DRD4_HUMAN
ID DRD4_HUMAN Reviewed; 419 AA.
AC P21917; B0M0J7; Q7Z7Q5; Q8NGM5;
DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
DT 10-APR-2019, sequence version 3.
DT 03-AUG-2022, entry version 202.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ALLELE D4.7), POLYMORPHISM, AND SUBCELLULAR
RP LOCATION.
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), FUNCTION, AND SUBCELLULAR
RP LOCATION.
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 affinity
RT 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] (ALLELE D.4.4).
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., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., 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] (ALLELE D.4.4).
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., 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., Livak K.J.;
RT "A hypervariable segment in the human dopamine receptor D4 (DRD4) gene.";
RL Hum. Mol. Genet. 2:767-773(1993).
RN [8]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=7512953; DOI=10.1016/s0021-9258(17)32645-5;
RA Chio C.L., Drong R.F., Riley D.T., Gill G.S., Slightom J.L., Huff R.M.;
RT "D4 dopamine receptor-mediated signaling events determined in transfected
RT Chinese hamster ovary cells.";
RL J. Biol. Chem. 269:11813-11819(1994).
RN [9]
RP POLYMORPHISM, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=8078498;
RA Asghari V., Schoots O., van Kats S., Ohara K., Jovanovic V., Guan H.-C.,
RA Bunzow J.R., Petronis A., Van Tol H.H.M.;
RT "Dopamine D4 receptor repeat: analysis of different native and mutant forms
RT of the human and rat genes.";
RL Mol. Pharmacol. 46:364-373(1994).
RN [10]
RP TISSUE SPECIFICITY.
RX PubMed=7769992; DOI=10.1016/0169-328x(94)00245-a;
RA Matsumoto M., Hidaka K., Tada S., Tasaki Y., Yamaguchi T.;
RT "Full-length cDNA cloning and distribution of human dopamine D4 receptor.";
RL Brain Res. Mol. Brain Res. 29:157-162(1995).
RN [11]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=7643093; DOI=10.1046/j.1471-4159.1995.65031157.x;
RA Asghari V., Sanyal S., Buchwaldt S., Paterson A., Jovanovic V.,
RA Van Tol H.H.;
RT "Modulation of intracellular cyclic AMP levels by different human dopamine
RT D4 receptor variants.";
RL J. Neurochem. 65:1157-1165(1995).
RN [12]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=9003072; DOI=10.1046/j.1471-4159.1997.68020804.x;
RA Lanau F., Zenner M.T., Civelli O., Hartman D.S.;
RT "Epinephrine and norepinephrine act as potent agonists at the recombinant
RT human dopamine D4 receptor.";
RL J. Neurochem. 68:804-812(1997).
RN [13]
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 [14]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND POLYMORPHISM.
RX PubMed=16423344; DOI=10.1016/j.ejphar.2005.11.063;
RA Czermak C., Lehofer M., Liebmann P.M., Traynor J.;
RT "[35S]GTPgammaS binding at the human dopamine D4 receptor variants hD4.2,
RT hD4.4 and hD4.7 following stimulation by dopamine, epinephrine and
RT norepinephrine.";
RL Eur. J. Pharmacol. 531:20-24(2006).
RN [15]
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 ubiquitination by
RT a Cul3-based E3 ligase.";
RL J. Biol. Chem. 283:11083-11096(2008).
RN [16]
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 [17]
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 target
RT the receptor for degradation.";
RL Cell. Signal. 22:900-913(2010).
RN [18]
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 receptor-
RT receptor interactions.";
RL Biochem. Biophys. Res. Commun. 404:928-934(2011).
RN [19]
RP PALMITOYLATION AT CYS-419, MUTAGENESIS OF CYS-418 AND CYS-419, SUBCELLULAR
RP LOCATION, AND FUNCTION.
RX PubMed=27659709; DOI=10.1016/j.bbrc.2016.09.094;
RA Zhang X., Kim K.M.;
RT "Palmitoylation of the carboxyl-terminal tail of dopamine D4 receptor is
RT required for surface expression, endocytosis, and signaling.";
RL Biochem. Biophys. Res. Commun. 479:398-403(2016).
RN [20]
RP 3D-STRUCTURE MODELING.
