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Protein

Histamine H4 receptor

Gene

HRH4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist).1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-HSA-390650. Histamine receptors.
R-HSA-418594. G alpha (i) signalling events.

Names & Taxonomyi

Protein namesi
Recommended name:
Histamine H4 receptor
Short name:
H4R
Short name:
HH4R
Alternative name(s):
AXOR35
G-protein coupled receptor 105
GPRv53
Pfi-013
SP9144
Gene namesi
Name:HRH4
Synonyms:GPCR105
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 18

Organism-specific databases

HGNCiHGNC:17383. HRH4.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 1919ExtracellularSequence analysisAdd
BLAST
Transmembranei20 – 4021Helical; Name=1Sequence analysisAdd
BLAST
Topological domaini41 – 5212CytoplasmicSequence analysisAdd
BLAST
Transmembranei53 – 7321Helical; Name=2Sequence analysisAdd
BLAST
Topological domaini74 – 8714ExtracellularSequence analysisAdd
BLAST
Transmembranei88 – 10821Helical; Name=3Sequence analysisAdd
BLAST
Topological domaini109 – 13123CytoplasmicSequence analysisAdd
BLAST
Transmembranei132 – 15221Helical; Name=4Sequence analysisAdd
BLAST
Topological domaini153 – 17220ExtracellularSequence analysisAdd
BLAST
Transmembranei173 – 19321Helical; Name=5Sequence analysisAdd
BLAST
Topological domaini194 – 304111CytoplasmicSequence analysisAdd
BLAST
Transmembranei305 – 32521Helical; Name=6Sequence analysisAdd
BLAST
Topological domaini326 – 34116ExtracellularSequence analysisAdd
BLAST
Transmembranei342 – 36221Helical; Name=7Sequence analysisAdd
BLAST
Topological domaini363 – 39028CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA134982275.

Chemistry

ChEMBLiCHEMBL2111378.
DrugBankiDB00321. Amitriptyline.
DB00543. Amoxapine.
DB00477. Chlorpromazine.
DB00363. Clozapine.
DB01142. Doxepin.
DB00667. Histamine Phosphate.
DB00408. Loxapine.
DB06148. Mianserin.
DB00334. Olanzapine.
GuidetoPHARMACOLOGYi265.

Polymorphism and mutation databases

BioMutaiHRH4.
DMDMi14194819.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 390390Histamine H4 receptorPRO_0000069693Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi5 – 51N-linked (GlcNAc...)Sequence analysis
Glycosylationi9 – 91N-linked (GlcNAc...)Sequence analysis
Disulfide bondi87 ↔ 164PROSITE-ProRule annotation

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ9H3N8.
PRIDEiQ9H3N8.

Expressioni

Tissue specificityi

Expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, dendritic cells, monocytes, mast cells, neutrophils. Also expressed in a wide variety of peripheral tissues, including the heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small intestine, spleen, testis, colon, fetal liver and lymph node.1 Publication

Inductioni

Expression is either up-regulated or down-regulated upon activation of the lymphoid tissues and this regulation may depend on the presence of IL10/interleukin-10 or IL13/interleukin-13.

Gene expression databases

BgeeiQ9H3N8.
CleanExiHS_HRH4.
GenevisibleiQ9H3N8. HS.

Organism-specific databases

HPAiHPA035009.

Interactioni

Protein-protein interaction databases

STRINGi9606.ENSP00000256906.

Chemistry

BindingDBiQ9H3N8.

Structurei

3D structure databases

ProteinModelPortaliQ9H3N8.
SMRiQ9H3N8. Positions 16-373.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
GeneTreeiENSGT00780000121874.
HOGENOMiHOG000048707.
HOVERGENiHBG102132.
InParanoidiQ9H3N8.
KOiK04152.
OMAiNIYWSLW.
OrthoDBiEOG7XWPNM.
PhylomeDBiQ9H3N8.
TreeFamiTF351747.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR008102. Histamine_H4_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01726. HISTAMINEH4R.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9H3N8-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MPDTNSTINL SLSTRVTLAF FMSLVAFAIM LGNALVILAF VVDKNLRHRS
60 70 80 90 100
SYFFLNLAIS DFFVGVISIP LYIPHTLFEW DFGKEICVFW LTTDYLLCTA
110 120 130 140 150
SVYNIVLISY DRYLSVSNAV SYRTQHTGVL KIVTLMVAVW VLAFLVNGPM
160 170 180 190 200
ILVSESWKDE GSECEPGFFS EWYILAITSF LEFVIPVILV AYFNMNIYWS
210 220 230 240 250
LWKRDHLSRC QSHPGLTAVS SNICGHSFRG RLSSRRSLSA STEVPASFHS
260 270 280 290 300
ERQRRKSSLM FSSRTKMNSN TIASKMGSFS QSDSVALHQR EHVELLRARR
310 320 330 340 350
LAKSLAILLG VFAVCWAPYS LFTIVLSFYS SATGPKSVWY RIAFWLQWFN
360 370 380 390
SFVNPLLYPL CHKRFQKAFL KIFCIKKQPL PSQHSRSVSS
Length:390
Mass (Da):44,496
Last modified:June 1, 2001 - v2
Checksum:iC986B8AE7FF912C3
GO
Isoform 2 (identifier: Q9H3N8-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     65-152: Missing.

