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P21917

- DRD4_HUMAN

UniProt

P21917 - DRD4_HUMAN

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Protein

D(4) dopamine receptor

Gene

DRD4

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

Functioni

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).By similarity

GO - Molecular functioni

  1. dopamine binding Source: BHF-UCL
  2. dopamine neurotransmitter receptor activity Source: BHF-UCL
  3. dopamine neurotransmitter receptor activity, coupled via Gi/Go Source: BHF-UCL
  4. drug binding Source: BHF-UCL
  5. identical protein binding Source: IntAct
  6. potassium channel regulator activity Source: BHF-UCL
  7. SH3 domain binding Source: BHF-UCL

GO - Biological processi

  1. activation of MAPK activity Source: BHF-UCL
  2. adenylate cyclase-inhibiting dopamine receptor signaling pathway Source: BHF-UCL
  3. adult locomotory behavior Source: BHF-UCL
  4. arachidonic acid secretion Source: BHF-UCL
  5. behavioral fear response Source: BHF-UCL
  6. behavioral response to cocaine Source: BHF-UCL
  7. behavioral response to ethanol Source: BHF-UCL
  8. cellular calcium ion homeostasis Source: BHF-UCL
  9. circadian rhythm Source: Ensembl
  10. dopamine metabolic process Source: BHF-UCL
  11. dopamine receptor signaling pathway Source: BHF-UCL
  12. fear response Source: BHF-UCL
  13. negative regulation of adenylate cyclase activity Source: BHF-UCL
  14. negative regulation of cAMP biosynthetic process Source: BHF-UCL
  15. negative regulation of protein secretion Source: BHF-UCL
  16. negative regulation of voltage-gated calcium channel activity Source: BHF-UCL
  17. olfactory learning Source: Ensembl
  18. photoperiodism Source: Ensembl
  19. positive regulation of dopamine uptake involved in synaptic transmission Source: BHF-UCL
  20. positive regulation of excitatory postsynaptic membrane potential Source: Ensembl
  21. positive regulation of kinase activity Source: BHF-UCL
  22. positive regulation of penile erection Source: Ensembl
  23. positive regulation of sodium:proton antiporter activity Source: BHF-UCL
  24. regulation of calcium-mediated signaling Source: Ensembl
  25. regulation of circadian rhythm Source: UniProtKB
  26. regulation of dopamine metabolic process Source: BHF-UCL
  27. regulation of inhibitory postsynaptic membrane potential Source: BHF-UCL
  28. regulation of neurotransmitter secretion Source: Ensembl
  29. response to amphetamine Source: BHF-UCL
  30. response to histamine Source: BHF-UCL
  31. response to steroid hormone Source: Ensembl
  32. retina development in camera-type eye Source: Ensembl
  33. short-term memory Source: Ensembl
  34. social behavior Source: BHF-UCL
  35. synaptic transmission, dopaminergic Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Keywords - Biological processi

Biological rhythms

Enzyme and pathway databases

ReactomeiREACT_16968. Dopamine receptors.
REACT_19231. G alpha (i) signalling events.

Names & Taxonomyi

Protein namesi
Recommended name:
D(4) dopamine receptor
Alternative name(s):
D(2C) dopamine receptor
Dopamine D4 receptor
Gene namesi
Name:DRD4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 11

Organism-specific databases

HGNCiHGNC:3025. DRD4.

Subcellular locationi

Cell membrane 1 Publication; Multi-pass membrane protein 1 Publication

GO - Cellular componenti

  1. cell cortex Source: Ensembl
  2. dendritic spine Source: Ensembl
  3. integral component of plasma membrane Source: BHF-UCL
  4. membrane Source: BHF-UCL
  5. neuronal cell body Source: Ensembl
  6. plasma membrane Source: Reactome
  7. terminal bouton Source: Ensembl
  8. vesicle membrane Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA27480.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 467467D(4) dopamine receptorPRO_0000069401Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi3 – 31N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi108 ↔ 185PROSITE-ProRule annotation

Post-translational modificationi

Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex: polyubiquitination does not lead to degradation of DRD4 protein.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Ubl conjugation

Proteomic databases

PRIDEiP21917.

PTM databases

PhosphoSiteiP21917.

Expressioni

Gene expression databases

BgeeiP21917.
CleanExiHS_DRD4.
ExpressionAtlasiP21917. baseline.
GenevestigatoriP21917.

Interactioni

Subunit structurei

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 KLHL12.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself3EBI-8592297,EBI-8592297

Protein-protein interaction databases

BioGridi108149. 10 interactions.
DIPiDIP-59865N.
MINTiMINT-8090293.
STRINGi9606.ENSP00000176183.

