HCN2_RAT
ID HCN2_RAT Reviewed; 863 AA.
AC Q9JKA9; Q6BCT5; Q9QZW6;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 06-DEC-2005, sequence version 3.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2;
GN Name=Hcn2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=15265006; DOI=10.1111/j.1356-9597.2004.00752.x;
RA Kimura K., Kitano J., Nakajima Y., Nakanishi S.;
RT "Hyperpolarization-activated, cyclic nucleotide-gated HCN2 cation channel
RT forms a protein assembly with multiple neuronal scaffold proteins in
RT distinct modes of protein-protein interaction.";
RL Genes Cells 9:631-640(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-863, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=11000485; DOI=10.1016/s0169-328x(00)00155-8;
RA Monteggia L.M., Eisch A.J., Tang M.D., Kaczmarek L.K., Nestler E.J.;
RT "Cloning and localization of the hyperpolarization-activated cyclic
RT nucleotide-gated channel family in rat brain.";
RL Brain Res. Mol. Brain Res. 81:129-139(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 184-350.
RC TISSUE=Heart;
RX PubMed=10400919; DOI=10.1161/01.res.85.1.e1;
RA Shi W., Wymore R., Yu H., Wu J., Wymore R.T., Pan Z., Robinson R.B.,
RA Dixon J.E., McKinnon D., Cohen I.S.;
RT "Distribution and prevalence of hyperpolarization-activated cation channel
RT (HCN) mRNA expression in cardiac tissues.";
RL Circ. Res. 85:1-6(1999).
RN [4]
RP INDUCTION BY THYROID HORMONES.
RX PubMed=10488052; DOI=10.1161/01.res.85.6.498;
RA Pachucki J., Burmeister L.A., Larsen P.R.;
RT "Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-
RT gated channel (HCN2) mRNA in the rat heart.";
RL Circ. Res. 85:498-503(1999).
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Kidney;
RX PubMed=21796099; DOI=10.1038/ki.2011.230;
RA Carrisoza-Gaytan R., Rangel C., Salvador C., Saldana-Meyer R., Escalona C.,
RA Satlin L.M., Liu W., Zavilowitz B., Trujillo J., Bobadilla N.A.,
RA Escobar L.I.;
RT "The hyperpolarization-activated cyclic nucleotide-gated HCN2 channel
RT transports ammonium in the distal nephron.";
RL Kidney Int. 80:832-840(2011).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-119; SER-134; SER-726;
RP SER-750 AND SER-842, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Hyperpolarization-activated ion channel exhibiting weak
CC selectivity for potassium over sodium ions. Contributes to the native
CC pacemaker currents in heart (If) and in neurons (Ih). Can also
CC transport ammonium in the distal nephron. Produces a large
CC instantaneous current. {ECO:0000269|PubMed:21796099}.
CC -!- ACTIVITY REGULATION: Activated by cAMP, and at 10-100 times higher
CC concentrations, also by cGMP. cAMP binding causes a conformation change
CC that leads to the assembly of an active tetramer and channel opening.
CC Channel activity is modulated by intracellular chloride ions and pH;
CC acidic pH shifts the activation to more negative voltages (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Homotetramer. Heterotetramer with HCN1. The potassium channel
CC is composed of a homo- or heterotetrameric complex of pore-forming
CC subunits. Forms an obligate 4:4 complex with accessory subunit PEX5L.
CC Interacts with KCNE2 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21796099};
CC Multi-pass membrane protein {ECO:0000269|PubMed:21796099}.
CC -!- TISSUE SPECIFICITY: Highly expressed in neonatal and adult ventricle
CC and in brain. Highly expressed in the pyramidal layer in hippocampus,
CC in anterior dorsal nucleus in thalamus, in the mammillary nucleus in
CC hypothalamus, in red nucleus, in trigeminal mesencephalic, spinal and
CC principal nuclei, in cochlear and trapezoid nuclei and in the dorsal
CC tegemental nucleus. {ECO:0000269|PubMed:11000485}.
