ID   HRH2_HUMAN              Reviewed;         359 AA.
AC   P25021; B5BUP7; Q14464; Q7Z5R9;
DT   01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1992, sequence version 1.
DT   27-MAR-2024, entry version 195.
DE   RecName: Full=Histamine H2 receptor;
DE            Short=H2R;
DE            Short=HH2R;
DE   AltName: Full=Gastric receptor I;
GN   Name=HRH2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=1714721; DOI=10.1016/0006-291x(91)91047-g;
RA   Gantz I., Munzert G., Tashiro T., Schaeffer M., Wang L.-D., DelValle J.,
RA   Yamada T.;
RT   "Molecular cloning of the human histamine H2 receptor.";
RL   Biochem. Biophys. Res. Commun. 178:1386-1392(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   TISSUE=Liver;
RX   PubMed=7755641; DOI=10.1006/bbrc.1995.1703;
RA   Nishi T., Koike T., Oka T., Maeda M., Futai M.;
RT   "Identification of the promoter region of the human histamine H2-receptor
RT   gene.";
RL   Biochem. Biophys. Res. Commun. 210:616-623(1995).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=10371214; DOI=10.1016/s0014-5793(99)00618-3;
RA   Murakami H., Sun-Wada G., Matsumoto M., Nishi T., Wada Y., Futai M.;
RT   "Human histamine H2 receptor gene: multiple transcription initiation and
RT   tissue-specific expression.";
RL   FEBS Lett. 451:327-331(1999).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=15014171; DOI=10.1093/molbev/msh100;
RA   Kitano T., Liu Y.-H., Ueda S., Saitou N.;
RT   "Human-specific amino acid changes found in 103 protein-coding genes.";
RL   Mol. Biol. Evol. 21:936-944(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Stomach;
RA   Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT   "cDNA clones of human proteins involved in signal transduction sequenced by
RT   the Guthrie cDNA resource center (www.cdna.org).";
RL   Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX   PubMed=19054851; DOI=10.1038/nmeth.1273;
RA   Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA   Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA   Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA   Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H., Maruyama Y.,
RA   Matsuo K., Minami K., Mitsubori M., Mori M., Morishita R., Murase A.,
RA   Nishikawa A., Nishikawa S., Okamoto T., Sakagami N., Sakamoto Y.,
RA   Sasaki Y., Seki T., Sono S., Sugiyama A., Sumiya T., Takayama T.,
RA   Takayama Y., Takeda H., Togashi T., Yahata K., Yamada H., Yanagisawa Y.,
RA   Endo Y., Imamoto F., Kisu Y., Tanaka S., Isogai T., Imai J., Watanabe S.,
RA   Nomura N.;
RT   "Human protein factory for converting the transcriptome into an in vitro-
RT   expressed proteome.";
RL   Nat. Methods 5:1011-1017(2008).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 4-351, AND POLYMORPHISM.
RC   TISSUE=Brain;
RX   PubMed=8817552; DOI=10.1097/00001756-199605170-00015;
RA   Orange P.R., Heath P.R., Wright S.R., Pearson R.C.A.;
RT   "Allelic variations of the human histamine H2 receptor gene.";
RL   NeuroReport 7:1293-1296(1996).
RN   [10]
RP   REVIEW.
RX   PubMed=9374694; DOI=10.1152/ajpgi.1997.273.5.g987;
RA   DelValle J., Gantz I.;
RT   "Novel insights into histamine H2 receptor biology.";
RL   Am. J. Physiol. 273:G987-G996(1997).
CC   -!- FUNCTION: The H2 subclass of histamine receptors mediates gastric acid
CC       secretion. Also appears to regulate gastrointestinal motility and
CC       intestinal secretion. Possible role in regulating cell growth and
CC       differentiation. The activity of this receptor is mediated by G
CC       proteins which activate adenylyl cyclase and, through a separate G
CC       protein-dependent mechanism, the phosphoinositide/protein kinase (PKC)
CC       signaling pathway (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P25021-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P25021-2; Sequence=VSP_043594;
CC   -!- MISCELLANEOUS: Antagonists for this receptor have proven to be
CC       effective therapy for acid peptic disorders of the gastrointestinal
CC       tract. Certain antagonists are used in the treatment of
CC       neuropsychiatric and neurological diseases such as schizophrenia,
CC       Alzheimer disease and Parkinson disease.
CC   -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC       {ECO:0000255|PROSITE-ProRule:PRU00521}.
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=H2 receptor entry;
CC       URL="https://en.wikipedia.org/wiki/H2_receptor";
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DR   EMBL; M64799; AAA58647.1; -; Genomic_DNA.
DR   EMBL; D49783; BAA08618.1; -; Genomic_DNA.