Structurei

3D structure databases

ProteinModelPortaliP21917.
SMRiP21917. Positions 44-212, 372-463.
ModBaseiSearch...
MobiDBiSearch...

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 3737ExtracellularSequence AnalysisAdd
BLAST
Topological domaini61 – 7010CytoplasmicSequence Analysis
Topological domaini94 – 10916ExtracellularSequence AnalysisAdd
BLAST
Topological domaini132 – 15120CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini176 – 19116ExtracellularSequence AnalysisAdd
BLAST
Topological domaini214 – 394181CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini418 – 4269ExtracellularSequence Analysis
Topological domaini450 – 46718CytoplasmicSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei38 – 6023Helical; Name=1Sequence AnalysisAdd
BLAST
Transmembranei71 – 9323Helical; Name=2Sequence AnalysisAdd
BLAST
Transmembranei110 – 13122Helical; Name=3Sequence AnalysisAdd
BLAST
Transmembranei152 – 17524Helical; Name=4Sequence AnalysisAdd
BLAST
Transmembranei192 – 21322Helical; Name=5Sequence AnalysisAdd
BLAST
Transmembranei395 – 41723Helical; Name=6Sequence AnalysisAdd
BLAST
Transmembranei427 – 44923Helical; Name=7Sequence AnalysisAdd
BLAST

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati249 – 264161; approximateAdd
BLAST
Repeati265 – 280162Add
BLAST
Repeati281 – 296163Add
BLAST
Repeati297 – 312164Add
BLAST
Repeati313 – 328165Add
BLAST
Repeati329 – 344166Add
BLAST
Repeati345 – 360167; approximateAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni249 – 3601127 X 16 AA approximate tandem repeats of [PA]-A-P-G-L-P-[PQR]-[DG]-P-C-G-P-D-C-A-PAdd
BLAST

Sequence similaritiesi

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

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

GeneTreeiENSGT00760000118795.
HOGENOMiHOG000239242.
HOVERGENiHBG106962.
InParanoidiP21917.
KOiK04147.
OrthoDBiEOG769ZMG.
PhylomeDBiP21917.
TreeFamiTF334382.

Family and domain databases

Gene3Di1.20.1070.10. 2 hits.
InterProiIPR002185. Dopamine_D4_rcpt.
IPR000929. Dopamine_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERiPTHR24249:SF37. PTHR24249:SF37. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
[Graphical view]
PRINTSiPR00569. DOPAMINED4R.
PR00242. DOPAMINER.
PR00237. GPCRRHODOPSN.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P21917 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MGNRSTADAD GLLAGRGPAA GASAGASAGL AGQGAAALVG GVLLIGAVLA
60 70 80 90 100
GNSLVCVSVA TERALQTPTN SFIVSLAAAD LLLALLVLPL FVYSEVQGGA
110 120 130 140 150
WLLSPRLCDA LMAMDVMLCT ASIFNLCAIS VDRFVAVAVP LRYNRQGGSR
160 170 180 190 200
RQLLLIGATW LLSAAVAAPV LCGLNDVRGR DPAVCRLEDR DYVVYSSVCS
210 220 230 240 250
FFLPCPLMLL LYWATFRGLQ RWEVARRAKL HGRAPRRPSG PGPPSPTPPA
260 270 280 290 300
PRLPQDPCGP DCAPPAPGLP RGPCGPDCAP AAPGLPPDPC GPDCAPPAPG
310 320 330 340 350
LPQDPCGPDC APPAPGLPRG PCGPDCAPPA PGLPQDPCGP DCAPPAPGLP
360 370 380 390 400
PDPCGSNCAP PDAVRAAALP PQTPPQTRRR RRAKITGRER KAMRVLPVVV
410 420 430 440 450
GAFLLCWTPF FVVHITQALC PACSVPPRLV SAVTWLGYVN SALNPVIYTV
460
FNAEFRNVFR KALRACC
Length:467
Mass (Da):48,361
Last modified:February 1, 1996 - v2
Checksum:iB6FF2E09269A02AF
GO

Sequence cautioni

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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti237 – 2371R → F in BAC05985. (PubMed:1840645)Curated

Polymorphismi

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.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti194 – 1941V → G in Afro-Caribbeans. 1 Publication
Corresponds to variant rs1800443 [ dbSNP | Ensembl ].
VAR_003464
Natural varianti265 – 34480Missing in allele D4.2.
VAR_003465Add
BLAST
Natural varianti281 – 32848Missing in allele D4.4.
VAR_003466Add
BLAST
Natural varianti281 – 2811A → P.
Corresponds to variant rs3889692 [ dbSNP | Ensembl ].
VAR_055914
Natural varianti329 – 3291P → A in allele D4.4.
VAR_003467
Natural varianti332 – 3321G → S in allele D4.4. 2 Publications
VAR_003468

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
PIRiS15079. DYHUD4.
S24195.
RefSeqiNP_000788.2. NM_000797.3.
UniGeneiHs.99922.

