O70507 · HCN4_MOUSE
- ProteinPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
- GeneHcn4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1201 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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).
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
- K+(in) = K+(out)
- Na+(in) = Na+(out)
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).
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 559 | 3',5'-cyclic GMP (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 562 | 3',5'-cyclic GMP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 564 | 3',5'-cyclic GMP (UniProtKB | ChEBI) | ||||
Sequence: F | ||||||
Binding site | 566 | 3',5'-cyclic GMP (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 659 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 660 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 662 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 669 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: R | ||||||
Binding site | 670 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 673 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 710 | 3',5'-cyclic AMP (UniProtKB | ChEBI) | ||||
Sequence: R |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | axon | |
Cellular Component | basolateral plasma membrane | |
Cellular Component | dendrite | |
Cellular Component | HCN channel complex | |
Cellular Component | neuronal cell body | |
Cellular Component | plasma membrane | |
Cellular Component | terminal bouton | |
Molecular Function | cAMP binding | |
Molecular Function | intracellularly cAMP-activated cation channel activity | |
Molecular Function | sodium channel activity | |
Molecular Function | voltage-gated potassium channel activity | |
Biological Process | cellular response to cAMP | |
Biological Process | in utero embryonic development | |
Biological Process | monoatomic cation transport | |
Biological Process | potassium ion transmembrane transport | |
Biological Process | regulation of heart contraction | |
Biological Process | regulation of heart rate | |
Biological Process | regulation of membrane depolarization | |
Biological Process | sodium ion transmembrane transport |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended namePotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
- Alternative names
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionO70507
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane, intramembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-263 | Cytoplasmic | ||||
Sequence: MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDGEEEGAGGRQDPSRRSIRLRPLPSPSPSVAAGCSESRGAALGATESEGPGRSAGKSSTNGDCRRFRGSLASLGSRGGGSGGAGGGSSLGHLHDSAEERRLIAAEGDASPGEDRTPPGLATEPERPATAAQPAASPPPQQPPQPASASCEQPSADTAIKVEGGAAASDQILPEAEVRLGQSGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSDFRF | ||||||
Transmembrane | 264-286 | Helical; Name=Segment S1 | ||||
Sequence: YWDLTMLLLMVGNLIIIPVGITF | ||||||
Topological domain | 287-293 | Extracellular | ||||
Sequence: FKDENTT | ||||||
Transmembrane | 294-314 | Helical; Name=Segment S2 | ||||
Sequence: PWIVFNVVSDTFFLIDLVLNF | ||||||
Topological domain | 315-336 | Cytoplasmic | ||||
Sequence: RTGIVVEDNTEIILDPQRIKMK | ||||||
Transmembrane | 337-359 | Helical; Name=Segment S3 | ||||
Sequence: YLKSWFVVDFISSIPVDYIFLIV | ||||||
Topological domain | 360-378 | Extracellular | ||||
Sequence: ETRIDSEVYKTARALRIVR | ||||||
Transmembrane | 379-399 | Helical; Voltage-sensor; Name=Segment S4 | ||||
Sequence: FTKILSLLRLLRLSRLIRYIH | ||||||
Topological domain | 400-413 | Cytoplasmic | ||||
Sequence: QWEEIFHMTYDLAS | ||||||
Transmembrane | 414-436 | Helical; Name=Segment S5 | ||||
Sequence: AVVRIVNLIGMMLLLCHWDGCLQ | ||||||
Topological domain | 437-464 | Extracellular | ||||
Sequence: FLVPMLQDFPHDCWVSINGMVNNSWGKQ | ||||||
Intramembrane | 465-486 | Pore-forming; Name=Segment H5 | ||||
Sequence: YSYALFKAMSHMLCIGYGRQAP | ||||||
Topological domain | 487-491 | Extracellular | ||||
Sequence: VGMSD | ||||||
Transmembrane | 492-517 | Helical; Name=Segment S6 | ||||
Sequence: VWLTMLSMIVGATCYAMFIGHATALI | ||||||
Topological domain | 518-1201 | Cytoplasmic | ||||
Sequence: QSLDSSRRQYQEKYKQVEQYMSFHKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANADPNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSILLHKVQHDLNSGVFNYQENEIIQQIVRHDREMAHCAHRVQAAASATPTPTPVIWTPLIQAPLQAAAATTSVAIALTHHPRLPAAIFRPPPGPGLGNLGAGQTPRHPRRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPPGLSPLLPSSSSSPPPGACGSPPAPTPSTSTAAAASTTGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPPPPLPGARGGLGLLEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLAAGPSSTPETPPRPERPSFMAGASGGASPVAFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESVAAFSLYPRAGGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARAASSGGPPLTTAAPQREPGARSEPVRSKLPSNL |
Keywords
- Cellular component
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).