DR   EMBL; AB023486; BAA84279.1; -; Genomic_DNA.
DR   EMBL; AB041384; BAA94469.1; -; Genomic_DNA.
DR   EMBL; AY136744; AAN01270.1; -; mRNA.
DR   EMBL; AB451483; BAG70297.1; -; mRNA.
DR   EMBL; CH471062; EAW61369.1; -; Genomic_DNA.
DR   EMBL; BC054510; AAH54510.1; -; mRNA.
DR   EMBL; X98133; CAA66832.1; -; Genomic_DNA.
DR   CCDS; CCDS47344.1; -. [P25021-2]
DR   PIR; JH0449; JH0449.
DR   RefSeq; NP_001124527.1; NM_001131055.1. [P25021-2]
DR   RefSeq; NP_071640.1; NM_022304.2.
DR   PDB; 7UL3; EM; 3.00 A; A=1-199, A=248-359.
DR   PDBsum; 7UL3; -.
DR   AlphaFoldDB; P25021; -.
DR   EMDB; EMD-26590; -.
DR   SMR; P25021; -.
DR   BioGRID; 109510; 1.
DR   STRING; 9606.ENSP00000366506; -.
DR   BindingDB; P25021; -.
DR   ChEMBL; CHEMBL1941; -.
DR   DrugBank; DB00321; Amitriptyline.
DR   DrugBank; DB01238; Aripiprazole.
DR   DrugBank; DB06216; Asenapine.
DR   DrugBank; DB00972; Azelastine.
DR   DrugBank; DB00272; Betazole.
DR   DrugBank; DB00501; Cimetidine.
DR   DrugBank; DB00434; Cyproheptadine.
DR   DrugBank; DB01142; Doxepin.
DR   DrugBank; DB00751; Epinastine.
DR   DrugBank; DB00927; Famotidine.
DR   DrugBank; DB05381; Histamine.
DR   DrugBank; DB05369; HZT-501.
DR   DrugBank; DB00408; Loxapine.
DR   DrugBank; DB00940; Methantheline.
DR   DrugBank; DB08805; Metiamide.
DR   DrugBank; DB13760; Niperotidine.
DR   DrugBank; DB00585; Nizatidine.
DR   DrugBank; DB00768; Olopatadine.
DR   DrugBank; DB01069; Promethazine.
DR   DrugBank; DB00863; Ranitidine.
DR   DrugBank; DB08806; Roxatidine acetate.
DR   DrugBank; DB00797; Tolazoline.
DR   DrugBank; DB09185; Viloxazine.
DR   DrugCentral; P25021; -.
DR   GuidetoPHARMACOLOGY; 263; -.
DR   GlyCosmos; P25021; 1 site, No reported glycans.
DR   GlyGen; P25021; 1 site.
DR   PhosphoSitePlus; P25021; -.
DR   BioMuta; HRH2; -.
DR   DMDM; 123120; -.
DR   PaxDb; 9606-ENSP00000366506; -.
DR   PeptideAtlas; P25021; -.
DR   Antibodypedia; 2931; 370 antibodies from 39 providers.
DR   DNASU; 3274; -.
DR   Ensembl; ENST00000377291.2; ENSP00000366506.2; ENSG00000113749.8. [P25021-2]
DR   GeneID; 3274; -.
DR   KEGG; hsa:3274; -.
DR   UCSC; uc003mdc.5; human. [P25021-1]
DR   AGR; HGNC:5183; -.
DR   CTD; 3274; -.
DR   DisGeNET; 3274; -.
DR   GeneCards; HRH2; -.
DR   HGNC; HGNC:5183; HRH2.
DR   HPA; ENSG00000113749; Tissue enhanced (bone marrow, heart muscle).
DR   MIM; 142703; gene.
DR   neXtProt; NX_P25021; -.
DR   OpenTargets; ENSG00000113749; -.
DR   PharmGKB; PA29457; -.
DR   VEuPathDB; HostDB:ENSG00000113749; -.
DR   eggNOG; KOG3656; Eukaryota.
DR   GeneTree; ENSGT00940000158761; -.
DR   HOGENOM; CLU_009579_11_0_1; -.
DR   InParanoid; P25021; -.
DR   OMA; SQKRMDF; -.
DR   OrthoDB; 2900736at2759; -.
DR   PhylomeDB; P25021; -.
DR   TreeFam; TF316350; -.
DR   PathwayCommons; P25021; -.
DR   Reactome; R-HSA-390650; Histamine receptors.
DR   Reactome; R-HSA-418555; G alpha (s) signalling events.
DR   SignaLink; P25021; -.
DR   SIGNOR; P25021; -.
DR   BioGRID-ORCS; 3274; 15 hits in 1155 CRISPR screens.
