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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. HCN4 is associated with famiial sinus bradycardia (Boulton et al. 2017). Activation of Hcn4 by cAMP has been reviewed (Porro et al. 2020). The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. Saponaro et al. 2021 presented cryo-EM structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures shed light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlighted the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation (Saponaro et al. 2021). 

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:

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   6GYN   6GYO     

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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