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.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000054118 | 1-1201 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 | |||
Sequence: MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDGEEEGAGGRQDPSRRSIRLRPLPSPSPSVAAGCSESRGAALGATESEGPGRSAGKSSTNGDCRRFRGSLASLGSRGGGSGGAGGGSSLGHLHDSAEERRLIAAEGDASPGEDRTPPGLATEPERPATAAQPAASPPPQQPPQPASASCEQPSADTAIKVEGGAAASDQILPEAEVRLGQSGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNVVSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFVVDFISSIPVDYIFLIVETRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVNLIGMMLLLCHWDGCLQFLVPMLQDFPHDCWVSINGMVNNSWGKQYSYALFKAMSHMLCIGYGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSFHKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANADPNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSILLHKVQHDLNSGVFNYQENEIIQQIVRHDREMAHCAHRVQAAASATPTPTPVIWTPLIQAPLQAAAATTSVAIALTHHPRLPAAIFRPPPGPGLGNLGAGQTPRHPRRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPPGLSPLLPSSSSSPPPGACGSPPAPTPSTSTAAAASTTGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPPPPLPGARGGLGLLEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLAAGPSSTPETPPRPERPSFMAGASGGASPVAFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESVAAFSLYPRAGGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARAASSGGPPLTTAAPQREPGARSEPVRSKLPSNL | ||||||
Modified residue | 139 | Phosphoserine | ||||
Sequence: S | ||||||
Glycosylation | 458 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 1105 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 1108 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
S-palmitoylated.
Keywords
- PTM
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).
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 25-121 | Disordered | ||||
Sequence: IMDEEEDGEEEGAGGRQDPSRRSIRLRPLPSPSPSVAAGCSESRGAALGATESEGPGRSAGKSSTNGDCRRFRGSLASLGSRGGGSGGAGGGSSLGH | ||||||
Compositional bias | 81-95 | Polar residues | ||||
Sequence: GRSAGKSSTNGDCRR | ||||||
Region | 135-183 | Disordered | ||||
Sequence: EGDASPGEDRTPPGLATEPERPATAAQPAASPPPQQPPQPASASCEQPS | ||||||
Compositional bias | 160-175 | Pro residues | ||||
Sequence: AQPAASPPPQQPPQPA | ||||||
Region | 209-260 | Involved in subunit assembly | ||||
Sequence: GQSGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSD | ||||||
Region | 789-887 | Disordered | ||||
Sequence: TSVAIALTHHPRLPAAIFRPPPGPGLGNLGAGQTPRHPRRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPPGLSPLLPSSSSSPPPGAC | ||||||
Compositional bias | 819-847 | Polar residues | ||||
Sequence: AGQTPRHPRRLQSLIPSALGSASPASSPS | ||||||
Compositional bias | 860-876 | Pro residues | ||||
Sequence: QQLAGFSAPPGLSPLLP | ||||||
Region | 899-1186 | Disordered | ||||
Sequence: TAAAASTTGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPPPPLPGARGGLGLLEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLAAGPSSTPETPPRPERPSFMAGASGGASPVAFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESVAAFSLYPRAGGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARAASSGGPPLTTAAPQREP | ||||||
Compositional bias | 902-920 | Polar residues | ||||
Sequence: AASTTGFGHFHKALGGSLS | ||||||
Compositional bias | 1012-1026 | Pro residues | ||||
Sequence: GGASPVAFTPRGGLS | ||||||
Compositional bias | 1040-1055 | Pro residues | ||||
Sequence: SAPPRASGSHGSLLLP | ||||||
Compositional bias | 1067-1097 | Polar residues | ||||
Sequence: QRRGTPPLTPGRLTQDLKLISASQPALPQDG |
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
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length1,201
- Mass (Da)129,065
- Last updated2024-10-02 v3
- Checksum7D04EBDE4D258517
Features
Showing features for compositional bias, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 81-95 | Polar residues | ||||
Sequence: GRSAGKSSTNGDCRR | ||||||
Compositional bias | 160-175 | Pro residues | ||||
Sequence: AQPAASPPPQQPPQPA | ||||||
Sequence conflict | 197-199 | in Ref. 2; AAC40126 | ||||
Sequence: SDQ → IDH | ||||||
Sequence conflict | 353 | in Ref. 2; AAC40126 | ||||
Sequence: D → E | ||||||
Sequence conflict | 374 | in Ref. 2; AAC40126 | ||||
Sequence: L → V | ||||||
Sequence conflict | 651 | in Ref. 2; AAC40126 | ||||
Sequence: K → R | ||||||
Compositional bias | 819-847 | Polar residues | ||||
Sequence: AGQTPRHPRRLQSLIPSALGSASPASSPS | ||||||
Compositional bias | 860-876 | Pro residues | ||||
Sequence: QQLAGFSAPPGLSPLLP | ||||||
Compositional bias | 902-920 | Polar residues | ||||
Sequence: AASTTGFGHFHKALGGSLS | ||||||
Compositional bias | 1012-1026 | Pro residues | ||||
Sequence: GGASPVAFTPRGGLS | ||||||
Compositional bias | 1040-1055 | Pro residues | ||||
Sequence: SAPPRASGSHGSLLLP | ||||||
Compositional bias | 1067-1097 | Polar residues | ||||
Sequence: QRRGTPPLTPGRLTQDLKLISASQPALPQDG |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
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 |