Tmic
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NamePotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
SynonymsNot Available
Gene NameHCN4
OrganismHuman
Amino acid sequence
>lcl|BSEQ0020824|Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDAEEEGAGGRQDPSRRSIRLRPLPSPSPSA
AAGGTESRSSALGAADSEGPARGAGKSSTNGDCRRFRGSLASLGSRGGGSGGTGSGSSHG
HLHDSAEERRLIAEGDASPGEDRTPPGLAAEPERPGASAQPAASPPPPQQPPQPASASCE
QPSVDTAIKVEGGAAAGDQILPEAEVRLGQAGFMQRQFGAMLQPGVNKFSLRMFGSQKAV
EREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNV
VSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFMVDFISSIPVDYIFLIVE
TRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVN
LIGMMLLLCHWDGCLQFLVPMLQDFPDDCWVSINNMVNNSWGKQYSYALFKAMSHMLCIG
YGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSF
HKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANAD
PNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGE
ICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSI
LLHKVQHDLNSGVFNYQENEIIQQIVQHDREMAHCAHRVQAAASATPTPTPVIWTPLIQA
PLQAAAATTSVAIALTHHPRLPAAIFRPPPGSGLGNLGAGQTPRHLKRLQSLIPSALGSA
SPASSPSQVDTPSSSSFHIQQLAGFSAPAGLSPLLPSSSSSPPPGACGSPSAPTPSAGVA
ATTIAGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPSPAPPGARGGLGLPEHFLP
PPPSSRSPSSSPGQLGQPPGELSLGLATGPLSTPETPPRQPEPPSLVAGASGGASPVGFT
PRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLT
QDLKLISASQPALPQDGAQTLRRASPHSSGESMAAFPLFPRAGGGSGGSGSSGGLGPPGR
PYGAIPGQHVTLPRKTSSGSLPPPLSLFGARATSSGGPPLTAGPQREPGARPEPVRSKLP
SNL
Number of residues1203
Molecular Weight129040.65
Theoretical pINot Available
GO Classification
Functions
  • cAMP binding
  • voltage-gated potassium channel activity
  • voltage-gated sodium channel activity
  • intracellular cAMP activated cation channel activity
  • identical protein binding
Processes
  • cellular response to cAMP
  • regulation of cardiac muscle contraction
  • cation transport
  • potassium ion transmembrane transport
  • regulation of heart rate
  • regulation of membrane depolarization
  • regulation of heart rate by cardiac conduction
  • cellular response to steroid hormone stimulus
  • SA node cell action potential
  • synaptic transmission
  • cellular response to cGMP
  • response to cisplatin
  • regulation of membrane potential
  • sodium ion transmembrane transport
  • muscle contraction
  • blood circulation
Components
  • basolateral plasma membrane
  • plasma membrane
  • intrinsic component of plasma membrane
  • perinuclear region of cytoplasm
  • neuronal cell body
  • integral component of plasma membrane
  • terminal bouton
General FunctionVoltage-gated sodium channel activity
Specific FunctionHyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli.
Pfam Domain Function
Transmembrane Regions267-287 294-314 341-361 369-389 421-441 497-517
GenBank Protein IDNot Available
UniProtKB IDQ9Y3Q4
UniProtKB Entry NameHCN4_HUMAN
