ID DRD4_HUMAN Reviewed; 467 AA. AC P21917; B0M0J7; Q7Z7Q5; Q8NGM5; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1996, sequence version 2. DT 11-NOV-2015, entry version 155. DE RecName: Full=D(4) dopamine receptor; DE AltName: Full=D(2C) dopamine receptor; DE AltName: Full=Dopamine D4 receptor; GN Name=DRD4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ALLELE D4.7). RX PubMed=1319557; DOI=10.1038/358149a0; RA van Tol H.H., Wu C.M., Guan H.C., Ohara K., Bunzow J.R., Civelli O., RA Kennedy J., Seeman P., Niznik H.B., Jovanovic V.; RT "Multiple dopamine D4 receptor variants in the human population."; RL Nature 358:149-152(1992). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE D4.2). RC TISSUE=Brain; RX PubMed=1840645; DOI=10.1038/350610a0; RA van Tol H.H.M., Bunzow J.R., Guan H.-C., Sunahara R.K., Seeman P., RA Niznik H.B., Civelli O.; RT "Cloning of the gene for a human dopamine D4 receptor with high RT affinity for the antipsychotic clozapine."; RL Nature 350:610-614(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE D.4.4). RA Suwa M., Sato T., Okouchi I., Arita M., Futami K., Matsumoto S., RA Tsutsumi S., Aburatani H., Asai K., Akiyama Y.; RT "Genome-wide discovery and analysis of human seven transmembrane helix RT receptor genes."; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-332. RC TISSUE=Brain; RA Kaighin V.A., Martin A.L., Aronstam R.S.; RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ALLELE D4.4). RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S., RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., RA Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT SER-332. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP POLYMORPHISM. RX PubMed=8353495; DOI=10.1093/hmg/2.6.767; RA Lichter J.B., Barr C.L., Kennedy J.L., Van Tol H.H., Kidd K.K., RA Livak K.J.; RT "A hypervariable segment in the human dopamine receptor D4 (DRD4) RT gene."; RL Hum. Mol. Genet. 2:767-773(1993). RN [8] RP POLYMORPHISM. RX PubMed=8078498; RA Asghari V., Schoots O., van Kats S., Ohara K., Jovanovic V., RA Guan H.-C., Bunzow J.R., Petronis A., Van Tol H.H.M.; RT "Dopamine D4 receptor repeat: analysis of different native and mutant RT forms of the human and rat genes."; RL Mol. Pharmacol. 46:364-373(1994). RN [9] RP INTERACTION WITH GPRASP1. RX PubMed=12142540; DOI=10.1126/science.1073308; RA Whistler J.L., Enquist J., Marley A., Fong J., Gladher F., Tsuruda P., RA Murray S.R., Von Zastrow M.; RT "Modulation of postendocytic sorting of G protein-coupled receptors."; RL Science 297:615-620(2002). RN [10] RP UBIQUITINATION, AND INTERACTION WITH KLHL12. RX PubMed=18303015; DOI=10.1074/jbc.M708473200; RA Rondou P., Haegeman G., Vanhoenacker P., Van Craenenbroeck K.; RT "BTB Protein KLHL12 targets the dopamine D4 receptor for RT ubiquitination by a Cul3-based E3 ligase."; RL J. Biol. Chem. 283:11083-11096(2008). RN [11] RP POSSIBLE INTERACTION WITH ADORA2A. RX PubMed=20836733; DOI=10.3109/10799893.2010.513842; RA Woods A.S.; RT "The dopamine D(4) receptor, the ultimate disordered protein."; RL J. Recept. Signal Transduct. 