RX PubMed=1358063; DOI=10.1042/bj2870277;
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 [21] {ECO:0007744|PDB:5WIU, ECO:0007744|PDB:5WIV}
RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 1-228 AND 335-419 IN COMPLEX WITH
RP NEMONAPRIDE, FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, TOPOLOGY,
RP DISULFIDE BONDS, AND MUTAGENESIS OF VAL-382.
RX PubMed=29051383; DOI=10.1126/science.aan5468;
RA Wang S., Wacker D., Levit A., Che T., Betz R.M., McCorvy J.D.,
RA Venkatakrishnan A.J., Huang X.P., Dror R.O., Shoichet B.K., Roth B.L.;
RT "D4 dopamine receptor high-resolution structures enable the discovery of
RT selective agonists.";
RL Science 358:381-386(2017).
RN [22]
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 the
CC mesolimbic system of the brain, an area of the brain that regulates
CC emotion and complex behavior. Activated by dopamine, but also by
CC epinephrine and norepinephrine, and by numerous synthetic agonists and
CC drugs (PubMed:9003072, PubMed:16423344, PubMed:27659709,
CC PubMed:29051383). Agonist binding triggers signaling via G proteins
CC that inhibit adenylyl cyclase (PubMed:7512953, PubMed:7643093,
CC PubMed:16423344, PubMed:27659709, PubMed:29051383). Modulates the
CC circadian rhythm of contrast sensitivity by regulating the rhythmic
CC expression of NPAS2 in the retinal ganglion cells (By similarity).
CC {ECO:0000250|UniProtKB:P51436, ECO:0000269|PubMed:16423344,
CC ECO:0000269|PubMed:1840645, ECO:0000269|PubMed:27659709,
CC ECO:0000269|PubMed:29051383, ECO:0000269|PubMed:7512953,
CC ECO:0000269|PubMed:7643093, ECO:0000269|PubMed:8078498,
CC ECO:0000269|PubMed:9003072}.
CC -!- ACTIVITY REGULATION: Signaling in response to agonists such as
CC dopamine, epinephrine and norepinephrine is modulated by Na(+); lower
CC Na(+) levels result in higher receptor activity (in vitro).
CC {ECO:0000269|PubMed:16423344, ECO:0000269|PubMed:29051383}.
CC -!- SUBUNIT: Forms homo- and heterooligomers with DRD2. D4.7 allele
CC exhibits higher affinity for homodimers compared to DRD2 heterodimers,
CC while alleles D42. and 4.4 have similar affinities for both. The
CC interaction with DRD2 may modulate agonist-induced downstream signaling
CC (PubMed:21184734). Interacts with CLIC6 (By similarity). Interacts with
CC GPRASP1 (PubMed:12142540). May interact with ADORA2A (PubMed:20836733).
CC Interacts with KLHL12 (PubMed:18303015). {ECO:0000250|UniProtKB:P30729,
CC ECO:0000269|PubMed:12142540, ECO:0000269|PubMed:18303015,
CC ECO:0000269|PubMed:21184734}.
CC -!- INTERACTION:
CC P21917; P05067: APP; NbExp=6; IntAct=EBI-8592297, EBI-77613;
CC P21917; P21917: DRD4; NbExp=5; IntAct=EBI-8592297, EBI-8592297;
CC P21917; P17677: GAP43; NbExp=3; IntAct=EBI-8592297, EBI-1267511;
CC P21917; P50579: METAP2; NbExp=3; IntAct=EBI-8592297, EBI-2214155;
CC P21917; Q96P71-2: NECAB3; NbExp=3; IntAct=EBI-8592297, EBI-15098952;
CC P21917; P61764: STXBP1; NbExp=3; IntAct=EBI-8592297, EBI-960169;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:1319557,
CC ECO:0000269|PubMed:16423344, ECO:0000269|PubMed:1840645,
CC ECO:0000269|PubMed:20100572, ECO:0000269|PubMed:27659709,
CC ECO:0000269|PubMed:29051383, ECO:0000269|PubMed:7512953,
CC ECO:0000269|PubMed:7643093, ECO:0000269|PubMed:8078498,
CC ECO:0000269|PubMed:9003072}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:20100572, ECO:0000269|PubMed:29051383}.
