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P21917 (DRD4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 141. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
D(4) dopamine receptor
Alternative name(s):
D(2C) dopamine receptor
Dopamine D4 receptor
Gene names
Name:DRD4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length467 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins which inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells By similarity.

Subunit structure

Forms homo- and heterooligomers with DRD2. D4.7 allele exhibits higher affinity for homodimers compared to DRD2 heterodimers, while alleles D42. and 4.4 have similar affinities for both. The interaction with DRD2 may modulate agonist-induced downstream signaling. Interacts with CLIC6 By similarity and GPRASP1. May interact with ADORA2A. Interacts with KLHL12. Ref.9 Ref.10 Ref.11 Ref.13

Subcellular location

Cell membrane; Multi-pass membrane protein Ref.12.

Post-translational modification

Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex: polyubiquitination does not lead to degradation of DRD4 protein.

Polymorphism

The number of repeats of 16 amino acids in the third cytoplasmic loop is highly polymorphic and varies among different alleles. Alleles corresponding in size to a 2 (D4.2), 3 (D4.3), 4 (D4.4), 5 (D4.5), 6 (D4.6), 7 (D4.7) and 9 (D4.9) repeats have been described. The sequence shown is that of allele D4.7. The polymorphic repeat sequence has little influence on DRD4-binding profiles and might not be essential for G protein interaction.

Sequence similarities

Belongs to the G-protein coupled receptor 1 family.

Sequence caution

The sequence AAL58637.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
   Biological processBiological rhythms
   Cellular componentCell membrane
Membrane
   Coding sequence diversityPolymorphism
   DomainRepeat
Transmembrane
Transmembrane helix
   Molecular functionG-protein coupled receptor
Receptor
Transducer
   PTMDisulfide bond
Glycoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of MAPK activity

Inferred from direct assay PubMed 15755724PubMed 9843378. Source: BHF-UCL

adenylate cyclase-inhibiting dopamine receptor signaling pathway

Inferred from direct assay PubMed 7512953. Source: BHF-UCL

adult locomotory behavior

Inferred from sequence or structural similarity. Source: BHF-UCL

arachidonic acid secretion

Inferred from direct assay PubMed 7512953. Source: BHF-UCL

behavioral fear response

Non-traceable author statement PubMed 12860355. Source: BHF-UCL

behavioral response to cocaine

Inferred from sequence or structural similarity. Source: BHF-UCL

behavioral response to ethanol

Traceable author statement PubMed 12888781. Source: BHF-UCL

cellular calcium ion homeostasis

Inferred by curator PubMed 7921596. Source: BHF-UCL

circadian rhythm

Inferred from electronic annotation. Source: Ensembl

dopamine metabolic process

Inferred by curator Ref.2. Source: BHF-UCL

dopamine receptor signaling pathway

Inferred from direct assay Ref.2. Source: BHF-UCL

fear response

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of adenylate cyclase activity

Inferred from direct assay PubMed 7512953. Source: BHF-UCL

negative regulation of cAMP biosynthetic process

Inferred from direct assay PubMed 7512953PubMed 9843378. Source: BHF-UCL

negative regulation of protein secretion

Inferred from direct assay PubMed 16839358. Source: BHF-UCL

negative regulation of voltage-gated calcium channel activity

Inferred from direct assay PubMed 7921596. Source: BHF-UCL

olfactory learning

Inferred from electronic annotation. Source: Ensembl

photoperiodism

Inferred from electronic annotation. Source: Ensembl

positive regulation of dopamine uptake involved in synaptic transmission

Inferred by curator Ref.2. Source: BHF-UCL

positive regulation of excitatory postsynaptic membrane potential

Inferred from electronic annotation. Source: Ensembl

positive regulation of kinase activity

Inferred from direct assay PubMed 15755724. Source: BHF-UCL

positive regulation of penile erection

Inferred from electronic annotation. Source: Ensembl

positive regulation of sodium:proton antiporter activity

Inferred from direct assay PubMed 7512953. Source: BHF-UCL

regulation of calcium-mediated signaling

Inferred from electronic annotation. Source: Ensembl

regulation of circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of dopamine metabolic process