Note: No experimental confirmation available.
Show »
Length:302
Mass (Da):34,497
Checksum:i9B67B07543663052
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti253 – 2531Q → R in BAB13698 (PubMed:10973974).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti138 – 1381A → V.1 Publication
Corresponds to variant rs11665084 [ dbSNP | Ensembl ].
VAR_033477
Natural varianti206 – 2061H → R.1 Publication
Corresponds to variant rs11662595 [ dbSNP | Ensembl ].
VAR_033478

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei65 – 15288Missing in isoform 2. 1 PublicationVSP_042737Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB044934 mRNA. Translation: BAB13698.1.
AB045370 mRNA. Translation: BAB20091.1.
AF307973 mRNA. Translation: AAG32052.1.
AF312230 mRNA. Translation: AAK12081.1.
AF329449 mRNA. Translation: AAK43542.1.
AF325356 mRNA. Translation: AAL01684.1.
AJ298292 mRNA. Translation: CAC83493.1.
DQ835186 mRNA. Translation: ABI54174.1.
AY136745 mRNA. Translation: AAN01271.1.
EF444982 Genomic DNA. Translation: ACA05997.1.
AC007922 Genomic DNA. No translation available.
CH471088 Genomic DNA. Translation: EAX01189.1.
BC069136 mRNA. Translation: AAH69136.1.
BC112348 mRNA. Translation: AAI12349.1.
CCDSiCCDS11887.1. [Q9H3N8-1]
CCDS45841.1. [Q9H3N8-2]
PIRiJC7566.
RefSeqiNP_001137300.1. NM_001143828.1. [Q9H3N8-2]
NP_001153638.1. NM_001160166.1.
NP_067637.2. NM_021624.3. [Q9H3N8-1]
UniGeneiHs.287388.

Genome annotation databases

EnsembliENST00000256906; ENSP00000256906; ENSG00000134489. [Q9H3N8-1]
ENST00000426880; ENSP00000402526; ENSG00000134489. [Q9H3N8-2]
GeneIDi59340.
KEGGihsa:59340.
UCSCiuc002kvi.3. human. [Q9H3N8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB044934 mRNA. Translation: BAB13698.1.
AB045370 mRNA. Translation: BAB20091.1.
AF307973 mRNA. Translation: AAG32052.1.
AF312230 mRNA. Translation: AAK12081.1.
AF329449 mRNA. Translation: AAK43542.1.
AF325356 mRNA. Translation: AAL01684.1.
AJ298292 mRNA. Translation: CAC83493.1.
DQ835186 mRNA. Translation: ABI54174.1.
AY136745 mRNA. Translation: AAN01271.1.
EF444982 Genomic DNA. Translation: ACA05997.1.
AC007922 Genomic DNA. No translation available.
CH471088 Genomic DNA. Translation: EAX01189.1.
BC069136 mRNA. Translation: AAH69136.1.
BC112348 mRNA. Translation: AAI12349.1.
CCDSiCCDS11887.1. [Q9H3N8-1]
CCDS45841.1. [Q9H3N8-2]
PIRiJC7566.
RefSeqiNP_001137300.1. NM_001143828.1. [Q9H3N8-2]
NP_001153638.1. NM_001160166.1.
NP_067637.2. NM_021624.3. [Q9H3N8-1]
UniGeneiHs.287388.

3D structure databases

ProteinModelPortaliQ9H3N8.
SMRiQ9H3N8. Positions 16-373.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000256906.

Chemistry

BindingDBiQ9H3N8.
ChEMBLiCHEMBL2111378.
DrugBankiDB00321. Amitriptyline.
DB00543. Amoxapine.
DB00477. Chlorpromazine.
DB00363. Clozapine.
DB01142. Doxepin.
DB00667. Histamine Phosphate.
DB00408. Loxapine.
DB06148. Mianserin.
DB00334. Olanzapine.
GuidetoPHARMACOLOGYi265.

Protein family/group databases

GPCRDBiSearch...

Polymorphism and mutation databases

BioMutaiHRH4.
DMDMi14194819.

Proteomic databases

PaxDbiQ9H3N8.
PRIDEiQ9H3N8.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000256906; ENSP00000256906; ENSG00000134489. [Q9H3N8-1]
ENST00000426880; ENSP00000402526; ENSG00000134489. [Q9H3N8-2]
GeneIDi59340.
KEGGihsa:59340.
UCSCiuc002kvi.3. human. [Q9H3N8-1]

Organism-specific databases

CTDi59340.
GeneCardsiHRH4.
HGNCiHGNC:17383. HRH4.
HPAiHPA035009.
MIMi606792. gene.
neXtProtiNX_Q9H3N8.
PharmGKBiPA134982275.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
GeneTreeiENSGT00780000121874.
HOGENOMiHOG000048707.
HOVERGENiHBG102132.
InParanoidiQ9H3N8.
KOiK04152.
OMAiNIYWSLW.
OrthoDBiEOG7XWPNM.
PhylomeDBiQ9H3N8.
TreeFamiTF351747.