CC -!- TISSUE SPECIFICITY: Highly expressed in retina. Detected at much lower
CC levels in brain, in amygdala, thalamus, hypothalamus, cerebellum and
CC pituitary. {ECO:0000269|PubMed:7769992}.
CC -!- PTM: Polyubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex:
CC polyubiquitination does not lead to degradation of DRD4 protein.
CC {ECO:0000269|PubMed:18303015, ECO:0000269|PubMed:20100572}.
CC -!- PTM: Palmitoylated. Palmitoylation of the C-terminal Cys is important
CC for normal expression at the cell membrane.
CC {ECO:0000269|PubMed:27659709}.
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 been
CC described. The sequence shown is that of allele D4.4. The polymorphic
CC repeat sequence has little influence on DRD4-binding profiles and might
CC not be essential for G protein interaction.
CC {ECO:0000269|PubMed:1319557, ECO:0000269|PubMed:16423344,
CC ECO:0000269|PubMed:8078498, ECO:0000269|PubMed:8353495}.
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};
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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 CCDS; CCDS7710.1; -.
DR PIR; S15079; DYHUD4.
DR PIR; S24195; S24195.
DR RefSeq; NP_000788.2; NM_000797.3.
DR PDB; 5WIU; X-ray; 1.96 A; A=1-228, A=335-419.
DR PDB; 5WIV; X-ray; 2.14 A; A=1-228, A=335-419.
DR PDBsum; 5WIU; -.
DR PDBsum; 5WIV; -.
DR AlphaFoldDB; P21917; -.
DR SMR; P21917; -.
DR BioGRID; 108149; 27.
DR CORUM; P21917; -.
DR DIP; DIP-59865N; -.
DR IntAct; P21917; 8.
DR MINT; P21917; -.
DR STRING; 9606.ENSP00000176183; -.
DR BindingDB; P21917; -.
DR ChEMBL; CHEMBL219; -.
DR DrugBank; DB00543; Amoxapine.
DR DrugBank; DB00714; Apomorphine.
DR DrugBank; DB01238; Aripiprazole.
DR DrugBank; DB14185; Aripiprazole lauroxil.
DR DrugBank; DB06216; Asenapine.
DR DrugBank; DB01200; Bromocriptine.
DR DrugBank; DB00490; Buspirone.
DR DrugBank; DB00248; Cabergoline.
DR DrugBank; DB00477; Chlorpromazine.
DR DrugBank; DB00363; Clozapine.
DR DrugBank; DB13345; Dihydroergocristine.
DR DrugBank; DB00320; Dihydroergotamine.
DR DrugBank; DB00988; Dopamine.
DR DrugBank; DB11275; Epicriptine.
DR DrugBank; DB01049; Ergoloid mesylate.
DR DrugBank; DB04908; Flibanserin.
DR DrugBank; DB00875; Flupentixol.
DR DrugBank; DB04946; Iloperidone.
DR DrugBank; DB01235; Levodopa.
DR DrugBank; DB00589; Lisuride.
DR DrugBank; DB00408; Loxapine.
DR DrugBank; DB01403; Methotrimeprazine.
DR DrugBank; DB08804; Nandrolone decanoate.
DR DrugBank; DB00334; Olanzapine.
DR DrugBank; DB01267; Paliperidone.
DR DrugBank; DB12061; Pardoprunox.
DR DrugBank; DB01186; Pergolide.
DR DrugBank; DB08922; Perospirone.
DR DrugBank; DB09286; Pipamperone.
DR DrugBank; DB00413; Pramipexole.
DR DrugBank; DB01224; Quetiapine.
DR DrugBank; DB00409; Remoxipride.
DR DrugBank; DB00268; Ropinirole.
DR DrugBank; DB05271; Rotigotine.
DR DrugBank; DB00391; Sulpiride.
DR DrugBank; DB06477; Sumanirole.
DR DrugBank; DB00246; Ziprasidone.
DR DrugCentral; P21917; -.
DR GuidetoPHARMACOLOGY; 217; -.
DR GlyGen; P21917; 1 site.
DR iPTMnet; P21917; -.
DR PhosphoSitePlus; P21917; -.
DR BioMuta; DRD4; -.
DR DMDM; 1345939; -.
DR MassIVE; P21917; -.
DR PeptideAtlas; P21917; -.
