HRH4_HUMAN
ID HRH4_HUMAN Reviewed; 390 AA.
AC Q9H3N8; B0YJ19; B2KJ48; Q4G0I6; Q9GZQ0;
DT 01-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 2.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=Histamine H4 receptor;
DE Short=H4R;
DE Short=HH4R;
DE AltName: Full=AXOR35;
DE AltName: Full=G-protein coupled receptor 105;
DE AltName: Full=GPRv53;
DE AltName: Full=Pfi-013;
DE AltName: Full=SP9144;
GN Name=HRH4; Synonyms=GPCR105;
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 [MRNA] (ISOFORM 1), AND VARIANTS VAL-138 AND ARG-206.
RX PubMed=10973974; DOI=10.1074/jbc.m006480200;
RA Oda T., Morikawa N., Saito Y., Masuho Y., Matsumoto S.;
RT "Molecular cloning and characterization of a novel type of histamine
RT receptor preferentially expressed in leukocytes.";
RL J. Biol. Chem. 275:36781-36786(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RC TISSUE=Leukocyte;
RX PubMed=11118334; DOI=10.1006/bbrc.2000.4008;
RA Nakamura T., Itadani H., Hidaka Y., Ohta M., Tanaka K.;
RT "Molecular cloning and characterization of a new human histamine receptor,
RT HH4R.";
RL Biochem. Biophys. Res. Commun. 279:615-620(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Jones P.G., Wu S., Betty M.;
RT "Cloning of a novel histamine receptor.";
RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RC TISSUE=Bone marrow;
RX PubMed=11179434; DOI=10.1124/mol.59.3.420;
RA Liu C., Ma X.-J., Jiang X., Wilson S.J., Hofstra C.L., Blevitt J.,
RA Pyati J., Li X., Chai W., Carruthers N., Lovenberg T.W.;
RT "Cloning and pharmacological characterization of a fourth histamine
RT receptor (H4) expressed in bone marrow.";
RL Mol. Pharmacol. 59:420-426(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION.
RC TISSUE=Eosinophil;
RX PubMed=11181941;
RA Morse K.L., Behan J., Laz T.M., West R.E. Jr., Greenfeder S.A.,
RA Anthes J.C., Umland S., Wan Y., Hipkin R.W., Gonsiorek W., Shin N.,
RA Gustafson E.L., Qiao X., Wang S., Hedrick J.A., Greene J., Bayne M.,
RA Monsma F.J. Jr.;
RT "Cloning and characterization of a novel human histamine receptor.";
RL J. Pharmacol. Exp. Ther. 296:1058-1066(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11179436; DOI=10.1124/mol.59.3.434;
RA Zhu Y., Michalovich D., Wu H.-L., Tan K.B., Dytko G.M., Mannan I.J.,
RA Boyce R., Alston J., Tierney L.A., Li X., Herrity N.C., Vawter L.,
RA Sarau H.M., Ames R.S., Davenport C.M., Hieble P., Wilson S., Bergsma D.J.,
RA Fitzgerald L.R.;
RT "Cloning, expression, and pharmacological characterization of a novel human
RT histamine receptor.";
RL Mol. Pharmacol. 59:434-441(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12503632; DOI=10.1081/rrs-120014612;
RA O'Reilly M.A., Alpert R., Jenkinson S., Gladue R.P., Foo S., Trim S.,
RA Peter B., Trevethick M., Fidock M.;
RT "Identification of a histamine H4 receptor on human eosinophils --role in
RT eosinophil chemotaxis.";
RL J. Recept. Signal Transduct. 22:431-448(2002).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Umbilical cord blood;
RX PubMed=18452403; DOI=10.1042/bj20071583;
RA van Rijn R.M., van Marle A., Chazot P.L., Langemeijer E., Qin Y.,
RA Shenton F.C., Lim H.D., Zuiderveld O.P., Sansuk K., Dy M., Smit M.J.,
RA Tensen C.P., Bakker R.A., Leurs R.;
RT "Cloning and characterization of dominant negative splice variants of the
RT human histamine H4 receptor.";
RL Biochem. J. 414:121-131(2008).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [12]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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).
CC -!- FUNCTION: The H4 subclass of histamine receptors could mediate the
CC histamine signals in peripheral tissues. Displays a significant level
CC of constitutive activity (spontaneous activity in the absence of
CC agonist). {ECO:0000269|PubMed:12503632}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H3N8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H3N8-2; Sequence=VSP_042737;
CC -!- TISSUE SPECIFICITY: Expressed primarily in the bone marrow and
CC eosinophils. Shows preferential distribution in cells of immunological
CC relevance such as T-cells, dendritic cells, monocytes, mast cells,
CC neutrophils. Also expressed in a wide variety of peripheral tissues,
CC including the heart, kidney, liver, lung, pancreas, skeletal muscle,
CC prostate, small intestine, spleen, testis, colon, fetal liver and lymph
CC node. {ECO:0000269|PubMed:12503632}.