30:331-336(2010). RN [12] RP UBIQUITINATION, AND SUBCELLULAR LOCATION. RX PubMed=20100572; DOI=10.1016/j.cellsig.2010.01.014; RA Rondou P., Skieterska K., Packeu A., Lintermans B., Vanhoenacker P., RA Vauquelin G., Haegeman G., Van Craenenbroeck K.; RT "KLHL12-mediated ubiquitination of the dopamine D4 receptor does not RT target the receptor for degradation."; RL Cell. Signal. 22:900-913(2010). RN [13] RP HOMOOLIGOMERIZATION, AND INTERACTION WITH DRD2. RX PubMed=21184734; DOI=10.1016/j.bbrc.2010.12.083; RA Borroto-Escuela D.O., Van Craenenbroeck K., Romero-Fernandez W., RA Guidolin D., Woods A.S., Rivera A., Haegeman G., Agnati L.F., RA Tarakanov A.O., Fuxe K.; RT "Dopamine D2 and D4 receptor heteromerization and its allosteric RT receptor-receptor interactions."; RL Biochem. Biophys. Res. Commun. 404:928-934(2011). RN [14] RP 3D-STRUCTURE MODELING. RX PubMed=1358063; RA Livingstone C.D., Strange P.G., Naylor L.H.; RT "Molecular modelling of D2-like dopamine receptors."; RL Biochem. J. 287:277-282(1992). RN [15] RP VARIANT GLY-194. RX PubMed=7726213; DOI=10.1002/ajmg.1320540419; RA Seeman P., Ulpian C., Chouinard G., van Tol H.H.M., Dwosh H., RA Lieberman J.A., Siminovitch K., Liu I.S.C., Waye J., Voruganti P., RA Hudson C., Serjeant G.R., Masibay A.S., Seeman M.V.; RT "Dopamine D4 receptor variant, D4-glycine-194, in Africans, but not in RT Caucasians: no association with schizophrenia."; RL Am. J. Med. Genet. 54:384-390(1994). CC -!- FUNCTION: Dopamine receptor responsible for neuronal signaling in CC the mesolimbic system of the brain, an area of the brain that CC regulates emotion and complex behavior. Its activity is mediated CC by G proteins which inhibit adenylyl cyclase. Modulates the CC circadian rhythm of contrast sensitivity by regulating the CC rhythmic expression of NPAS2 in the retinal ganglion cells (By CC similarity). {ECO:0000250}. CC -!- SUBUNIT: Forms homo- and heterooligomers with DRD2. D4.7 allele CC exhibits higher affinity for homodimers compared to DRD2 CC heterodimers, while alleles D42. and 4.4 have similar affinities CC for both. The interaction with DRD2 may modulate agonist-induced CC downstream signaling. Interacts with CLIC6 (By similarity) and CC GPRASP1. May interact with ADORA2A. Interacts with KLHL12. CC {ECO:0000250, ECO:0000269|PubMed:12142540, CC ECO:0000269|PubMed:18303015, ECO:0000269|PubMed:21184734}. CC -!- INTERACTION: CC Self; NbExp=3; IntAct=EBI-8592297, EBI-8592297; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20100572}; CC Multi-pass membrane protein {ECO:0000269|PubMed:20100572}. CC -!- PTM: Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase CC complex: polyubiquitination does not lead to degradation of DRD4 CC protein. {ECO:0000269|PubMed:18303015, CC ECO:0000269|PubMed:20100572}. CC -!