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1.A.1.5.11
Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current-carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009).  Functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures (Page et al. 2020). Rhythmic activity in pacemaker cells, as in the sino-atrial node in the heart, depends on the activation of HCN channels. As in depolarization-activated K+ channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels (Wu et al. 2021). S4 in HCN channels moves in two steps in response to hyperpolarizations, and the second S4 step correlates with gate opening (Wu et al. 2021). It is a nuclear hormone receptor that binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (Koyama et al. 2010). It may lack ligand binding ability and has no or only very low ERE binding activity, resulting in the loss of ligand-dependent transactivation ability. Male moujse ejaculation drives sexual satiety and selectively activates Esr2neurons in the BNSTpr of both sexes (Zhou et al. 2023).  Changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels (Porro et al. 2024).

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 cation

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