HCN4
entrez
10021
canonical
uniprot
Q9Y3Q4
canonical
ensembl
ENSG00000138622
resolver
ensp
ENSP00000261917
resolver
enst
ENST00000261917
resolver
genesymbol
HCN4
resolver
hgnc
HGNC:16882
resolver
uniprot
Q9UMQ7
resolver
uniprot_entry
HCN4_HUMAN
resolver
uniprot_sec
Q9UMQ7
resolver
activity_regulation
ACTIVITY REGULATION: Activated by cAMP and to a lesser extent by cGMP and cCMP (PubMed:10228147, PubMed:10430953, PubMed:16407510, PubMed:20829353, PubMed:22006928, PubMed:24776929). 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 (PubMed:24776929). Inhibited by extracellular Cs(+) ions (PubMed:10228147). 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 (By similarity). {ECO:0000250|UniProtKB:O70507, ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:20829353, ECO:0000269|PubMed:22006928, ECO:0000269|PubMed:24776929}.
uniprot
proteins
amino_acid_sequence
MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDAEEEGAGGRQDPSRRSIRLRPLPSPSPSAAAGGTESRSSALGAADSEGPARGAGKSSTNGDCRRFRGSLASLGSRGGGSGGTGSGSSHGHLHDSAEERRLIAEGDASPGEDRTPPGLAAEPERPGASAQPAASPPPPQQPPQPASASCEQPSVDTAIKVEGGAAAGDQILPEAEVRLGQAGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNVVSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFMVDFISSIPVDYIFLIVETRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVNLIGMMLLLCHWDGCLQFLVPMLQDFPDDCWVSINNMVNNSWGKQYSYALFKAMSHMLCIGYGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSFHKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANADPNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSILLHKVQHDLNSGVFNYQENEIIQQIVQHDREMAHCAHRVQAAASATPTPTPVIWTPLIQAPLQAAAATTSVAIALTHHPRLPAAIFRPPPGSGLGNLGAGQTPRHLKRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPAGLSPLLPSSSSSPPPGACGSPSAPTPSAGVAATTIAGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPSPAPPGARGGLGLPEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLATGPLSTPETPPRQPEPPSLVAGASGGASPVGFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESMAAFPLFPRAGGGSGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARATSSGGPPLTAGPQREPGARPEPVRSKLPSNL
uniprot
proteins
disease_involvement
DISEASE: Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. {ECO:0000269|PubMed:15123648, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:20662977, ECO:0000269|PubMed:23103389}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:19165230}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Epilepsy, idiopathic generalized 18 (EIG18) [MIM:619521]: An autosomal dominant form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. EIG18 is characterized by onset of myoclonic seizures in infancy. Although the seizures remit, some patients may have later speech or cognitive impairment. {ECO:0000269|PubMed:30127718}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: Hyperpolarization-activated ion channel that are permeable to Na(+) and K(+) ions with very slow activation and inactivation (PubMed:10228147, PubMed:10430953, PubMed:20829353). Exhibits higher selectivity for K(+) over Na(+) ions (PubMed:10228147). Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat (Probable) (PubMed:10228147, PubMed:16407510, PubMed:19165230). Contributes to the native pacemaker currents in neurons (Ih) (Probable). May mediate responses to sour stimuli (By similarity). {ECO:0000250|UniProtKB:Q9JKA7, ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:19165230, ECO:0000269|PubMed:20829353, ECO:0000305|PubMed:10430953}.
uniprot
proteins
mass_dalton
129042
uniprot
proteins
mutagenesis
MUTAGEN 559; /note="Y->T: Alters the channel response to c-di-GMP."; /evidence="ECO:0000269|PubMed:24776929"; MUTAGEN 564; /note="F->T: Alters the channel response to c-di-GMP."; /evidence="ECO:0000269|PubMed:24776929"; MUTAGEN 566; /note="E->K: Alters the channel response to c-di-GMP."; /evidence="ECO:0000269|PubMed:24776929"; MUTAGEN 680; /note="R->E: Abolishes cyclic-dinucleotide modulation of HCN4 channels."; /evidence="ECO:0000269|PubMed:24776929
uniprot
proteins
post_translational_modification
PTM: S-palmitoylated. {ECO:0000269|PubMed:26546007}.
uniprot
proteins
protein_family
Potassium channel HCN family
uniprot
proteins
pubmed
10228147
uniprot
proteins
pubmed
10430953
uniprot
proteins
pubmed
12928435
uniprot
proteins
pubmed
15123648
uniprot
proteins
pubmed
16407510
uniprot
proteins
pubmed
16572171
uniprot
proteins
pubmed
19165230
uniprot
proteins
pubmed
20662977
uniprot
proteins
pubmed
20829353
uniprot
proteins
pubmed
22006928
uniprot
proteins
pubmed
23103389
uniprot
proteins
pubmed
24776929
uniprot
proteins
pubmed
26546007
uniprot
proteins
pubmed
30127718
uniprot
proteins
sequence_length
1203
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510}; Multi-pass membrane protein {ECO:0000269|Ref.10}.
uniprot
proteins
transmembrane_region
TRANSMEM 264..286; /note="Helical; Name=Segment S1"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN"; TRANSMEM 294..314; /note="Helical; Name=Segment S2"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN"; TRANSMEM 337..359; /note="Helical; Name=Segment S3"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN"; TRANSMEM 379..399; /note="Helical; Voltage-sensor; Name=Segment S4"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN"; TRANSMEM 414..436; /note="Helical; Name=Segment S5"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN"; TRANSMEM 492..517; /note="Helical; Name=Segment S6"; /evidence="ECO:0000269|Ref.10, ECO:0007744|PDB:6GYN
uniprot
proteins