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 28-JAN-2026, entry version 203. 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). RN [11] {ECO:0007744|PDB:8YUT} RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF 2-359, DISULFIDE RP BONDS, FUNCTION, AND INTERACTION WITH GNAS. RX PubMed=38647423; DOI=10.1002/advs.202310120; RA Shen Q., Tang X., Wen X., Cheng S., Xiao P., Zang S.K., Shen D.D., RA Jiang L., Zheng Y., Zhang H., Xu H., Mao C., Zhang M., Hu W., Sun J.P., RA Zhang Y., Chen Z.; RT "Molecular Determinant Underlying Selective Coupling of Primary G-Protein RT by Class A GPCRs."; RL Adv. Sci. 11:e2310120-e2310120(2024). RN [12] {ECO:0007744|PDB:8POK} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), DISULFIDE BONDS, AND RP TOPOLOGY. RX PubMed=38418462; DOI=10.1038/s41467-024-46096-z; RA Kock Z., Schnelle K., Persechino M., Umbach S., Schihada H., Januliene D., RA Parey K., Pockes S., Kolb P., Dotsch V., Moller A., Hilger D., Bernhard F.; RT "Cryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs RT complex in nanodisc environment."; RL Nat. Commun. 15:1831-1831(2024). RN [13] {ECO:0007744|PDB:8YN3, ECO:0007744|PDB:8YN4} RP STRUCTURE BY ELECTRON MICROSCOPY (2.56 ANGSTROMS) OF 1-312, DISULFIDE RP BONDS, AND FUNCTION. RX PubMed=39333117; DOI=10.1038/s41467-024-52585-y; RA Zhang X., Liu G., Zhong Y.N., Zhang R., Yang C.C., Niu C., Pu X., Sun J., RA Zhang T., Yang L., Zhang C., Li X., Shen X., Xiao P., Sun J.P., Gong W.; RT "Structural basis of ligand recognition and activation of the histamine RT receptor family."; RL Nat. Commun. 15:8296-8296(2024). CC -!- FUNCTION: G-protein coupled receptor for histamine, primarily mediating CC gastric acid secretion. Predominantly expressed in the gastric mucosa, CC couples to G(s) G alpha proteins upon histamine binding, leading to CC activation of adenylate cyclase and increased intracellular cyclic AMP CC (cAMP) levels (PubMed:38647423, PubMed:39333117). This signaling CC cascade stimulates parietal cells to secrete hydrochloric acid, playing CC a key role in digestive physiology. Also expressed in other tissues, CC including the heart and central nervous system, where it may contribute CC to cardiac stimulation and modulate neurotransmitter release (By CC similarity). {ECO:0000250|UniProtKB:P97292, CC ECO:0000269|PubMed:38647423, ECO:0000269|PubMed:39333117}. CC -!- SUBUNIT: Interacts with GNAS. {ECO:0000269|PubMed:38647423}. 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"; 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; 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_001131055.2. [P25021-2] DR PDB; 7UL3; EM; 3.00 A; A=1-199, A=248-359. DR PDB; 8POK; EM; 3.40 A; A=1-359. DR PDB; 8YN3; EM; 2.56 A; R=1-312. DR PDB; 8YN4; EM; 2.97 A; R=1-312. DR PDB; 8YUT; EM; 2.70 A; R=2-359. DR PDB; 9IXJ; EM; 2.92 A; R=1-359. DR PDBsum; 7UL3; -. DR PDBsum; 8POK; -. DR PDBsum; 8YN3; -. DR PDBsum; 8YN4; -. DR PDBsum; 8YUT; -. DR PDBsum; 9IXJ; -. DR AlphaFoldDB; P25021; -. DR EMDB; EMD-17793; -. DR EMDB; EMD-26590; -. DR EMDB; EMD-39413; -. DR EMDB; EMD-39414; -. DR EMDB; EMD-39582; -. DR EMDB; EMD-60971; -. DR SMR; P25021; -. DR BioGRID; 109510; 1. DR CORUM; P25021; -. DR FunCoup; P25021; 1004. 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; DB12884; Lavoltidine. 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; 339 antibodies from 38 providers. DR DNASU; 3274; -. DR Ensembl; ENST00000377291.2; ENSP00000366506.2; ENSG00000113749.9. [P25021-2] DR GeneID; 3274; -. DR KEGG; hsa:3274; -. DR UCSC; uc003mdc.5; human. [P25021-1] DR AGR; HGNC:5183; -. DR ClinPGx; PA29457; -. 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 OpenTargets; ENSG00000113749; -. DR VEuPathDB; HostDB:ENSG00000113749; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT00940000158761; -. DR HOGENOM; CLU_009579_11_0_1; -. DR InParanoid; P25021; -. DR OMA; CGNVMVC; -. DR OrthoDB; 5951059at2759; -. DR PAN-GO; P25021; 6 GO annotations based on evolutionary models. DR PhylomeDB; P25021; -. 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 Agora; ENSG00000113749; -. 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; IBA:GO_Central. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0004969; F:histamine receptor activity; IDA:UniProt. DR GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; TAS:UniProt. 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 FunFam; 1.20.1070.10:FF:000121; Histamine H2 receptor; 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:SF278; 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. 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 Proteomics identification; Receptor; Reference proteome; Transducer; KW Transmembrane; Transmembrane helix. FT CHAIN 1..359 FT /note="Histamine H2 receptor" FT /id="PRO_0000069684" FT TOPO_DOM 1..20 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 21..44 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 45..53 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 54..75 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 76..91 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 92..114 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 115..133 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 134..156 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 157..174 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 175..202 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 203..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 233..259 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 260..268 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:38418462" FT TRANSMEM 269..291 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:38418462" FT TOPO_DOM 292..359 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:38418462" FT REGION 316..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 317..327 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 328..340 FT /note="Basic and acidic residues" 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:0000269|PubMed:38418462, FT ECO:0000269|PubMed:38647423, ECO:0000269|PubMed:39333117" 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 15..45 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 52..54 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 55..70 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 72..81 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 88..121 FT /evidence="ECO:0007829|PDB:8YN3" FT TURN 123..125 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 126..129 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 132..155 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 180..190 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 192..217 FT /evidence="ECO:0007829|PDB:8YN3" FT STRAND 221..223 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 231..260 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 267..287 FT /evidence="ECO:0007829|PDB:8YN3" FT TURN 288..291 FT /evidence="ECO:0007829|PDB:8YN3" FT HELIX 293..301 FT /evidence="ECO:0007829|PDB:8YN3" 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 //