CC -!- INDUCTION: Expression is either up-regulated or down-regulated upon
CC activation of the lymphoid tissues and this regulation may depend on
CC the presence of IL10/interleukin-10 or IL13/interleukin-13.
CC -!- MISCELLANEOUS: Does not bind diphenhydramine, loratadine, ranitidine,
CC cimetidine and chlorpheniramine. Shows modest affinity for dimaprit,
CC impromidine, clobenpropit, thioperamide, burimamide clozapine, immepip
CC and imetit. The order of inhibitory activity was imetit > clobenpropit
CC > burimamide > thioperamide. Clobenpropit behaves as a partial agonist,
CC dimaprit and impromidine show some agonist activity while clozapine
CC behaves as a full agonist. Thioperamide shows inverse agonism (enhances
CC cAMP activity). The order of inhibitory activity of histamine
CC derivatives was Histamine > N-alpha-methylhistamine > R(-)-alpha-
CC methylhistamine > S(+)-alpha-methylhistamine. Both N-alpha-
CC methylhistamine > R(-)-alpha-methylhistamine behave as full agonists.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AB044934; BAB13698.1; -; mRNA.
DR EMBL; AB045370; BAB20091.1; -; mRNA.
DR EMBL; AF307973; AAG32052.1; -; mRNA.
DR EMBL; AF312230; AAK12081.1; -; mRNA.
DR EMBL; AF329449; AAK43542.1; -; mRNA.
DR EMBL; AF325356; AAL01684.1; -; mRNA.
DR EMBL; AJ298292; CAC83493.1; -; mRNA.
DR EMBL; DQ835186; ABI54174.1; -; mRNA.
DR EMBL; AY136745; AAN01271.1; -; mRNA.
DR EMBL; EF444982; ACA05997.1; -; Genomic_DNA.
DR EMBL; AC007922; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471088; EAX01189.1; -; Genomic_DNA.
DR EMBL; BC069136; AAH69136.1; -; mRNA.
DR EMBL; BC112348; AAI12349.1; -; mRNA.
DR CCDS; CCDS11887.1; -. [Q9H3N8-1]
DR CCDS; CCDS45841.1; -. [Q9H3N8-2]
DR PIR; JC7566; JC7566.
DR RefSeq; NP_001137300.1; NM_001143828.1. [Q9H3N8-2]
DR RefSeq; NP_001153638.1; NM_001160166.1.
DR RefSeq; NP_067637.2; NM_021624.3. [Q9H3N8-1]
DR AlphaFoldDB; Q9H3N8; -.
DR SMR; Q9H3N8; -.
DR STRING; 9606.ENSP00000256906; -.
DR BindingDB; Q9H3N8; -.
DR ChEMBL; CHEMBL3759; -.
DR DrugBank; DB00321; Amitriptyline.
DR DrugBank; DB00543; Amoxapine.
DR DrugBank; DB01238; Aripiprazole.
DR DrugBank; DB00477; Chlorpromazine.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB01142; Doxepin.
DR DrugBank; DB05381; Histamine.
DR DrugBank; DB00408; Loxapine.
DR DrugBank; DB06148; Mianserin.
DR DrugBank; DB01620; Pheniramine.
DR DrugBank; DB05032; REV131.
DR DrugCentral; Q9H3N8; -.
DR GuidetoPHARMACOLOGY; 265; -.
DR GlyGen; Q9H3N8; 2 sites.
DR iPTMnet; Q9H3N8; -.
DR PhosphoSitePlus; Q9H3N8; -.
DR BioMuta; HRH4; -.
DR DMDM; 14194819; -.
DR jPOST; Q9H3N8; -.
DR PaxDb; Q9H3N8; -.
DR PeptideAtlas; Q9H3N8; -.
DR PRIDE; Q9H3N8; -.
DR ProteomicsDB; 80734; -. [Q9H3N8-1]
DR ProteomicsDB; 80735; -. [Q9H3N8-2]
DR Antibodypedia; 7806; 295 antibodies from 29 providers.
DR DNASU; 59340; -.
DR Ensembl; ENST00000256906.5; ENSP00000256906.4; ENSG00000134489.7. [Q9H3N8-1]
DR Ensembl; ENST00000426880.2; ENSP00000402526.2; ENSG00000134489.7. [Q9H3N8-2]
DR GeneID; 59340; -.