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of inhibitory postsynaptic membrane potential

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of neurotransmitter secretion

Inferred from electronic annotation. Source: Ensembl

response to amphetamine

Inferred from sequence or structural similarity. Source: BHF-UCL

response to histamine

Inferred from direct assay PubMed 16839358. Source: BHF-UCL

response to steroid hormone

Inferred from electronic annotation. Source: Ensembl

retina development in camera-type eye

Inferred from electronic annotation. Source: Ensembl

short-term memory

Inferred from electronic annotation. Source: Ensembl

social behavior

Non-traceable author statement PubMed 11126393PubMed 11409696. Source: BHF-UCL

synaptic transmission, dopaminergic

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcell cortex

Inferred from electronic annotation. Source: Ensembl

dendritic spine

Inferred from electronic annotation. Source: Ensembl

integral component of plasma membrane

Inferred from direct assay PubMed 15755724PubMed 8413587PubMed 9843378. Source: BHF-UCL

membrane

Inferred from direct assay PubMed 7512953. Source: BHF-UCL

neuronal cell body

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Traceable author statement. Source: Reactome

terminal bouton

Inferred from electronic annotation. Source: Ensembl

vesicle membrane

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionSH3 domain binding

Inferred from direct assay PubMed 9843378. Source: BHF-UCL

dopamine binding

Inferred from direct assay Ref.1. Source: BHF-UCL

dopamine neurotransmitter receptor activity

Inferred from direct assay PubMed 8413587. Source: BHF-UCL

dopamine neurotransmitter receptor activity, coupled via Gi/Go

Inferred from direct assay Ref.2. Source: BHF-UCL

drug binding

Inferred from direct assay Ref.1Ref.2PubMed 8413587. Source: BHF-UCL

identical protein binding

Inferred from physical interaction PubMed 21320289. Source: IntAct

potassium channel regulator activity

Non-traceable author statement PubMed 12297500. Source: BHF-UCL

protein binding

Inferred from physical interaction PubMed 12297500. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

itself3EBI-8592297,EBI-8592297

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 467467D(4) dopamine receptor
PRO_0000069401

Regions

Topological domain1 – 3737Extracellular Potential
Transmembrane38 – 6023Helical; Name=1; Potential
Topological domain61 – 7010Cytoplasmic Potential
Transmembrane71 – 9323Helical; Name=2; Potential
Topological domain94 – 10916Extracellular Potential
Transmembrane110 – 13122Helical; Name=3; Potential
Topological domain132 – 15120Cytoplasmic Potential
Transmembrane152 – 17524Helical; Name=4; Potential
Topological domain176 – 19116Extracellular Potential
Transmembrane192 – 21322Helical; Name=5; Potential
Topological domain214 – 394181Cytoplasmic Potential
Transmembrane395 – 41723Helical; Name=6; Potential
Topological domain418 – 4269Extracellular Potential
Transmembrane427 – 44923Helical; Name=7; Potential
Topological domain450 – 46718Cytoplasmic Potential
Repeat249 – 264161; approximate
Repeat265 – 280162
Repeat281 – 296163
Repeat297 – 312164
Repeat313 – 328165
Repeat329 – 344166
Repeat345 – 360167; approximate
Region249 – 3601127 X 16 AA approximate tandem repeats of [PA]-A-P-G-L-P-[PQR]-[DG]-P-C-G-P-D-C-A-P

Amino acid modifications

Glycosylation31N-linked (GlcNAc...) Potential
Disulfide bond108 ↔ 185 By similarity

Natural variations

Natural variant1941V → G in Afro-Caribbeans. Ref.15
Corresponds to variant rs1800443 [ dbSNP | Ensembl ].
VAR_003464
Natural variant265 – 34480Missing in allele D4.2.
VAR_003465
Natural variant281 – 32848Missing in allele D4.4.
VAR_003466
Natural variant2811A → P.
Corresponds to variant rs3889692 [ dbSNP | Ensembl ].
VAR_055914
Natural variant3291P → A in allele D4.4.
VAR_003467
Natural variant3321G → S in allele D4.4. Ref.4 Ref.6
VAR_003468

Experimental info

Sequence conflict2371R → F in BAC05985. Ref.2

Sequences

Sequence LengthMass (Da)Tools
P21917 [UniParc].

