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Protein

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2

Gene

HCN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Produces a large instantaneous current. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages (By similarity).By similarity2 Publications

Miscellaneous

Inhibited by extracellular cesium ions.

Enzyme regulationi

Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Channel activity is modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages.2 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi608 – 611cAMP1 Publication4
Nucleotide bindingi618 – 619cAMP1 Publication2
Nucleotide bindingi659 – 662cAMP1 Publication4

GO - Molecular functioni

  • cAMP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • intracellular cAMP activated cation channel activity Source: UniProtKB
  • voltage-gated potassium channel activity Source: UniProtKB
  • voltage-gated sodium channel activity Source: UniProtKB

GO - Biological processi

  • cell-cell signaling Source: ProtInc
  • cellular response to cAMP Source: UniProtKB
  • cellular response to cGMP Source: UniProtKB
  • membrane depolarization during cardiac muscle cell action potential Source: BHF-UCL
  • potassium ion import across plasma membrane Source: BHF-UCL
  • potassium ion transmembrane transport Source: UniProtKB
  • regulation of ion transmembrane transport Source: UniProtKB-KW
  • regulation of membrane potential Source: UniProtKB
  • sodium ion import across plasma membrane Source: BHF-UCL
  • sodium ion transmembrane transport Source: UniProtKB

Keywordsi

Molecular functionIon channel, Ligand-gated ion channel, Potassium channel, Sodium channel, Voltage-gated channel
Biological processIon transport, Potassium transport, Sodium transport, Transport
LigandcAMP, cAMP-binding, Nucleotide-binding, Potassium, Sodium

Enzyme and pathway databases

ReactomeiR-HSA-1296061 HCN channels

Protein family/group databases

TCDBi1.A.1.5.11 the voltage-gated ion channel (vic) superfamily

Names & Taxonomyi

Protein namesi
Recommended name:
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Alternative name(s):
Brain cyclic nucleotide-gated channel 2
Short name:
BCNG-2
Gene namesi
Name:HCN2
Synonyms:BCNG2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000099822.2
HGNCiHGNC:4846 HCN2
MIMi602781 gene
neXtProtiNX_Q9UL51

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 215CytoplasmicSequence analysisAdd BLAST215
Transmembranei216 – 236Helical; Name=Segment S1Sequence analysisAdd BLAST21
Topological domaini237 – 240ExtracellularSequence analysis4
Transmembranei241 – 261Helical; Name=Segment S2Sequence analysisAdd BLAST21
Topological domaini262 – 288CytoplasmicSequence analysisAdd BLAST27
Transmembranei289 – 309Helical; Name=Segment S3Sequence analysisAdd BLAST21
Topological domaini310 – 317ExtracellularSequence analysis8
Transmembranei318 – 338Helical; Voltage-sensor; Name=Segment S4Sequence analysisAdd BLAST21
Topological domaini339 – 369CytoplasmicSequence analysisAdd BLAST31
Transmembranei370 – 390Helical; Name=Segment S5Sequence analysisAdd BLAST21
Topological domaini391 – 413ExtracellularSequence analysisAdd BLAST23
Intramembranei414 – 435Pore-forming; Name=Segment H5Sequence analysisAdd BLAST22
Topological domaini436 – 440ExtracellularSequence analysis5
Transmembranei441 – 461Helical; Name=Segment S6Sequence analysisAdd BLAST21
Topological domaini462 – 889CytoplasmicSequence analysisAdd BLAST428

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi610
OpenTargetsiENSG00000099822
PharmGKBiPA78

Chemistry databases

ChEMBLiCHEMBL1795172
DrugBankiDB02527 Cyclic Adenosine Monophosphate
DB02315 Cyclic Guanosine Monophosphate
GuidetoPHARMACOLOGYi401

Polymorphism and mutation databases

BioMutaiHCN2
DMDMi108935843

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000541111 – 889Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2Add BLAST889

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei146PhosphoserineBy similarity1
Modified residuei161PhosphoserineBy similarity1
Glycosylationi407N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei668Phosphoserine; by PKG/PRKG2By similarity1
Modified residuei754PhosphoserineBy similarity1
Modified residuei756Omega-N-methylarginineBy similarity1
Modified residuei771PhosphoserineBy similarity1
Modified residuei779PhosphoserineBy similarity1
Modified residuei786PhosphoserineBy similarity1
Modified residuei866PhosphoserineBy similarity1
Modified residuei868PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylation at Ser-668 by PRKG2 shifts the voltage-dependence to more negative voltages, hence counteracting the stimulatory effect of cGMP on gating.By similarity

Keywords - PTMi

Glycoprotein, Methylation, Phosphoprotein

Proteomic databases

MaxQBiQ9UL51
PaxDbiQ9UL51
PeptideAtlasiQ9UL51
PRIDEiQ9UL51

PTM databases

iPTMnetiQ9UL51
PhosphoSitePlusiQ9UL51

Expressioni

Tissue specificityi

Highly expressed throughout the brain. Detected at low levels in heart.2 Publications

Gene expression databases

BgeeiENSG00000099822
CleanExiHS_HCN2
GenevisibleiQ9UL51 HS

Interactioni

Subunit structurei

The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Heterotetramer with HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2 (By similarity). Homotetramer.By similarity1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

BioGridi107081, 4 interactors
DIPiDIP-52285N
IntActiQ9UL51, 6 interactors
STRINGi9606.ENSP00000251287

