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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

Enzyme 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

  • dopamine binding Source: UniProtKB
  • dopamine neurotransmitter receptor activity Source: BHF-UCL
  • dopamine neurotransmitter receptor activity, coupled via Gi/Go Source: UniProtKB
  • drug binding Source: BHF-UCL
  • epinephrine binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • metal ion binding Source: UniProtKB-KW
  • norepinephrine binding Source: UniProtKB
  • potassium channel regulator activity Source: BHF-UCL
  • SH3 domain binding Source: BHF-UCL

GO - Biological processi

  • activation of MAPK activity Source: BHF-UCL
  • adenylate cyclase-inhibiting dopamine receptor signaling pathway Source: UniProtKB
  • adult locomotory behavior Source: BHF-UCL
  • arachidonic acid secretion Source: BHF-UCL
  • behavioral fear response Source: BHF-UCL
  • behavioral response to cocaine Source: BHF-UCL
  • behavioral response to ethanol Source: BHF-UCL
  • cellular calcium ion homeostasis Source: BHF-UCL
  • dopamine metabolic process Source: BHF-UCL
  • dopamine receptor signaling pathway Source: BHF-UCL
  • fear response Source: BHF-UCL
  • G-protein coupled receptor signaling pathway Source: Reactome
  • inhibitory postsynaptic potential Source: BHF-UCL
  • negative regulation of protein secretion Source: BHF-UCL
  • negative regulation of voltage-gated calcium channel activity Source: BHF-UCL
  • positive regulation of dopamine uptake involved in synaptic transmission Source: BHF-UCL
  • positive regulation of kinase activity Source: BHF-UCL
  • positive regulation of sodium:proton antiporter activity Source: BHF-UCL
  • regulation of circadian rhythm Source: UniProtKB
  • regulation of dopamine metabolic process Source: BHF-UCL
  • response to amphetamine Source: BHF-UCL
  • response to histamine Source: BHF-UCL
  • rhythmic process Source: UniProtKB-KW
  • social behavior Source: BHF-UCL

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.

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.
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

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • SH3 domain binding Source: BHF-UCL

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
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi35 – 61Combined sources27
Helixi63 – 65Combined sources3
Helixi68 – 86Combined sources19
Helixi88 – 96Combined sources9
Turni97 – 99Combined sources3
Helixi105 – 138Combined sources34
Beta strandi144 – 147Combined sources4
Helixi151 – 171Combined sources21
Helixi190 – 200Combined sources11
Turni201 – 203Combined sources3
Helixi204 – 220Combined sources17
Helixi388 – 392Combined sources5
Helixi395 – 419Combined sources25
Helixi427 – 451Combined sources25
Helixi453 – 460Combined sources8

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...

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.

Sequencei

Sequence statusi: Complete.

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

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:rs1800443Ensembl.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

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: February 28, 2018
This is version 175 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