytoplasmic
Transmembrane337-359Helical; Name=Segment S3
Topological domain360-378Extracellular
Transmembrane379-399Helical; Voltage-sensor; Name=Segment S4
Topological domain400-413Cytoplasmic
Transmembrane414-436Helical; Name=Segment S5
Topological domain437-464Extracellular
Intramembrane465-486Pore-forming; Name=Segment H5
Topological domain487-491Extracellular
Transmembrane492-517Helical; Name=Segment S6
Topological domain518-1201Cytoplasmic

Keywords

Phenotypes & Variants

Disruption phenotype

Hcn4-deficient mice are embryonically lethal, dying between embryonic days 9.5 and 11.5 due to a failure to generate mature pacemaking cells (PubMed:14657344).
Conditional deletion in the adult heart results in cardiac arrhythmia with recurrent sinus pauses, bradycardia, and atrioventricular bloc (PubMed:21220308).

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 29 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Chemistry

PTM/Processing

Features

Showing features for chain, modified residue, glycosylation.

TypeIDPosition(s)Description
ChainPRO_00000541181-1201Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Modified residue139Phosphoserine
Glycosylation458N-linked (GlcNAc...) asparagine
Modified residue1105Phosphoserine
Modified residue1108Phosphoserine

Post-translational modification

S-palmitoylated.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Detected in a subset of elongated cells in taste buds.

Gene expression databases

Interaction

Subunit

Homotetramer (By similarity).
The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits (By similarity).
Interacts with PEX5L with a 4:4 HCN4:PEX5L stoichiometry; reduces the effects of cAMP on the voltage-dependence and rate of activation (By similarity).
Interacts with IRAG1; regulates HCN4 channel activity (PubMed:32647060).
Interacts with IRAG2; regulates HCN4 channel activity (PubMed:32647060).

Protein-protein interaction databases

Chemistry

Miscellaneous

Structure

Family & Domains

Features

Showing features for region, compositional bias.

TypeIDPosition(s)Description
Region25-121Disordered
Compositional bias81-95Polar residues
Region135-183Disordered
Compositional bias160-175Pro residues
Region209-260Involved in subunit assembly
Region789-887Disordered
Compositional bias819-847Polar residues
Compositional bias860-876Pro residues
Region899-1186Disordered
Compositional bias902-920Polar residues
Compositional bias1012-1026Pro residues
Compositional bias1040-1055Pro residues
Compositional bias1067-1097Polar residues

Domain

Contains six transmembrane segments (S1-S6) and an intervening P-loop. The segment S4 is the voltage-sensor and is characterized by a series of positively charged amino acids at every third position, while the S5-S6 segments together with the P-loop form a centrally located pore of the channel. Contains a cyclic nucleotide-binding domain (CNBD) in their C-terminal region. The CNBD is connected to the pore forming transmembrane segment via the C-linker.
Contains a unique pocket located in the cytosolic C-terminal domain, identified as a likely binding site for di-cyclic nucleotides.

Sequence similarities

Belongs to the potassium channel HCN family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    1,201
  • Mass (Da)
    129,065
  • Last updated
    2024-10-02 v3
  • Checksum
    7D04EBDE4D258517
MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDGEEEGAGGRQDPSRRSIRLRPLPSPSPSVAAGCSESRGAALGATESEGPGRSAGKSSTNGDCRRFRGSLASLGSRGGGSGGAGGGSSLGHLHDSAEERRLIAAEGDASPGEDRTPPGLATEPERPATAAQPAASPPPQQPPQPASASCEQPSADTAIKVEGGAAASDQILPEAEVRLGQSGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNVVSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFVVDFISSIPVDYIFLIVETRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVNLIGMMLLLCHWDGCLQFLVPMLQDFPHDCWVSINGMVNNSWGKQYSYALFKAMSHMLCIGYGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSFHKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANADPNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSILLHKVQHDLNSGVFNYQENEIIQQIVRHDREMAHCAHRVQAAASATPTPTPVIWTPLIQAPLQAAAATTSVAIALTHHPRLPAAIFRPPPGPGLGNLGAGQTPRHPRRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPPGLSPLLPSSSSSPPPGACGSPPAPTPSTSTAAAASTTGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPPPPLPGARGGLGLLEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLAAGPSSTPETPPRPERPSFMAGASGGASPVAFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESVAAFSLYPRAGGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARAASSGGPPLTTAAPQREPGARSEPVRSKLPSNL

Features

Showing features for compositional bias, sequence conflict.

TypeIDPosition(s)Description
Compositional bias81-95Polar residues
Compositional bias160-175Pro residues
Sequence conflict197-199in Ref. 2; AAC40126
Sequence conflict353in Ref. 2; AAC40126
Sequence conflict374in Ref. 2; AAC40126
Sequence conflict651in Ref. 2; AAC40126
Compositional bias819-847Polar residues
Compositional bias860-876Pro residues
Compositional bias902-920Polar residues
Compositional bias1012-1026Pro residues
Compositional bias1040-1055Pro residues
Compositional bias1067-1097Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AC110530
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
AF064874
EMBL· GenBank· DDBJ
AAC40126.1
EMBL· GenBank· DDBJ
mRNA
BC158106
EMBL· GenBank· DDBJ
AAI58107.1
EMBL· GenBank· DDBJ
mRNA
BC158108
EMBL· GenBank· DDBJ
AAI58109.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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