DR PRIDE; P21917; -.
DR ProteomicsDB; 53940; -.
DR Antibodypedia; 22579; 461 antibodies from 35 providers.
DR DNASU; 1815; -.
DR Ensembl; ENST00000176183.6; ENSP00000176183.5; ENSG00000069696.7.
DR Ensembl; ENST00000611962.2; ENSP00000478431.1; ENSG00000276825.2.
DR GeneID; 1815; -.
DR KEGG; hsa:1815; -.
DR MANE-Select; ENST00000176183.6; ENSP00000176183.5; NM_000797.4; NP_000788.2.
DR UCSC; uc001lqp.3; human.
DR CTD; 1815; -.
DR DisGeNET; 1815; -.
DR GeneCards; DRD4; -.
DR HGNC; HGNC:3025; DRD4.
DR HPA; ENSG00000069696; Low tissue specificity.
DR MalaCards; DRD4; -.
DR MIM; 126452; gene.
DR neXtProt; NX_P21917; -.
DR OpenTargets; ENSG00000069696; -.
DR PharmGKB; PA27480; -.
DR VEuPathDB; HostDB:ENSG00000069696; -.
DR GeneTree; ENSGT00940000160974; -.
DR HOGENOM; CLU_009579_11_1_1; -.
DR InParanoid; P21917; -.
DR OMA; VVHITQA; -.
DR OrthoDB; 1215361at2759; -.
DR PhylomeDB; P21917; -.
DR TreeFam; TF334382; -.
DR PathwayCommons; P21917; -.
DR Reactome; R-HSA-390651; Dopamine receptors.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR SignaLink; P21917; -.
DR SIGNOR; P21917; -.
DR BioGRID-ORCS; 1815; 8 hits in 1062 CRISPR screens.
DR ChiTaRS; DRD4; human.
DR GeneWiki; Dopamine_receptor_D4; -.
DR GenomeRNAi; 1815; -.
DR Pharos; P21917; Tchem.
DR PRO; PR:P21917; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P21917; protein.
DR Bgee; ENSG00000069696; Expressed in lower esophagus mucosa and 90 other tissues.
DR Genevisible; P21917; HS.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:SYSCILIA_CCNET.
DR GO; GO:0098794; C:postsynapse; IEA:GOC.
DR GO; GO:0035240; F:dopamine binding; IDA:UniProtKB.
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:UniProtKB.
DR GO; GO:0051379; F:epinephrine binding; IDA:UniProtKB.
DR GO; GO:0004993; F:G protein-coupled serotonin receptor activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central.
DR GO; GO:0051380; F:norepinephrine binding; IDA:UniProtKB.
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:0007195; P:adenylate cyclase-inhibiting dopamine receptor signaling pathway; IDA:UniProtKB.
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:0007268; P:chemical synaptic transmission; IBA:GO_Central.
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:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; IBA:GO_Central.
DR GO; GO:0060080; P:inhibitory postsynaptic potential; ISS: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:0051586; P:positive regulation of dopamine uptake involved in synaptic transmission; IC:BHF-UCL.
DR GO; GO:0033674; P:positive regulation of kinase activity; IDA:BHF-UCL.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:0032417; P:positive regulation of sodium:proton antiporter activity; IDA:BHF-UCL.
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:0099149; P:regulation of postsynaptic neurotransmitter receptor internalization; 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:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0035176; P:social behavior; NAS:BHF-UCL.
DR InterPro; IPR002185; Dopamine_D4_rcpt.
DR InterPro; IPR000929; Dopamine_rcpt.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR PANTHER; PTHR24248:SF143; PTHR24248:SF143; 1.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00569; DOPAMINED4R.
DR PRINTS; PR00242; DOPAMINER.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR SMART; SM01381; 7TM_GPCR_Srsx; 1.