DR KEGG; hsa:59340; -.
DR MANE-Select; ENST00000256906.5; ENSP00000256906.4; NM_021624.4; NP_067637.2.
DR UCSC; uc002kvi.3; human. [Q9H3N8-1]
DR CTD; 59340; -.
DR DisGeNET; 59340; -.
DR GeneCards; HRH4; -.
DR HGNC; HGNC:17383; HRH4.
DR HPA; ENSG00000134489; Not detected.
DR MIM; 606792; gene.
DR neXtProt; NX_Q9H3N8; -.
DR OpenTargets; ENSG00000134489; -.
DR PharmGKB; PA134982275; -.
DR VEuPathDB; HostDB:ENSG00000134489; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT00940000162118; -.
DR HOGENOM; CLU_009579_11_2_1; -.
DR InParanoid; Q9H3N8; -.
DR OMA; VSYRTQH; -.
DR OrthoDB; 614573at2759; -.
DR PhylomeDB; Q9H3N8; -.
DR TreeFam; TF351747; -.
DR PathwayCommons; Q9H3N8; -.
DR Reactome; R-HSA-390650; Histamine receptors.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR SignaLink; Q9H3N8; -.
DR SIGNOR; Q9H3N8; -.
DR BioGRID-ORCS; 59340; 16 hits in 1067 CRISPR screens.
DR GeneWiki; Histamine_H4_receptor; -.
DR GenomeRNAi; 59340; -.
DR Pharos; Q9H3N8; Tchem.
DR PRO; PR:Q9H3N8; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q9H3N8; protein.
DR Bgee; ENSG00000134489; Expressed in monocyte and 41 other tissues.
DR Genevisible; Q9H3N8; HS.
DR GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045202; C:synapse; IBA:GO_Central.
DR GO; GO:0016907; F:G protein-coupled acetylcholine receptor activity; IBA:GO_Central.
DR GO; GO:0004993; F:G protein-coupled serotonin receptor activity; IBA:GO_Central.
DR GO; GO:0004969; F:histamine receptor activity; NAS:UniProtKB.
DR GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central.
DR GO; GO:0007197; P:adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway; 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:0006954; P:inflammatory response; IBA:GO_Central.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IEA:InterPro.
DR GO; GO:0043408; P:regulation of MAPK cascade; IEA:InterPro.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR008102; Histamine_H4_rcpt.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01726; HISTAMINEH4R.
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 Alternative splicing; Cell membrane; Disulfide bond;
KW G-protein coupled receptor; Glycoprotein; Membrane; Receptor;
KW Reference proteome; Transducer; Transmembrane; Transmembrane helix.
FT CHAIN 1..390
FT /note="Histamine H4 receptor"
FT /id="PRO_0000069693"
FT TOPO_DOM 1..19
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 20..40
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 41..52
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 53..73
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 74..87
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 88..108
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 109..131
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 132..152
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 153..172
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 173..193
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 194..304
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 305..325
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 326..341
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 342..362
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 363..390
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT CARBOHYD 5
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 9
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 87..164
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VAR_SEQ 65..152
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:18452403"
FT /id="VSP_042737"
FT VARIANT 138
FT /note="A -> V (in dbSNP:rs11665084)"
FT /evidence="ECO:0000269|PubMed:10973974"
FT /id="VAR_033477"
FT VARIANT 206
FT /note="H -> R (in dbSNP:rs11662595)"
FT /evidence="ECO:0000269|PubMed:10973974"
FT /id="VAR_033478"
FT CONFLICT 253
FT /note="Q -> R (in Ref. 1; BAB13698)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 390 AA; 44496 MW; C986B8AE7FF912C3 CRC64;
MPDTNSTINL SLSTRVTLAF FMSLVAFAIM LGNALVILAF VVDKNLRHRS SYFFLNLAIS
DFFVGVISIP LYIPHTLFEW DFGKEICVFW LTTDYLLCTA SVYNIVLISY DRYLSVSNAV
SYRTQHTGVL KIVTLMVAVW VLAFLVNGPM ILVSESWKDE GSECEPGFFS EWYILAITSF
LEFVIPVILV AYFNMNIYWS LWKRDHLSRC QSHPGLTAVS SNICGHSFRG RLSSRRSLSA
STEVPASFHS ERQRRKSSLM FSSRTKMNSN TIASKMGSFS QSDSVALHQR EHVELLRARR
LAKSLAILLG VFAVCWAPYS LFTIVLSFYS SATGPKSVWY RIAFWLQWFN SFVNPLLYPL
CHKRFQKAFL KIFCIKKQPL PSQHSRSVSS