Cellular LocationCell membrane
Gene sequence
>lcl|BSEQ0020825|Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)
ATGGACAAGCTGCCGCCGTCCATGCGCAAGCGGCTCTACAGCCTCCCGCAGCAGGTGGGG
GCCAAGGCGTGGATCATGGACGAGGAAGAGGACGCCGAGGAGGAGGGGGCCGGGGGCCGC
CAAGACCCCAGCCGCAGGAGCATCCGGCTGCGGCCACTGCCCTCGCCCTCCCCCTCGGCG
GCCGCGGGTGGCACGGAGTCCCGGAGCTCGGCCCTCGGGGCAGCGGACAGCGAAGGGCCG
GCCCGCGGCGCGGGCAAGTCCAGCACGAACGGCGACTGCAGGCGCTTCCGCGGGAGCCTG
GCCTCGCTGGGCAGCCGGGGCGGCGGCAGCGGCGGCACGGGGAGCGGCAGCAGTCACGGA
CACCTGCATGACTCCGCGGAGGAGCGGCGGCTCATCGCCGAGGGCGACGCGTCCCCCGGC
GAGGACAGGACGCCCCCAGGCCTGGCGGCCGAGCCCGAGCGCCCCGGCGCCTCGGCGCAG
CCCGCAGCCTCGCCGCCGCCGCCCCAGCAGCCACCGCAGCCGGCCTCCGCCTCCTGCGAG
CAGCCCTCGGTGGACACCGCTATCAAAGTGGAGGGAGGCGCGGCTGCCGGCGACCAGATC
CTCCCGGAGGCCGAGGTGCGCCTGGGCCAGGCCGGCTTCATGCAGCGCCAGTTCGGGGCC
ATGCTCCAACCCGGGGTCAACAAATTCTCCCTAAGGATGTTCGGCAGCCAGAAAGCCGTG
GAGCGCGAACAGGAGAGGGTCAAGTCGGCCGGATTTTGGATTATCCACCCCTACAGTGAC
TTCAGATTTTACTGGGACCTGACCATGCTGCTGCTGATGGTGGGAAACCTGATTATCATT
CCTGTGGGCATCACCTTCTTCAAGGATGAGAACACCACACCCTGGATTGTCTTCAATGTG
GTGTCAGACACATTCTTCCTCATCGACTTGGTCCTCAACTTCCGCACAGGGATCGTGGTG
GAGGACAACACAGAGATCATCCTGGACCCGCAGCGGATTAAAATGAAGTACCTGAAAAGC
TGGTTCATGGTAGATTTCATTTCCTCCATCCCCGTGGACTACATCTTCCTCATTGTGGAG
ACACGCATCGACTCGGAGGTCTACAAGACTGCCCGGGCCCTGCGCATTGTCCGCTTCACG
AAGATCCTCAGCCTCTTACGCCTGTTACGCCTCTCCCGCCTCATTCGATATATTCACCAG
TGGGAAGAGATCTTCCACATGACCTACGACCTGGCCAGCGCCGTGGTGCGCATCGTGAAC
CTCATCGGCATGATGCTCCTGCTCTGCCACTGGGACGGCTGCCTGCAGTTCCTGGTACCC
ATGCTACAGGACTTCCCTGACGACTGCTGGGTGTCCATCAACAACATGGTGAACAACTCC
TGGGGGAAGCAGTACTCCTACGCGCTCTTCAAGGCCATGAGCCACATGCTGTGCATCGGC
TACGGGCGGCAGGCGCCCGTGGGCATGTCCGACGTCTGGCTCACCATGCTCAGCATGATC
GTGGGTGCCACCTGCTACGCCATGTTCATTGGCCACGCCACTGCCCTCATCCAGTCCCTG
GACTCCTCCCGGCGCCAGTACCAGGAAAAGTACAAGCAGGTGGAGCAGTACATGTCCTTT
CACAAGCTCCCGCCCGACACCCGGCAGCGCATCCACGACTACTACGAGCACCGCTACCAG
GGCAAGATGTTCGACGAGGAGAGCATCCTGGGCGAGCTAAGCGAGCCCCTGCGGGAGGAG
ATCATCAACTTTAACTGTCGGAAGCTGGTGGCCTCCATGCCACTGTTTGCCAATGCGGAC
CCCAACTTCGTGACGTCCATGCTGACCAAGCTGCGTTTCGAGGTCTTCCAGCCTGGGGAC
TACATCATCCGGGAAGGCACCATTGGCAAGAAGATGTACTTCATCCAGCATGGCGTGGTC
AGCGTGCTCACCAAGGGCAACAAGGAGACCAAGCTGGCCGACGGCTCCTACTTTGGAGAG
ATCTGCCTGCTGACCCGGGGCCGGCGCACAGCCAGCGTGAGGGCCGACACCTACTGCCGC
CTCTACTCGCTGAGCGTGGACAACTTCAATGAGGTGCTGGAGGAGTACCCCATGATGCGA
AGGGCCTTCGAGACCGTGGCGCTGGACCGCCTGGACCGCATTGGCAAGAAGAACTCCATC
CTCCTCCACAAAGTCCAGCACGACCTCAACTCCGGCGTCTTCAACTACCAGGAGAATGAG
ATCATCCAGCAGATTGTGCAGCATGACCGGGAGATGGCCCACTGCGCGCACCGCGTCCAG
GCTGCTGCCTCTGCCACCCCAACCCCCACGCCCGTCATCTGGACCCCGCTGATCCAGGCA
CCACTGCAGGCTGCCGCTGCCACCACTTCTGTGGCCATAGCCCTCACCCACCACCCTCGC
CTGCCTGCTGCCATCTTCCGCCCTCCCCCAGGATCTGGGCTGGGCAACCTCGGTGCCGGG
CAGACGCCAAGGCACCTGAAACGGCTGCAGTCCCTGATCCCTTCTGCGCTGGGCTCCGCC
TCGCCCGCCAGCAGCCCGTCCCAGGTGGACACACCGTCTTCATCCTCCTTCCACATCCAA
CAGCTGGCTGGATTCTCTGCCCCCGCTGGACTGAGCCCACTCCTGCCCTCATCCAGCTCC