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 3D-structure; Biological rhythms; Cell membrane; Disulfide bond;
KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane;
KW Metal-binding; Palmitate; Receptor; Reference proteome; Repeat; Sodium;
KW Transducer; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..419
FT /note="D(4) dopamine receptor"
FT /id="PRO_0000069401"
FT TOPO_DOM 1..29
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 30..50
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 51..71
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 72..92
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 93..110
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 111..131
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 132..152
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 153..173
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 174..192
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 193..213
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 214..346
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 347..367
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 368..382
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TRANSMEM 383..403
FT /note="Helical; Name=7"
FT /evidence="ECO:0000269|PubMed:29051383"
FT TOPO_DOM 404..419
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29051383"
FT REPEAT 249..264
FT /note="1; approximate"
FT REPEAT 265..280
FT /note="2"
FT REPEAT 281..296
FT /note="3"
FT REPEAT 297..312
FT /note="4; approximate"
FT REGION 230..264
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 249..312
FT /note="4 X 16 AA approximate tandem repeats of [PA]-A-P-G-
FT L-P-[PQR]-[DG]-P-C-G-P-D-C-A-P"
FT REGION 317..336
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 237..264
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 80
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /evidence="ECO:0000305|PubMed:29051383"
FT BINDING 115
FT /ligand="(2R,3R)-nemonapride"
FT /ligand_id="ChEBI:CHEBI:188145"
FT /ligand_note="antagonist"
FT /evidence="ECO:0000269|PubMed:29051383,
FT ECO:0007744|PDB:5WIU, ECO:0007744|PDB:5WIV"
FT BINDING 122
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /evidence="ECO:0000305|PubMed:29051383"
FT BINDING 196
FT /ligand="(2R,3R)-nemonapride"
FT /ligand_id="ChEBI:CHEBI:188145"
FT /ligand_note="antagonist"
FT /evidence="ECO:0000269|PubMed:29051383,
FT ECO:0007744|PDB:5WIU, ECO:0007744|PDB:5WIV"
FT LIPID 419
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:27659709"
FT CARBOHYD 3
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 108..185
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521,
FT ECO:0000269|PubMed:29051383, ECO:0007744|PDB:5WIU,
FT ECO:0007744|PDB:5WIV"
FT DISULFID 372..375
FT /evidence="ECO:0000269|PubMed:29051383,
FT ECO:0007744|PDB:5WIU, ECO:0007744|PDB:5WIV"
FT VARIANT 194
FT /note="V -> G (in dbSNP:rs1800443)"
FT /evidence="ECO:0000269|PubMed:7726213"
FT /id="VAR_003464"
FT VARIANT 265..296
FT /note="Missing (in allele D4.2)"
FT /evidence="ECO:0000269|PubMed:1840645"
FT /id="VAR_003465"
FT VARIANT 284
FT /note="S -> GLPPDPCGPDCAPPAPGLPQDPCGPDCAPPAPGLPRGPCGPDCAPPA
FT PG (in allele D4.7)"
FT /evidence="ECO:0000269|PubMed:1319557"
FT /id="VAR_081438"
FT MUTAGEN 382
FT /note="V->Y: Increased basal level of G protein-mediated
FT signaling."
FT /evidence="ECO:0000269|PubMed:29051383"
FT MUTAGEN 418
FT /note="C->G: No effect on palmitoylation."
FT /evidence="ECO:0000269|PubMed:27659709"
FT MUTAGEN 419
FT /note="C->G: Loss of palmitoylation."
FT /evidence="ECO:0000269|PubMed:27659709"
FT CONFLICT 237
FT /note="R -> F (in Ref. 2; BAC05985)"
FT /evidence="ECO:0000305"
FT HELIX 35..61
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 63..65
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 68..86
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 88..96
FT /evidence="ECO:0007829|PDB:5WIU"
FT TURN 97..99
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 105..138
FT /evidence="ECO:0007829|PDB:5WIU"
FT STRAND 144..147
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 151..171
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 190..200
FT /evidence="ECO:0007829|PDB:5WIU"
FT TURN 201..203
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 204..220
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 340..344
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 347..371
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 379..403
FT /evidence="ECO:0007829|PDB:5WIU"
FT HELIX 405..412
FT /evidence="ECO:0007829|PDB:5WIU"
SQ SEQUENCE 419 AA; 43901 MW; 34CBE8320302008E 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 AAPSLPQDPC GPDCAPPAPG
LPPDPCGSNC APPDAVRAAA LPPQTPPQTR RRRRAKITGR ERKAMRVLPV VVGAFLLCWT
PFFVVHITQA LCPACSVPPR LVSAVTWLGY VNSALNPVIY TVFNAEFRNV FRKALRACC