CC -!- INDUCTION: By thyroid hormones in hypothyroid animals.
CC {ECO:0000269|PubMed:10488052}.
CC -!- DOMAIN: The segment S4 is probably the voltage-sensor and is
CC characterized by a series of positively charged amino acids at every
CC third position.
CC -!- PTM: Phosphorylation at Ser-641 by PRKG2 shifts the voltage-dependence
CC to more negative voltages, hence counteracting the stimulatory effect
CC of cGMP on gating. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the potassium channel HCN family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB164197; BAD32628.1; -; mRNA.
DR EMBL; AF247451; AAF62174.1; -; mRNA.
DR EMBL; AF155164; AAF01491.1; -; mRNA.
DR RefSeq; NP_446136.1; NM_053684.1.
DR AlphaFoldDB; Q9JKA9; -.
DR BMRB; Q9JKA9; -.
DR SMR; Q9JKA9; -.
DR BioGRID; 250321; 1.
DR STRING; 10116.ENSRNOP00000011837; -.
DR GlyGen; Q9JKA9; 1 site.
DR iPTMnet; Q9JKA9; -.
DR PhosphoSitePlus; Q9JKA9; -.
DR PaxDb; Q9JKA9; -.
DR PRIDE; Q9JKA9; -.
DR ABCD; Q9JKA9; 1 sequenced antibody.
DR GeneID; 114244; -.
DR KEGG; rno:114244; -.
DR UCSC; RGD:620689; rat.
DR CTD; 610; -.
DR RGD; 620689; Hcn2.
DR eggNOG; KOG0498; Eukaryota.
DR InParanoid; Q9JKA9; -.
DR OrthoDB; 281394at2759; -.
DR PhylomeDB; Q9JKA9; -.
DR Reactome; R-RNO-1296061; HCN channels.
DR PRO; PR:Q9JKA9; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0030424; C:axon; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR GO; GO:0032590; C:dendrite membrane; IDA:RGD.
DR GO; GO:0043198; C:dendritic shaft; IDA:RGD.
DR GO; GO:0098855; C:HCN channel complex; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0036477; C:somatodendritic compartment; IDA:RGD.
DR GO; GO:0045202; C:synapse; IDA:RGD.
DR GO; GO:0030552; F:cAMP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0005222; F:intracellular cAMP-activated cation channel activity; ISS:UniProtKB.
DR GO; GO:0060090; F:molecular adaptor activity; IDA:RGD.
DR GO; GO:0030165; F:PDZ domain binding; IPI:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; ISS:UniProtKB.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; ISO:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:1904045; P:cellular response to aldosterone; IEP:RGD.
DR GO; GO:0071320; P:cellular response to cAMP; ISS:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; IEP:RGD.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; ISO:RGD.
DR GO; GO:0071805; P:potassium ion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0003254; P:regulation of membrane depolarization; ISO:RGD.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:RGD.
DR GO; GO:0072718; P:response to cisplatin; IEP:RGD.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; ISO:RGD.
DR GO; GO:0035725; P:sodium ion transmembrane transport; ISO:RGD.
DR CDD; cd00038; CAP_ED; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR018488; cNMP-bd_CS.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR013621; Ion_trans_N.
DR InterPro; IPR003938; K_chnl_volt-dep_EAG/ELK/ERG.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR Pfam; PF00027; cNMP_binding; 1.
DR Pfam; PF00520; Ion_trans; 1.
DR Pfam; PF08412; Ion_trans_N; 1.
DR PRINTS; PR01463; EAGCHANLFMLY.
DR SMART; SM00100; cNMP; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; 1.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
PE 1: Evidence at protein level;
KW cAMP; cAMP-binding; Cell membrane; Glycoprotein; Ion channel;
KW Ion transport; Ligand-gated ion channel; Membrane; Methylation;
KW Nucleotide-binding; Phosphoprotein; Potassium; Potassium channel;
KW Potassium transport; Reference proteome; Sodium; Sodium channel;
KW Sodium transport; Transmembrane; Transmembrane helix; Transport;
KW Voltage-gated channel.