- POLYMORPHISM: The number of repeats of 16 amino acids in the third CC cytoplasmic loop is highly polymorphic and varies among different CC alleles. Alleles corresponding in size to a 2 (D4.2), 3 (D4.3), 4 CC (D4.4), 5 (D4.5), 6 (D4.6), 7 (D4.7) and 9 (D4.9) repeats have CC been described. The sequence shown is that of allele D4.7. The CC polymorphic repeat sequence has little influence on DRD4-binding CC profiles and might not be essential for G protein interaction. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- SEQUENCE CAUTION: CC Sequence=AAL58637.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L12398; AAB59386.1; -; mRNA. DR EMBL; L12397; AAL58637.1; ALT_SEQ; Genomic_DNA. DR EMBL; AB065765; BAC05985.1; -; Genomic_DNA. DR EMBL; EU432112; ABY87911.1; -; mRNA. DR EMBL; AP006284; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471158; EAX02369.1; -; Genomic_DNA. DR PIR; S15079; DYHUD4. DR PIR; S24195; S24195. DR RefSeq; NP_000788.2; NM_000797.3. DR UniGene; Hs.99922; -. DR ProteinModelPortal; P21917; -. DR SMR; P21917; 44-212, 372-463. DR BioGrid; 108149; 10. DR DIP; DIP-59865N; -. DR MINT; MINT-8090293; -. DR BindingDB; P21917; -. DR ChEMBL; CHEMBL2331075; -. DR DrugBank; DB00543; Amoxapine. DR DrugBank; DB00714; Apomorphine. DR DrugBank; DB01238; Aripiprazole. DR DrugBank; DB06216; Asenapine. DR DrugBank; DB01200; Bromocriptine. DR DrugBank; DB00248; Cabergoline. DR DrugBank; DB00477; Chlorpromazine. DR DrugBank; DB00363; Clozapine. DR DrugBank; DB00988; Dopamine. DR DrugBank; DB04908; Flibanserin. DR DrugBank; DB04946; Iloperidone. DR DrugBank; DB01235; Levodopa. DR DrugBank; DB00589; Lisuride. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB01403; Methotrimeprazine. DR DrugBank; DB00334; Olanzapine. DR DrugBank; DB01267; Paliperidone. DR DrugBank; DB01186; Pergolide. DR DrugBank; DB00413; Pramipexole. DR DrugBank; DB00420; Promazine. DR DrugBank; DB00777; Propiomazine. DR DrugBank; DB01224; Quetiapine. DR DrugBank; DB00409; Remoxipride. DR DrugBank; DB00734; Risperidone. DR DrugBank; DB00268; Ropinirole. DR DrugBank; DB05271; Rotigotine. DR DrugBank; DB00246; Ziprasidone. DR GuidetoPHARMACOLOGY; 217; -. DR PhosphoSite; P21917; -. DR BioMuta; DRD4; -. DR DMDM; 1345939; -. DR PRIDE; P21917; -. DR DNASU; 1815; -. DR Ensembl; ENST00000176183; ENSP00000176183; ENSG00000069696. DR GeneID; 1815; -. DR KEGG; hsa:1815; -. DR UCSC; uc001lqp.2; human. DR CTD; 1815; -. DR GeneCards; DRD4; -. DR HGNC; HGNC:3025; DRD4. DR MIM; 126452; gene. DR neXtProt; NX_P21917; -. DR PharmGKB; PA27480; -. DR HOGENOM; HOG000239242; -. DR HOVERGEN; HBG106962; -. DR InParanoid; P21917; -. DR KO; K04147; -. DR OrthoDB; EOG769ZMG; -. DR PhylomeDB; P21917; -. DR TreeFam; TF334382; -. DR Reactome; R-HSA-390651; Dopamine receptors. DR Reactome; R-HSA-418594; G alpha (i) signalling events. DR ChiTaRS; DRD4; human. DR GeneWiki; Dopamine_receptor_D4; -. DR GenomeRNAi; 1815; -. DR NextBio; 7401; -. DR PRO; PR:P21917; -. DR Proteomes; UP000005640; Chromosome 11. DR Bgee; P21917; -. DR CleanEx; HS_DRD4; -. DR Genevisible; P21917; HS. DR GO; GO:0005938; C:cell cortex; IEA:Ensembl. DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:SYSCILIA_CCNET. DR GO; GO:0043195; C:terminal bouton; IEA:Ensembl. DR GO; GO:0012506; C:vesicle membrane; IEA:Ensembl. DR GO; GO:0035240; F:dopamine binding; IDA:BHF-UCL. DR GO; GO:0004952; F:dopamine neurotransmitter receptor activity; IDA:BHF-UCL. DR GO; GO:0001591; F:dopamine neurotransmitter receptor activity, coupled via Gi/Go; IDA:BHF-UCL. DR GO; GO:0008144; F:drug binding; IDA:BHF-UCL. DR GO; GO:0008227; F:G-protein coupled amine receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0015459; F:potassium channel regulator activity; NAS:BHF-UCL. DR GO; GO:0017124; F:SH3 domain binding; IDA:BHF-UCL. DR GO; GO:0000187; P:activation of MAPK activity; IDA:BHF-UCL. DR GO; GO:0007195; P:adenylate cyclase-inhibiting dopamine receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0008344; P:adult locomotory behavior; ISS:BHF-UCL. DR GO; GO:0050482; P:arachidonic acid secretion; IDA:BHF-UCL. DR GO; GO:0001662; P:behavioral fear response; NAS:BHF-UCL. DR GO; GO:0048148; P:behavioral response to cocaine; ISS:BHF-UCL. DR GO; GO:0048149; P:behavioral response to ethanol; TAS:BHF-UCL. DR GO; GO:0006874; P:cellular calcium ion homeostasis; IC:BHF-UCL. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0042417; P:dopamine metabolic process; IC:BHF-UCL. DR GO; GO:0007212; P:dopamine receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0042596; P:fear response; ISS:BHF-UCL. DR GO; GO:0060080; P:inhibitory postsynaptic potential; ISS:BHF-UCL. DR GO; GO:0007194; P:negative regulation of adenylate cyclase activity; IDA:BHF-UCL. DR GO; GO:0030818; P:negative regulation of cAMP biosynthetic process; IDA:BHF-UCL. DR GO; GO:0050709; P:negative regulation of protein secretion; IDA:BHF-UCL. DR GO; GO:1901386; P:negative regulation of voltage-gated calcium channel activity; IDA:BHF-UCL. DR GO; GO:0008355; P:olfactory learning; IEA:Ensembl. DR GO; GO:0009648; P:photoperiodism; IEA:Ensembl. DR GO; GO:0051586; P:positive regulation of dopamine uptake involved in synaptic transmission; IC:BHF-UCL. DR GO; GO:2000463; P:positive regulation of excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0033674; P:positive regulation of kinase activity; IDA:BHF-UCL. DR GO; GO:0060406; P:positive regulation of penile erection; IEA:Ensembl. DR GO; GO:0032417; P:positive regulation of sodium:proton antiporter activity; IDA:BHF-UCL. DR GO; GO:0050848; P:regulation of calcium-mediated signaling; IEA:Ensembl. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0042053; P:regulation of dopamine metabolic process; ISS:BHF-UCL. DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:0001975; P:response to amphetamine; ISS:BHF-UCL. DR GO; GO:0034776; P:response to histamine; IDA:BHF-UCL. DR GO; GO:0048545; P:response to steroid hormone; IEA:Ensembl. DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl. DR GO; GO:0007606; P:sensory perception of chemical stimulus; IBA:GO_Central. DR GO; GO:0007614; P:short-term memory; IEA:Ensembl. DR GO; GO:0035176; P:social behavior; NAS:BHF-UCL. DR GO; GO:0007268; P:synaptic transmission; IBA:GO_Central. DR GO; GO:0001963; P:synaptic transmission, dopaminergic; IEA:Ensembl. DR InterPro; IPR002185; Dopamine_D4_rcpt. DR InterPro; IPR000929; Dopamine_rcpt. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR PANTHER; PTHR24249:SF37; PTHR24249:SF37; 2. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00569; DOPAMINED4R. DR PRINTS; PR00242; DOPAMINER. DR PRINTS; PR00237; GPCRRHODOPSN. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. PE 1: Evidence at protein level; KW Biological rhythms; Cell membrane; Complete proteome; Disulfide bond; KW G-protein coupled receptor; Glycoprotein; Membrane; Polymorphism; KW Receptor; Reference proteome; Repeat; Transducer; Transmembrane; KW Transmembrane helix; Ubl conjugation. FT CHAIN 1 467 D(4) dopamine receptor. FT /FTId=PRO_0000069401. FT TOPO_DOM 1 37 Extracellular. {ECO:0000255}. FT TRANSMEM 38 60 Helical; Name=1. {ECO:0000255}. FT TOPO_DOM 61 70 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 71 93 Helical; Name=2. {ECO:0000255}. FT TOPO_DOM 94 109 Extracellular. {ECO:0000255}. FT TRANSMEM 110 131 Helical; Name=3. {ECO:0000255}. FT TOPO_DOM 132 151 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 152 175 Helical; Name=4. {ECO:0000255}. FT TOPO_DOM 176 191 Extracellular. {ECO:0000255}. FT TRANSMEM 192 213 Helical; Name=5. {ECO:0000255}. FT TOPO_DOM 214 394 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 395 417 Helical; Name=6. {ECO:0000255}. FT TOPO_DOM 418 426 Extracellular. {ECO:0000255}. FT TRANSMEM 427 449 Helical; Name=7. {ECO:0000255}. FT TOPO_DOM 450 467 Cytoplasmic. {ECO:0000255}. FT REPEAT 249 264 1; approximate. FT REPEAT 265 280 2. FT REPEAT 281 296 3. FT REPEAT 297 312 4. FT REPEAT 313 328 5. FT REPEAT 329 344 6. FT REPEAT 345 360 7; approximate. FT REGION 249 360 7 X 16 AA approximate tandem repeats of FT [PA]-A-P-G-L-P-[PQR]-[DG]-P-C-G-P-D-C-A- FT P. FT CARBOHYD 3 3 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 108 185 {ECO:0000255|PROSITE-ProRule:PRU00521}. FT VARIANT 194 194 V -> G (in Afro-Caribbeans; FT dbSNP:rs1800443). FT {ECO:0000269|PubMed:7726213}. FT /FTId=VAR_003464. FT VARIANT 265 344 Missing (in allele D4.2). FT /FTId=VAR_003465. FT VARIANT 281 328 Missing (in allele D4.4). FT /FTId=VAR_003466. FT VARIANT 281 281 A -> P (in dbSNP:rs3889692). FT /FTId=VAR_055914. FT VARIANT 329 329 P -> A (in allele D4.4). FT /FTId=VAR_003467. FT VARIANT 332 332 G -> S (in allele D4.4). FT {ECO:0000269|Ref.4, ECO:0000269|Ref.6}. FT /FTId=VAR_003468. FT CONFLICT 237 237 R -> F (in Ref. 2; BAC05985). FT {ECO:0000305}. SQ SEQUENCE 467 AA; 48361 MW; B6FF2E09269A02AF CRC64; MGNRSTADAD GLLAGRGPAA GASAGASAGL AGQGAAALVG GVLLIGAVLA GNSLVCVSVA TERALQTPTN SFIVSLAAAD LLLALLVLPL FVYSEVQGGA WLLSPRLCDA LMAMDVMLCT ASIFNLCAIS VDRFVAVAVP LRYNRQGGSR RQLLLIGATW LLSAAVAAPV LCGLNDVRGR DPAVCRLEDR DYVVYSSVCS FFLPCPLMLL LYWATFRGLQ RWEVARRAKL HGRAPRRPSG PGPPSPTPPA PRLPQDPCGP DCAPPAPGLP RGPCGPDCAP AAPGLPPDPC GPDCAPPAPG LPQDPCGPDC APPAPGLPRG PCGPDCAPPA PGLPQDPCGP DCAPPAPGLP PDPCGSNCAP PDAVRAAALP PQTPPQTRRR RRAKITGRER KAMRVLPVVV GAFLLCWTPF FVVHITQALC PACSVPPRLV SAVTWLGYVN SALNPVIYTV FNAEFRNVFR KALRACC //