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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:Q9UL51
Protein Name:Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Length:889
Molecular Weight:96950.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:8
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate cation

Cross database links:

Entrez Gene ID: 610   
Pfam: PF00027    PF00520    PF08412   
KEGG: hsa:610   

Gene Ontology

GO:0008076 C:voltage-gated potassium channel complex
GO:0030552 F:cAMP binding
GO:0005272 F:sodium channel activity
GO:0005249 F:voltage-gated potassium channel activity
GO:0006936 P:muscle contraction
GO:0007268 P:synaptic transmission

References (4)

[1] “The human gene coding for HCN2, a pacemaker channel of the heart.”  Vaccari T.et.al.   10524219
[2] “Two pacemaker channels from human heart with profoundly different activation kinetics.”  Ludwig A.et.al.   10228147
[3] “The DNA sequence and biology of human chromosome 19.”  Grimwood J.et.al.   15057824
[4] “Identification of a gene encoding a hyperpolarization-activated 'pacemaker' channel of brain.”  Santoro B.et.al.   9630217
Structure:
2MPF   3U10     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA PPQHPPRAEA 
61:	LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG ECGRGEPQCS PAGPEGPARG 
121:	PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL 
181:	RMFGSQKAVE REQERVKSAG AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET 
241:	TAPWIVFNVV SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP 
301:	VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW EEIFHMTYDL 
361:	ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV SINGMVNHSW SELYSFALFK 
421:	AMSHMLCIGY GRQAPESMTD IWLTMLSMIV GATCYAMFIG HATALIQSLD SSRRQYQEKY 
481:	KQVEQYMSFH KLPADFRQKI HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA 
541:	SMPLFANADP NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK 
601:	LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR AFETVAIDRL 
661:	DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE MVQQAELGQR VGLFPPPPPP 
721:	PQVTSAIATL QQAAAMSFCP QVARPLVGPL ALGSPRLVRR PPPGPAPAAA SPGPPPPASP 
781:	PGAPASPRAP RTSPYGGLPA APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP 
841:	ASSSTPRLGP TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL