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P21917

- DRD4_HUMAN

UniProt

P21917 - DRD4_HUMAN

Protein

D(4) dopamine receptor

Gene

DRD4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 143 (01 Oct 2014)
      Sequence version 2 (01 Feb 1996)
      Previous versions | rss
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    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. protein binding Source: BHF-UCL
    8. 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

    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

    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

    ArrayExpressiP21917.
    BgeeiP21917.
    CleanExiHS_DRD4.
    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 39-465.
    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

    HOGENOMiHOG000239242.
    HOVERGENiHBG106962.
    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.

    P21917-1 [UniParc]FASTAAdd to Basket

    « Hide

    MGNRSTADAD GLLAGRGPAA GASAGASAGL AGQGAAALVG GVLLIGAVLA    50
    GNSLVCVSVA TERALQTPTN SFIVSLAAAD LLLALLVLPL FVYSEVQGGA 100
    WLLSPRLCDA LMAMDVMLCT ASIFNLCAIS VDRFVAVAVP LRYNRQGGSR 150
    RQLLLIGATW LLSAAVAAPV LCGLNDVRGR DPAVCRLEDR DYVVYSSVCS 200
    FFLPCPLMLL LYWATFRGLQ RWEVARRAKL HGRAPRRPSG PGPPSPTPPA 250
    PRLPQDPCGP DCAPPAPGLP RGPCGPDCAP AAPGLPPDPC GPDCAPPAPG 300
    LPQDPCGPDC APPAPGLPRG PCGPDCAPPA PGLPQDPCGP DCAPPAPGLP 350
    PDPCGSNCAP PDAVRAAALP PQTPPQTRRR RRAKITGRER KAMRVLPVVV 400
    GAFLLCWTPF FVVHITQALC PACSVPPRLV SAVTWLGYVN SALNPVIYTV 450
    FNAEFRNVFR KALRACC 467
    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 39-465.
    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 DB00714. Apomorphine.
    DB00363. Clozapine.
    DB00334. Olanzapine.
    DB00413. Pramipexole.
    DB00420. Promazine.
    DB00777. Propiomazine.
    DB00268. Ropinirole.
    DB00372. Thiethylperazine.
    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 GC11P000653.
    HGNCi HGNC:3025. DRD4.
    MIMi 126452. gene.
    neXtProti NX_P21917.
    PharmGKBi PA27480.
    GenAtlasi Search...

    Phylogenomic databases

    HOGENOMi HOG000239242.
    HOVERGENi HBG106962.
    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

    ArrayExpressi P21917.
    Bgeei P21917.
    CleanExi HS_DRD4.
    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

    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 1, 2014
    This is version 143 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