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1.A.1.5.10
Orthologue K+/Na+ pacemaker channel, Hcn4 (Scicchitano et al., 2012).  Hyperpolarization-activated cyclic nucleotide-regulated HCN channels underlie the Na+-K+ permeable IH pacemaker current. As with other voltage-gated members of the 6-transmembrane KV channel superfamily, opening of HCN channels involves dilation of a helical bundle formed by the intracellular ends of S6, but this is promoted by inward, not outward, displacement of S4. Direct agonist binding to a ring of cyclic nucleotide-binding sites, one of which lies immediately distal to each S6 helix, imparts cAMP sensitivity to HCN channel opening. At depolarized potentials, HCN channels are further modulated by intracellular Mg2+ which blocks the open channel pore and blunts the inhibitory effect of outward K+ flux. Lyashchenko et al. 2014 showed that cAMP binding to the gating ring enhances not only channel opening but also the kinetics of Mg2+ block.  Mutations in HCN4 cause sick sinus and the Brugada syndrome, cardiac abnormalities. Associated withfamiial sinus bradycardia (Boulton et al. 2017).

Accession Number:Q9Y3Q4
Protein Name:Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Length:1203
Molecular Weight:129042.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:6
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate K+, Na+

Cross database links:

Genevestigator: Q9Y3Q4 Q9Y3Q4
eggNOG: prNOG13780 prNOG13780
HEGENOM: HBG447083 HBG447083
Entrez Gene ID: 10021   
Pfam: PF00027    PF00520    PF08412   
KEGG: hsa:10021    hsa:10021   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0030552 F:cAMP binding
GO:0005272 F:sodium channel activity
GO:0005249 F:voltage-gated potassium channel activity
GO:0008015 P:blood circulation
GO:0006936 P:muscle contraction
GO:0007268 P:synaptic transmission

References (11)

[1] “Two pacemaker channels from human heart with profoundly different activation kinetics.”  Ludwig A.et.al.   10228147
[2] “Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.”  Seifert R.et.al.   10430953
[3] “Role of HCN4 channel in preventing ventricular arrhythmia.”  Ueda K.et.al.   19165230
[4] “Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.”  Ueda K.et.al.   15123648
[5] “Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.”  Milanesi R.et.al.   16407510
[6] “Two pacemaker channels from human heart with profoundly different activation kinetics.”  Ludwig A.et.al.   10228147
[7] “Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis.”  Seifert R.et.al.   10430953
[8] “Role of HCN4 channel in preventing ventricular arrhythmia.”  Ueda K.et.al.   19165230
[9] “Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.”  Ueda K.et.al.   15123648
[10] “Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.”  Milanesi R.et.al.   16407510
[11] “A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews.”  Laish-Farkash A.et.al.   20662977
Structure:
2MNG   3OTF   3U11   4HBN   4KL1   4NVP     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA 
61:	AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG 
121:	HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE 
181:	QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV 
241:	EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV 
301:	VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE 
361:	TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN 
421:	LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG 
481:	YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF 
541:	HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD 
601:	PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE 
661:	ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI 
721:	LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA 
781:	PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA 
841:	SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA 
901:	ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP 
961:	PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT 
1021:	PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT 
1081:	QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR 
1141:	PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP 
1201:	SNL