DR   GeneWiki; Histamine_H2_receptor; -.
DR   GenomeRNAi; 3274; -.
DR   Pharos; P25021; Tclin.
DR   PRO; PR:P25021; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   RNAct; P25021; Protein.
DR   Bgee; ENSG00000113749; Expressed in monocyte and 116 other cell types or tissues.
DR   ExpressionAtlas; P25021; baseline and differential.
DR   GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0045202; C:synapse; IEA:GOC.
DR   GO; GO:0004993; F:G protein-coupled serotonin receptor activity; IBA:GO_Central.
DR   GO; GO:0004969; F:histamine receptor activity; TAS:ProtInc.
DR   GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central.
DR   GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
DR   GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; IBA:GO_Central.
DR   GO; GO:0001696; P:gastric acid secretion; IEA:InterPro.
DR   GO; GO:0006955; P:immune response; TAS:ProtInc.
DR   GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:InterPro.
DR   CDD; cd15051; 7tmA_Histamine_H2R; 1.
DR   Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1.
DR   InterPro; IPR000276; GPCR_Rhodpsn.
DR   InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR   InterPro; IPR000503; Histamine_H2_rcpt.
DR   PANTHER; PTHR24247; 5-HYDROXYTRYPTAMINE RECEPTOR; 1.
DR   PANTHER; PTHR24247:SF276; HISTAMINE H2 RECEPTOR; 1.
DR   Pfam; PF00001; 7tm_1; 1.
DR   PRINTS; PR00237; GPCRRHODOPSN.
DR   PRINTS; PR00531; HISTAMINEH2R.
DR   SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR   SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1.
DR   PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR   PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
DR   Genevisible; P25021; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell membrane; Disulfide bond;
KW   G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Palmitate;
KW   Receptor; Reference proteome; Transducer; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..359
FT                   /note="Histamine H2 receptor"
FT                   /id="PRO_0000069684"
FT   TOPO_DOM        1..22
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        23..44
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        45..57
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        58..81
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        82..92
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        93..114
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        115..134
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        135..159
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        160..180
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        181..204
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        205..234
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        235..258
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        259..267
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        268..289
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        290..359
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          316..340
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            98
FT                   /note="Essential for histamine binding"
FT                   /evidence="ECO:0000250"
FT   SITE            186
FT                   /note="Essential for tiotidine binding and implicated in H2
FT                   selectivity"
FT                   /evidence="ECO:0000250"
FT   SITE            190
FT                   /note="Implicated in histamine binding"
FT                   /evidence="ECO:0000250"
FT   LIPID           305
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        4
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        91..174
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT   VAR_SEQ         359
FT                   /note="R -> RPWLCLPECWSVELTHSFIHLFIHSFANIHPIPTTCQEL (in
FT                   isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_043594"
FT   VARIANT         217
FT                   /note="N -> D"
FT                   /id="VAR_009958"
FT   VARIANT         231
FT                   /note="K -> R"
FT                   /id="VAR_009959"
FT   VARIANT         268
FT                   /note="V -> M"
FT                   /id="VAR_009960"
FT   CONFLICT        133
FT                   /note="V -> A (in Ref. 9; CAA66832)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        175
FT                   /note="K -> N (in Ref. 9; CAA66832)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        207
FT                   /note="K -> R (in Ref. 9; CAA66832)"
FT                   /evidence="ECO:0000305"
FT   HELIX           17..45
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           54..69
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           71..81
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           88..103
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   TURN            104..107
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           108..121
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           126..129
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           132..152
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   TURN            153..156
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           182..190
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           192..199
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           245..260
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           267..291
FT                   /evidence="ECO:0007829|PDB:7UL3"
FT   HELIX           293..302
FT                   /evidence="ECO:0007829|PDB:7UL3"
SQ   SEQUENCE   359 AA;  40098 MW;  9835AE2BA60B9B0F CRC64;
     MAPNGTASSF CLDSTACKIT ITVVLAVLIL ITVAGNVVVC LAVGLNRRLR NLTNCFIVSL
     AITDLLLGLL VLPFSAIYQL SCKWSFGKVF CNIYTSLDVM LCTASILNLF MISLDRYCAV
     MDPLRYPVLV TPVRVAISLV LIWVISITLS FLSIHLGWNS RNETSKGNHT TSKCKVQVNE
     VYGLVDGLVT FYLPLLIMCI TYYRIFKVAR DQAKRINHIS SWKAATIREH KATVTLAAVM
     GAFIICWFPY FTAFVYRGLR GDDAINEVLE AIVLWLGYAN SALNPILYAA LNRDFRTGYQ
     QLFCCRLANR NSHKTSLRSN ASQLSRTQSR EPRQQEEKPL KLQVWSGTEV TAPQGATDR
//