Last modified February 1, 1996. Version 2.
Checksum: B6FF2E09269A02AF

FASTA46748,361
        10         20         30         40         50         60 
MGNRSTADAD GLLAGRGPAA GASAGASAGL AGQGAAALVG GVLLIGAVLA GNSLVCVSVA 

        70         80         90        100        110        120 
TERALQTPTN SFIVSLAAAD LLLALLVLPL FVYSEVQGGA WLLSPRLCDA LMAMDVMLCT 

       130        140        150        160        170        180 
ASIFNLCAIS VDRFVAVAVP LRYNRQGGSR RQLLLIGATW LLSAAVAAPV LCGLNDVRGR 

       190        200        210        220        230        240 
DPAVCRLEDR DYVVYSSVCS FFLPCPLMLL LYWATFRGLQ RWEVARRAKL HGRAPRRPSG 

       250        260        270        280        290        300 
PGPPSPTPPA PRLPQDPCGP DCAPPAPGLP RGPCGPDCAP AAPGLPPDPC GPDCAPPAPG 

       310        320        330        340        350        360 
LPQDPCGPDC APPAPGLPRG PCGPDCAPPA PGLPQDPCGP DCAPPAPGLP PDPCGSNCAP 

       370        380        390        400        410        420 
PDAVRAAALP PQTPPQTRRR RRAKITGRER KAMRVLPVVV GAFLLCWTPF FVVHITQALC 

       430        440        450        460 
PACSVPPRLV SAVTWLGYVN SALNPVIYTV FNAEFRNVFR KALRACC 

« Hide

References

« Hide 'large scale' references
[1]"Multiple dopamine D4 receptor variants in the human population."
van Tol H.H., Wu C.M., Guan H.C., Ohara K., Bunzow J.R., Civelli O., Kennedy J., Seeman P., Niznik H.B., Jovanovic V.
Nature 358:149-152(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE D4.7).
[2]"Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine."
van Tol H.H.M., Bunzow J.R., Guan H.-C., Sunahara R.K., Seeman P., Niznik H.B., Civelli O.
Nature 350:610-614(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE D4.2).
Tissue: Brain.
[3]"Genome-wide discovery and analysis of human seven transmembrane helix receptor genes."
Suwa M., Sato T., Okouchi I., Arita M., Futami K., Matsumoto S., Tsutsumi S., Aburatani H., Asai K., Akiyama Y.
Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE D.4.4).
[4]Kaighin V.A., Martin A.L., Aronstam R.S.
Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT SER-332.
Tissue: Brain.
[5]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ALLELE D4.4).
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT SER-332.
[7]"A hypervariable segment in the human dopamine receptor D4 (DRD4) gene."
Lichter J.B., Barr C.L., Kennedy J.L., Van Tol H.H., Kidd K.K., Livak K.J.
Hum. Mol. Genet. 2:767-773(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: POLYMORPHISM.
[8]"Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes."
Asghari V., Schoots O., van Kats S., Ohara K., Jovanovic V., Guan H.-C., Bunzow J.R., Petronis A., Van Tol H.H.M.
Mol. Pharmacol. 46:364-373(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: POLYMORPHISM.
[9]"Modulation of postendocytic sorting of G protein-coupled receptors."
Whistler J.L., Enquist J., Marley A., Fong J., Gladher F., Tsuruda P., Murray S.R., Von Zastrow M.
Science 297:615-620(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GPRASP1.
[10]"BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase."
Rondou P., Haegeman G., Vanhoenacker P., Van Craenenbroeck K.
J. Biol. Chem. 283:11083-11096(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, INTERACTION WITH KLHL12.
[11]"The dopamine D(4) receptor, the ultimate disordered protein."
Woods A.S.
J. Recept. Signal Transduct. 30:331-336(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE INTERACTION WITH ADORA2A.
[12]"KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation."
Rondou P., Skieterska K., Packeu A., Lintermans B., Vanhoenacker P., Vauquelin G., Haegeman G., Van Craenenbroeck K.
Cell. Signal. 22:900-913(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, SUBCELLULAR LOCATION.
[13]"Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions."
Borroto-Escuela D.O., Van Craenenbroeck K., Romero-Fernandez W., Guidolin D., Woods A.S., Rivera A., Haegeman G., Agnati L.F., Tarakanov A.O., Fuxe K.
Biochem. Biophys. Res. Commun. 404:928-934(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: HOMOOLIGOMERIZATION, INTERACTION WITH DRD2.
[14]"Molecular modelling of D2-like dopamine receptors."
Livingstone C.D., Strange P.G., Naylor L.H.
Biochem. J. 287:277-282(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: 3D-STRUCTURE MODELING.
[15]"Dopamine D4 receptor variant, D4-glycine-194, in Africans, but not in Caucasians: no association with schizophrenia."
Seeman P., Ulpian C., Chouinard G., van Tol H.H.M., Dwosh H., Lieberman J.A., Siminovitch K., Liu I.S.C., Waye J., Voruganti P., Hudson C., Serjeant G.R., Masibay A.S., Seeman M.V.
Am. J. Med. Genet. 54:384-390(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT GLY-194.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L12398 mRNA. Translation: AAB59386.1.
L12397 Genomic DNA. Translation: AAL58637.1. Sequence problems.
AB065765 Genomic DNA. Translation: BAC05985.1.
EU432112 mRNA. Translation: ABY87911.1.
AP006284 Genomic DNA. No translation available.
CH471158 Genomic DNA. Translation: EAX02369.1.
PIRDYHUD4. S15079.
S24195.
RefSeqNP_000788.2. NM_000797.3.
UniGeneHs.99922.