TCCCCACCCCCCGGGGCCTGTGGCTCCCCCTCGGCTCCCACACCATCAGCTGGCGTAGCC
GCCACCACCATAGCCGGGTTTGGCCACTTCCACAAGGCGCTGGGTGGCTCCCTGTCCTCC
TCCGACTCTCCCCTGCTCACCCCGCTGCAGCCAGGCGCCCGCTCCCCGCAGGCTGCCCAG
CCATCTCCCGCGCCACCCGGGGCCCGGGGAGGCCTGGGACTCCCGGAGCACTTCCTGCCA
CCCCCACCCTCATCCAGATCCCCGTCATCTAGCCCCGGGCAGCTGGGCCAGCCTCCCGGG
GAGTTGTCCCTAGGTCTGGCCACTGGCCCACTGAGCACGCCAGAGACACCCCCACGGCAG
CCTGAGCCGCCGTCCCTTGTGGCAGGGGCCTCTGGGGGGGCTTCCCCTGTAGGCTTTACT
CCCCGAGGAGGTCTCAGCCCCCCTGGCCACAGCCCAGGCCCCCCAAGAACCTTCCCGAGT
GCCCCGCCCCGGGCCTCTGGCTCCCACGGATCCTTGCTCCTGCCACCTGCATCCAGCCCC
CCACCACCCCAGGTCCCCCAGCGCCGGGGCACACCCCCGCTCACCCCCGGCCGCCTCACC
CAGGACCTCAAGCTCATCTCCGCGTCTCAGCCAGCCCTGCCTCAGGACGGGGCGCAGACT
CTCCGCAGAGCCTCCCCGCACTCCTCAGGGGAGTCCATGGCTGCCTTCCCGCTCTTCCCC
AGGGCTGGGGGTGGCAGCGGGGGCAGTGGGAGCAGCGGGGGCCTCGGTCCCCCTGGGAGG
CCCTATGGTGCCATCCCCGGCCAGCACGTCACTCTGCCTCGGAAGACATCCTCAGGTTCT
TTGCCACCCCCTCTGTCTTTGTTTGGGGCAAGAGCCACCTCTTCTGGGGGGCCCCCTCTG
ACTGCTGGACCCCAGAGGGAACCTGGGGCCAGGCCTGAGCCAGTGCGCTCCAAACTGCCA
TCCAATCTATGA
GenBank Gene IDNot Available
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:16882
Chromosome Location15
LocusNot Available
References
  1. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M: Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 1999 May 4;18(9):2323-9. 10228147
  2. Seifert R, Scholten A, Gauss R, Mincheva A, Lichter P, Kaupp UB: Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9391-6. 10430953
  3. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A: Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009 Feb;54(2):115-21. doi: 10.1038/jhg.2008.16. Epub 2009 Jan 23. 19165230
  4. Xu X, Vysotskaya ZV, Liu Q, Zhou L: Structural basis for the cAMP-dependent gating in the human HCN4 channel. J Biol Chem. 2010 Nov 19;285(47):37082-91. doi: 10.1074/jbc.M110.152033. Epub 2010 Sep 9. 20829353
  5. Lolicato M, Nardini M, Gazzarrini S, Moller S, Bertinetti D, Herberg FW, Bolognesi M, Martin H, Fasolini M, Bertrand JA, Arrigoni C, Thiel G, Moroni A: Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem. 2011 Dec 30;286(52):44811-20. doi: 10.1074/jbc.M111.297606. Epub 2011 Oct 17. 22006928
  6. Xu X, Marni F, Wu S, Su Z, Musayev F, Shrestha S, Xie C, Gao W, Liu Q, Zhou L: Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel. Structure. 2012 Dec 5;20(12):2116-23. doi: 10.1016/j.str.2012.09.017. Epub 2012 Oct 25. 23103389
  7. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A: Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004 Jun 25;279(26):27194-8. Epub 2004 Apr 30. 15123648
  8. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D: Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006 Jan 12;354(2):151-7. 16407510
  9. Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D: A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol. 2010 Dec;21(12):1365-72. doi: 10.1111/j.1540-8167.2010.01844.x. 20662977