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Protein

D(4) dopamine receptor

Gene

DRD4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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. Activated by dopamine, but also by epinephrine and norepinephrine, and by numerous synthetic agonists and drugs (PubMed:9003072, PubMed:16423344, PubMed:27659709, PubMed:29051383). Agonist binding triggers signaling via G proteins that inhibit adenylyl cyclase (PubMed:7512953, PubMed:7643093, PubMed:16423344, PubMed:27659709, PubMed:29051383). Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells (By similarity).By similarity8 Publications

Activity regulationi

Signaling in response to agonists such as dopamine, epinephrine and norepinephrine is modulated by Na+; lower Na+ levels result in higher receptor activity (in vitro).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi80Sodium1 Publication1
Binding sitei115Agonist1 Publication1
Metal bindingi122Sodium1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer
Biological processBiological rhythms
LigandMetal-binding, Sodium

Enzyme and pathway databases

ReactomeiR-HSA-390651 Dopamine receptors
R-HSA-418594 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
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000069696.6
HGNCiHGNC:3025 DRD4
MIMi126452 gene
neXtProtiNX_P21917

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 37Extracellular1 PublicationAdd BLAST37
Transmembranei38 – 60Helical; Name=11 PublicationAdd BLAST23
Topological domaini61 – 70Cytoplasmic1 Publication10
Transmembranei71 – 93Helical; Name=21 PublicationAdd BLAST23
Topological domaini94 – 109Extracellular1 PublicationAdd BLAST16
Transmembranei110 – 131Helical; Name=31 PublicationAdd BLAST22
Topological domaini132 – 151Cytoplasmic1 PublicationAdd BLAST20
Transmembranei152 – 175Helical; Name=41 PublicationAdd BLAST24
Topological domaini176 – 191Extracellular1 PublicationAdd BLAST16
Transmembranei192 – 213Helical; Name=51 PublicationAdd BLAST22
Topological domaini214 – 394Cytoplasmic1 PublicationAdd BLAST181
Transmembranei395 – 417Helical; Name=61 PublicationAdd BLAST23
Topological domaini418 – 426Extracellular1 Publication9
Transmembranei427 – 449Helical; Name=71 PublicationAdd BLAST23
Topological domaini450 – 467Cytoplasmic1 PublicationAdd BLAST18

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi430V → Y: Increased basal level of G protein-mediated signaling. 1 Publication1
Mutagenesisi466C → G: No effect on palmitoylation. 1 Publication1
Mutagenesisi467C → G: Loss of palmitoylation. 1 Publication1

Organism-specific databases

DisGeNETi1815
MalaCardsiDRD4
PharmGKBiPA27480

Chemistry databases

ChEMBLiCHEMBL219
DrugBankiDB00543 Amoxapine
DB00714 Apomorphine
DB01238 Aripiprazole
DB06216 Asenapine
DB01200 Bromocriptine
DB00248 Cabergoline
DB00477 Chlorpromazine
DB00363 Clozapine
DB00988 Dopamine
DB04908 Flibanserin
DB04946 Iloperidone
DB01235 Levodopa
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
DB05280 SLV 308
DB00372 Thiethylperazine
DB00246 Ziprasidone
GuidetoPHARMACOLOGYi217

Polymorphism and mutation databases

BioMutaiDRD4
DMDMi1345939

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000694011 – 467D(4) dopamine receptorAdd BLAST467

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi3N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi108 ↔ 185PROSITE-ProRule annotationCombined sources1 Publication
Disulfide bondi420 ↔ 423Combined sources1 Publication
Lipidationi467S-palmitoyl cysteine1 Publication1

Post-translational modificationi

Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex: polyubiquitination does not lead to degradation of DRD4 protein.2 Publications
Palmitoylated. Palmitoylation of the C-terminal Cys is important for normal expression at the cell membrane.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Lipoprotein, Palmitate, Ubl conjugation

Proteomic databases

PeptideAtlasiP21917
PRIDEiP21917
ProteomicsDBi53940

PTM databases

iPTMnetiP21917
PhosphoSitePlusiP21917

Expressioni

Tissue specificityi

Highly expressed in retina. Detected at much lower levels in brain, in amygdala, thalamus, hypothalamus, cerebellum and pituitary.1 Publication

Gene expression databases

BgeeiENSG00000069696 Expressed in 84 organ(s), highest expression level in cerebellum
CleanExiHS_DRD4
GenevisibleiP21917 HS

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 (PubMed:21184734). Interacts with CLIC6 (By similarity). Interacts with GPRASP1 (PubMed:12142540). May interact with ADORA2A (PubMed:20836733). Interacts with KLHL12 (PubMed:18303015).By similarity3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi108149, 11 interactors
CORUMiP21917
DIPiDIP-59865N
IntActiP21917, 3 interactors
MINTiP21917

Chemistry databases

BindingDBiP21917

Structurei

Secondary structure

1467
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP21917
SMRiP21917
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati249 – 2641; approximateAdd BLAST16
Repeati265 – 2802Add BLAST16
Repeati281 – 2963Add BLAST16
Repeati297 – 3124Add BLAST16
Repeati313 – 3285Add BLAST16
Repeati329 – 3446Add BLAST16
Repeati345 – 3607; approximateAdd BLAST16

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni249 – 3607 X 16 AA approximate tandem repeats of [PA]-A-P-G-L-P-[PQR]-[DG]-P-C-G-P-D-C-A-PAdd BLAST112