Enzyme and pathway databases

ReactomeiR-HSA-390650. Histamine receptors.
R-HSA-418594. G alpha (i) signalling events.

Miscellaneous databases

GeneWikiiHistamine_H4_receptor.
GenomeRNAii59340.
NextBioi65224.
PROiQ9H3N8.
SOURCEiSearch...

Gene expression databases

BgeeiQ9H3N8.
CleanExiHS_HRH4.
GenevisibleiQ9H3N8. HS.

Family and domain databases

InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR008102. Histamine_H4_rcpt.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00237. GPCRRHODOPSN.
PR01726. HISTAMINEH4R.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes."
    Oda T., Morikawa N., Saito Y., Masuho Y., Matsumoto S.
    J. Biol. Chem. 275:36781-36786(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS VAL-138 AND ARG-206.
  2. "Molecular cloning and characterization of a new human histamine receptor, HH4R."
    Nakamura T., Itadani H., Hidaka Y., Ohta M., Tanaka K.
    Biochem. Biophys. Res. Commun. 279:615-620(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION.
    Tissue: Leukocyte.
  3. "Cloning of a novel histamine receptor."
    Jones P.G., Wu S., Betty M.
    Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  4. "Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow."
    Liu C., Ma X.-J., Jiang X., Wilson S.J., Hofstra C.L., Blevitt J., Pyati J., Li X., Chai W., Carruthers N., Lovenberg T.W.
    Mol. Pharmacol. 59:420-426(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION.
    Tissue: Bone marrow.
  5. "Cloning and characterization of a novel human histamine receptor."
    Morse K.L., Behan J., Laz T.M., West R.E. Jr., Greenfeder S.A., Anthes J.C., Umland S., Wan Y., Hipkin R.W., Gonsiorek W., Shin N., Gustafson E.L., Qiao X., Wang S., Hedrick J.A., Greene J., Bayne M., Monsma F.J. Jr.
    J. Pharmacol. Exp. Ther. 296:1058-1066(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION.
    Tissue: Eosinophil.
  6. "Cloning, expression, and pharmacological characterization of a novel human histamine receptor."
    Zhu Y., Michalovich D., Wu H.-L., Tan K.B., Dytko G.M., Mannan I.J., Boyce R., Alston J., Tierney L.A., Li X., Herrity N.C., Vawter L., Sarau H.M., Ames R.S., Davenport C.M., Hieble P., Wilson S., Bergsma D.J., Fitzgerald L.R.
    Mol. Pharmacol. 59:434-441(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
  7. "Identification of a histamine H4 receptor on human eosinophils --role in eosinophil chemotaxis."
    O'Reilly M.A., Alpert R., Jenkinson S., Gladue R.P., Foo S., Trim S., Peter B., Trevethick M., Fidock M.
    J. Recept. Signal Transduct. 22:431-448(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY.
  8. "Cloning and characterization of dominant negative splice variants of the human histamine H4 receptor."
    van Rijn R.M., van Marle A., Chazot P.L., Langemeijer E., Qin Y., Shenton F.C., Lim H.D., Zuiderveld O.P., Sansuk K., Dy M., Smit M.J., Tensen C.P., Bakker R.A., Leurs R.
    Biochem. J. 414:121-131(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
    Tissue: Umbilical cord blood.
  9. "cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org)."
    Puhl H.L. III, Ikeda S.R., Aronstam R.S.
    Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
  10. NHLBI resequencing and genotyping service (RS&G)
    Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  11. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  12. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  13. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).

Entry informationi

Entry nameiHRH4_HUMAN
AccessioniPrimary (citable) accession number: Q9H3N8
Secondary accession number(s): B0YJ19
, B2KJ48, Q4G0I6, Q9GZQ0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: June 1, 2001
Last modified: May 11, 2016
This is version 145 of the entry and version 2 of the sequence. [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

Miscellaneous

Does not bind diphenhydramine, loratadine, ranitidine, cimetidine and chlorpheniramine. Shows modest affinity for dimaprit, impromidine, clobenpropit, thioperamide, burimamide clozapine, immepip and imetit. The order of inhibitory activity was imetit > clobenpropit > burimamide > thioperamide. Clobenpropit behaves as a partial agonist, dimaprit and impromidine show some agonist activity while clozapine behaves as a full agonist. Thioperamide shows inverse agonism (enhances cAMP activity). The order of inhibitory activity of histamine derivatives was Histamine > N-alpha-methylhistamine > R--alpha-methylhistamine > S+-alpha-methylhistamine. Both N-alpha-methylhistamine > R--alpha-methylhistamine behave as full agonists.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 18
    Human chromosome 18: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.