3D structure databases

ProteinModelPortalP21917.
SMRP21917. Positions 39-465.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108149. 10 interactions.
DIPDIP-59865N.
MINTMINT-8090293.
STRING9606.ENSP00000176183.

Chemistry

BindingDBP21917.
ChEMBLCHEMBL2331075.
DrugBankDB00714. Apomorphine.
DB00363. Clozapine.
DB00334. Olanzapine.
DB00413. Pramipexole.
DB00420. Promazine.
DB00777. Propiomazine.
DB00268. Ropinirole.
DB00372. Thiethylperazine.
DB00246. Ziprasidone.
GuidetoPHARMACOLOGY217.

Protein family/group databases

GPCRDBSearch...

PTM databases

PhosphoSiteP21917.

Polymorphism databases

DMDM1345939.

Proteomic databases

PRIDEP21917.

Protocols and materials databases

DNASU1815.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000176183; ENSP00000176183; ENSG00000069696.
GeneID1815.
KEGGhsa:1815.
UCSCuc001lqp.2. human.

Organism-specific databases

CTD1815.
GeneCardsGC11P000653.
HGNCHGNC:3025. DRD4.
MIM126452. gene.
neXtProtNX_P21917.
PharmGKBPA27480.
GenAtlasSearch...

Phylogenomic databases

HOGENOMHOG000239242.
HOVERGENHBG106962.
KOK04147.
OrthoDBEOG769ZMG.
PhylomeDBP21917.
TreeFamTF334382.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

ArrayExpressP21917.
BgeeP21917.
CleanExHS_DRD4.
GenevestigatorP21917.

Family and domain databases

Gene3D1.20.1070.10. 2 hits.
InterProIPR002185. Dopamine_D4_rcpt.
IPR000929. Dopamine_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERPTHR24249:SF37. PTHR24249:SF37. 1 hit.
PfamPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSPR00569. DOPAMINED4R.
PR00242. DOPAMINER.
PR00237. GPCRRHODOPSN.
PROSITEPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSDRD4. human.
GeneWikiDopamine_receptor_D4.
GenomeRNAi1815.
NextBio7401.
PROP21917.
SOURCESearch...

Entry information

Entry nameDRD4_HUMAN
AccessionPrimary (citable) accession number: P21917
Secondary accession number(s): B0M0J7, Q7Z7Q5, Q8NGM5
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: February 1, 1996
Last modified: July 9, 2014
This is version 141 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM

7-transmembrane G-linked receptors

List of 7-transmembrane G-linked receptor entries