Genome annotation databases

EnsembliENST00000176183; ENSP00000176183; ENSG00000069696.
GeneIDi1815.
KEGGihsa:1815.
UCSCiuc001lqp.2. human.

Polymorphism databases

DMDMi1345939.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
PIRi S15079. DYHUD4.
S24195.
RefSeqi NP_000788.2. NM_000797.3.
UniGenei Hs.99922.

3D structure databases

ProteinModelPortali P21917.
SMRi P21917. Positions 44-212, 372-463.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 108149. 10 interactions.
DIPi DIP-59865N.
MINTi MINT-8090293.
STRINGi 9606.ENSP00000176183.

Chemistry

BindingDBi P21917.
ChEMBLi CHEMBL2331075.
DrugBanki DB00543. Amoxapine.
DB00714. Apomorphine.
DB01238. Aripiprazole.
DB06216. Asenapine.
DB01200. Bromocriptine.
DB00248. Cabergoline.
DB00477. Chlorpromazine.
DB00363. Clozapine.
DB00988. Dopamine.
DB04946. Iloperidone.
DB01235. L-DOPA.
DB00589. Lisuride.
DB00408. Loxapine.
DB01403. Methotrimeprazine.
DB00334. Olanzapine.
DB01267. Paliperidone.
DB01186. Pergolide.
DB00413. Pramipexole.
DB00420. Promazine.
DB00777. Propiomazine.
DB01224. Quetiapine.
DB00409. Remoxipride.
DB00734. Risperidone.
DB00268. Ropinirole.
DB05271. Rotigotine.
DB00246. Ziprasidone.
GuidetoPHARMACOLOGYi 217.

Protein family/group databases

GPCRDBi Search...

PTM databases

PhosphoSitei P21917.

Polymorphism databases

DMDMi 1345939.

Proteomic databases

PRIDEi P21917.

Protocols and materials databases

DNASUi 1815.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000176183 ; ENSP00000176183 ; ENSG00000069696 .
GeneIDi 1815.
KEGGi hsa:1815.
UCSCi uc001lqp.2. human.

Organism-specific databases

CTDi 1815.
GeneCardsi GC11P000656.
HGNCi HGNC:3025. DRD4.
MIMi 126452. gene.
neXtProti NX_P21917.
PharmGKBi PA27480.
GenAtlasi Search...

Phylogenomic databases

GeneTreei ENSGT00760000118795.
HOGENOMi HOG000239242.
HOVERGENi HBG106962.
InParanoidi P21917.
KOi K04147.
OrthoDBi EOG769ZMG.
PhylomeDBi P21917.
TreeFami TF334382.

Enzyme and pathway databases

Reactomei REACT_16968. Dopamine receptors.
REACT_19231. G alpha (i) signalling events.

Miscellaneous databases

ChiTaRSi DRD4. human.
GeneWikii Dopamine_receptor_D4.
GenomeRNAii 1815.
NextBioi 7401.
PROi P21917.
SOURCEi Search...

Gene expression databases

Bgeei P21917.
CleanExi HS_DRD4.
ExpressionAtlasi P21917. baseline.
Genevestigatori P21917.

Family and domain databases

Gene3Di 1.20.1070.10. 2 hits.
InterProi IPR002185. Dopamine_D4_rcpt.
IPR000929. Dopamine_rcpt.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view ]
PANTHERi PTHR24249:SF37. PTHR24249:SF37. 1 hit.
Pfami PF00001. 7tm_1. 1 hit.
[Graphical view ]
PRINTSi PR00569. DOPAMINED4R.
PR00242. DOPAMINER.
PR00237. GPCRRHODOPSN.
PROSITEi PS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. 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. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ALLELE D4.4).
  6. 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. 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.

Entry informationi

Entry nameiDRD4_HUMAN
AccessioniPrimary (citable) accession number: P21917
Secondary accession number(s): B0M0J7, Q7Z7Q5, Q8NGM5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: February 1, 1996
Last modified: October 29, 2014
This is version 144 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

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 11
    Human chromosome 11: 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

External Data

Dasty 3