FT CHAIN 1..863
FT /note="Potassium/sodium hyperpolarization-activated cyclic
FT nucleotide-gated channel 2"
FT /id="PRO_0000054113"
FT TOPO_DOM 1..188
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 189..209
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 210..213
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 214..234
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 235..261
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..290
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 291..311
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 312..342
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 343..363
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 364..386
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 387..408
FT /note="Pore-forming; Name=Segment H5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 409..413
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 414..434
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 435..863
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..131
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 131..182
FT /note="Involved in subunit assembly"
FT /evidence="ECO:0000250"
FT REGION 730..863
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 15..51
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 732..759
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 811..825
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 581..584
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250"
FT BINDING 591..592
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250"
FT BINDING 632..635
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250"
FT MOD_RES 119
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 641
FT /note="Phosphoserine; by PKG/PRKG2"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 726
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 728
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 743
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 750
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 757
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 840
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 842
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 847
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT CARBOHYD 380
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CONFLICT 16
FT /note="T -> A (in Ref. 1; BAD32628)"
FT /evidence="ECO:0000305"
FT CONFLICT 32..34
FT /note="LQL -> PQP (in Ref. 1; BAD32628)"
FT /evidence="ECO:0000305"
FT CONFLICT 686
FT /note="F -> L (in Ref. 1; BAD32628)"
FT /evidence="ECO:0000305"
FT CONFLICT 693
FT /note="R -> P (in Ref. 1; BAD32628)"
FT /evidence="ECO:0000305"
FT CONFLICT 696
FT /note="R -> T (in Ref. 1; BAD32628)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 863 AA; 94920 MW; 4EF55435C2384A26 CRC64;
MDARGGGGRP GDSPGTTPAP GPPPPPPPPA PLQLQPPPAP PPNPTTPSHP ESADEPGPRS
RLCSRDSSCT PGAAKGGANG ECGRGEPQCS PEGPARGPKV SFSCRGAASG PAAAEEAGSE
EAGPAGEPRG SQASFLQRQF GALLQPGVNK FSLRMFGSQK AVEREQERVK SAGAWIIHPY
SDFRFYWDFT MLLFMVGNLI IIPVGITFFK DETTAPWIVF NVVSDTFFLM DLVLNFRTGI
VIEDNTEIIL DPEKIKKKYL RTWFVVDFVS SIPVDYIFLI VEKGIDSEVY KTARALRIVR
FTKILSLLRL LRLSRLIRYI HQWEEIFHMT YDLASAVMRI CNLISMMLLL CHWDGCLQFL
VPMLQDFPSD CWVSINNMVN HSWSELYSFA LFKAMSHMLC IGYGRQAPES MTDIWLTMLS
MIVGATCYAM FIGHATALIQ SLDSSRRQYQ EKYKQVEQYM SFHKLPADFR QKIHDYYEHR
YQGKMFDEDS ILGELNGPLR EEIVNFNCRK LVASMPLFAN ADPNFVTAML TKLKFEVFQP
GDYIIREGTI GKKMYFIQHG VVSVLTKGNK EMKLSDGSYF GEICLLTRGR RTASVRADTY
CRLYSLSVDN FNEVLEEYPM MRRAFETVAI DRLDRIGKKN SILLHKVQHD LSSGVFNNQE
NAIIQEIVKY DREMVQQAEL GQRVGFFPPP PPRQVRSAIA TLQQAVAMSF CPQVARPLVG
PLALGSPRLV RRAPPGPLPP AASPGPPAAS PPAAPSSPRA PRTSPYGVPG SPATRVGPAL
PARRLSRASR PLSASQPSLP HGAPAPSPAA SARPASSSTP RLGPAPTTRT AAPSPDRRDS
ASPGAASGLD PLDSARSRLS SNL