Chemistry databases

BindingDBiQ9UL51

Structurei

Secondary structure

1889
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi471 – 489Combined sources19
Helixi494 – 508Combined sources15
Helixi515 – 520Combined sources6
Helixi524 – 534Combined sources11
Helixi536 – 540Combined sources5
Turni543 – 547Combined sources5
Helixi550 – 557Combined sources8
Beta strandi561 – 565Combined sources5
Beta strandi570 – 572Combined sources3
Beta strandi576 – 578Combined sources3
Beta strandi580 – 586Combined sources7
Beta strandi589 – 592Combined sources4
Beta strandi598 – 601Combined sources4
Beta strandi606 – 608Combined sources3
Helixi610 – 614Combined sources5
Beta strandi619 – 626Combined sources8
Beta strandi628 – 634Combined sources7
Helixi635 – 644Combined sources10
Helixi646 – 661Combined sources16
Turni662 – 664Combined sources3
Helixi668 – 670Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MPFNMR-A521-672[»]
3U10X-ray2.30A470-672[»]
ProteinModelPortaliQ9UL51
SMRiQ9UL51
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni158 – 209Involved in subunit assemblyBy similarityAdd BLAST52

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi10 – 140Pro-richAdd BLAST131
Compositional biasi715 – 861Pro-richAdd BLAST147

Domaini

The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.

Sequence similaritiesi

Belongs to the potassium channel HCN family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0498 Eukaryota
ENOG410XPSE LUCA
GeneTreeiENSGT00900000140801
HOGENOMiHOG000230717
HOVERGENiHBG039489
InParanoidiQ9UL51
KOiK04955
OMAiCPQVARP
OrthoDBiEOG091G0JQU
PhylomeDBiQ9UL51
TreeFamiTF318250

Family and domain databases

CDDicd00038 CAP_ED, 1 hit
Gene3Di2.60.120.10, 1 hit
InterProiView protein in InterPro
IPR018490 cNMP-bd-like
IPR018488 cNMP-bd_CS
IPR000595 cNMP-bd_dom
IPR005821 Ion_trans_dom
IPR013621 Ion_trans_N
IPR003938 K_chnl_volt-dep_EAG/ELK/ERG
IPR014710 RmlC-like_jellyroll
PfamiView protein in Pfam
PF00027 cNMP_binding, 1 hit
PF00520 Ion_trans, 1 hit
PF08412 Ion_trans_N, 1 hit
PRINTSiPR01463 EAGCHANLFMLY
SMARTiView protein in SMART
SM00100 cNMP, 1 hit
SUPFAMiSSF51206 SSF51206, 1 hit
PROSITEiView protein in PROSITE
PS00888 CNMP_BINDING_1, 1 hit
PS50042 CNMP_BINDING_3, 1 hit

Sequencei

Sequence statusi: Complete.

Q9UL51-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA
60 70 80 90 100
PPQHPPRAEA LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG
110 120 130 140 150
ECGRGEPQCS PAGPEGPARG PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG
160 170 180 190 200
PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL RMFGSQKAVE REQERVKSAG
210 220 230 240 250
AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET TAPWIVFNVV
260 270 280 290 300
SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP
310 320 330 340 350
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW
360 370 380 390 400
EEIFHMTYDL ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV
410 420 430 440 450
SINGMVNHSW SELYSFALFK AMSHMLCIGY GRQAPESMTD IWLTMLSMIV
460 470 480 490 500
GATCYAMFIG HATALIQSLD SSRRQYQEKY KQVEQYMSFH KLPADFRQKI
510 520 530 540 550
HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA SMPLFANADP
560 570 580 590 600
NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK
610 620 630 640 650
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR
660 670 680 690 700
AFETVAIDRL DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE
710 720 730 740 750
MVQQAELGQR VGLFPPPPPP PQVTSAIATL QQAAAMSFCP QVARPLVGPL
760 770 780 790 800
ALGSPRLVRR PPPGPAPAAA SPGPPPPASP PGAPASPRAP RTSPYGGLPA
810 820 830 840 850
APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP ASSSTPRLGP
860 870 880
TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL
Length:889
Mass (Da):96,950
Last modified:June 13, 2006 - v3
Checksum:i4B263E0C06C2A47D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti17 – 20TPAP → SPTT in AAC28444 (PubMed:10524219).Curated4
Sequence conflicti29A → R in AAC28444 (PubMed:10524219).Curated1
Sequence conflicti32Q → K in AAC28444 (PubMed:10524219).Curated1
Sequence conflicti294D → V in AAC39760 (PubMed:9630217).Curated1
Sequence conflicti713L → F in AAC39760 (PubMed:9630217).Curated1
Sequence conflicti849G → R in CAB42602 (PubMed:10228147).Curated1
Sequence conflicti849G → R in CAB42630 (PubMed:10228147).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_061106527R → Q. Corresponds to variant dbSNP:rs55687900Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF065164 mRNA Translation: AAC28444.2
AJ012582 mRNA Translation: CAB42602.1
AJ133727
, AJ133728, AJ133729, AJ133730, AJ133731, AJ133732, AJ133733, AJ133734 Genomic DNA Translation: CAB42630.1
AC004449 Genomic DNA No translation available.
AC005559 Genomic DNA Translation: AAC33280.2
AF064877 mRNA Translation: AAC39760.1
CCDSiCCDS12035.1
RefSeqiNP_001185.3, NM_001194.3
UniGeneiHs.124161

Genome annotation databases

EnsembliENST00000251287; ENSP00000251287; ENSG00000099822
GeneIDi610
KEGGihsa:610
UCSCiuc002lpe.3 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHCN2_HUMAN
AccessioniPrimary (citable) accession number: Q9UL51
Secondary accession number(s): O60742
, O60743, O75267, Q9UBS2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: June 13, 2006
Last modified: May 23, 2018
This is version 155 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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