Sequence similaritiesi

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

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

HOGENOMiHOG000239242
HOVERGENiHBG106962
InParanoidiP21917
KOiK04147
OrthoDBiEOG091G06VI
PhylomeDBiP21917
TreeFamiTF334382

Family and domain databases

InterProiView protein in InterPro
IPR002185 Dopamine_D4_rcpt
IPR000929 Dopamine_rcpt
IPR000276 GPCR_Rhodpsn
IPR017452 GPCR_Rhodpsn_7TM
PANTHERiPTHR44250:SF1 PTHR44250:SF1, 1 hit
PfamiView protein in Pfam
PF00001 7tm_1, 1 hit
PRINTSiPR00569 DOPAMINED4R
PR00242 DOPAMINER
PR00237 GPCRRHODOPSN
SMARTiView protein in SMART
SM01381 7TM_GPCR_Srsx, 1 hit
PROSITEiView protein in PROSITE
PS00237 G_PROTEIN_RECEP_F1_1, 1 hit
PS50262 G_PROTEIN_RECEP_F1_2, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

P21917-1 [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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0G2JM26A0A0G2JM26_HUMAN
D(4) dopamine receptor
DRD4
419Annotation score:

Sequence cautioni

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

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti237R → F in BAC05985 (PubMed:1840645).Curated1

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.4 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_003464194V → G in Afro-Caribbeans. 1 PublicationCorresponds to variant dbSNP:rs1800443EnsemblClinVar.1
Natural variantiVAR_003465265 – 344Missing in allele D4.2. Add BLAST80
Natural variantiVAR_003466281 – 328Missing in allele D4.4. Add BLAST48
Natural variantiVAR_055914281A → P. Corresponds to variant dbSNP:rs3889692Ensembl.1
Natural variantiVAR_003467329P → A in allele D4.4. 1
Natural variantiVAR_003468332G → S in allele D4.4. 2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.3 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5WIUX-ray1.96A1-228[»]
A383-467[»]
5WIVX-ray2.14A1-228[»]
A383-467[»]
ProteinModelPortaliP21917
SMRiP21917
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108149, 11 interactors
CORUMiP21917
DIPiDIP-59865N
IntActiP21917, 3 interactors
MINTiP21917

Chemistry databases

BindingDBiP21917
ChEMBLiCHEMBL219
DrugBankiDB00543 Amoxapine
DB00714 Apomorphine
DB01238 Aripiprazole
DB06216 Asenapine
DB01200 Bromocriptine
DB00248 Cabergoline
DB00477 Chlorpromazine
DB00363 Clozapine
DB00988 Dopamine
DB04908 Flibanserin
DB04946 Iloperidone
DB01235 Levodopa
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
DB05280 SLV 308
DB00372 Thiethylperazine
DB00246 Ziprasidone
GuidetoPHARMACOLOGYi217

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiP21917
PhosphoSitePlusiP21917

Polymorphism and mutation databases

BioMutaiDRD4
DMDMi1345939

Proteomic databases

PeptideAtlasiP21917
PRIDEiP21917
ProteomicsDBi53940

Protocols and materials databases

DNASUi1815
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000176183; ENSP00000176183; ENSG00000069696
GeneIDi1815
KEGGihsa:1815
UCSCiuc001lqp.3 human

Organism-specific databases

CTDi1815
DisGeNETi1815
EuPathDBiHostDB:ENSG00000069696.6
GeneCardsiDRD4
HGNCiHGNC:3025 DRD4
MalaCardsiDRD4
MIMi126452 gene
neXtProtiNX_P21917
PharmGKBiPA27480
GenAtlasiSearch...

Phylogenomic databases

HOGENOMiHOG000239242
HOVERGENiHBG106962
InParanoidiP21917
KOiK04147
OrthoDBiEOG091G06VI
PhylomeDBiP21917
TreeFamiTF334382

Enzyme and pathway databases

ReactomeiR-HSA-390651 Dopamine receptors
R-HSA-418594 G alpha (i) signalling events

Miscellaneous databases

ChiTaRSiDRD4 human
GeneWikiiDopamine_receptor_D4
GenomeRNAii1815
PROiPR:P21917
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000069696 Expressed in 84 organ(s), highest expression level in cerebellum
CleanExiHS_DRD4
GenevisibleiP21917 HS

Family and domain databases

InterProiView protein in InterPro
IPR002185 Dopamine_D4_rcpt
IPR000929 Dopamine_rcpt
IPR000276 GPCR_Rhodpsn
IPR017452 GPCR_Rhodpsn_7TM
PANTHERiPTHR44250:SF1 PTHR44250:SF1, 1 hit
PfamiView protein in Pfam
PF00001 7tm_1, 1 hit
PRINTSiPR00569 DOPAMINED4R
PR00242 DOPAMINER
PR00237 GPCRRHODOPSN
SMARTiView protein in SMART
SM01381 7TM_GPCR_Srsx, 1 hit
PROSITEiView protein in PROSITE
PS00237 G_PROTEIN_RECEP_F1_1, 1 hit
PS50262 G_PROTEIN_RECEP_F1_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiDRD4_HUMAN
AccessioniPrimary (citable) accession number: P21917
Secondary accession number(s): B0M0J7, Q7Z7Q5, Q8NGM5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: February 1, 1996
Last modified: October 10, 2018
This is version 178 of the entry and version 2 of the sequence. See 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  3. SIMILARITY comments
    Index of protein domains and families
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  6. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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