P21917 (DRD4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
D(4) dopamine receptor

Alternative name(s):
D(2C) dopamine receptor
Dopamine D4 receptor

Gene names

Name:

DRD4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Subunit structure	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. Ref.9 Ref.10 Ref.11
Subcellular location	Cell membrane; Multi-pass membrane protein.
Polymorphism	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.
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.
Sequence caution	The sequence AAL58637.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Domain	Repeat Transmembrane Transmembrane helix
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	activation of MAPK activity Inferred from direct assay. Source: BHF-UCL adult locomotory behavior Inferred from sequence or structural similarity. Source: BHF-UCL arachidonic acid secretion Inferred from direct assay. Source: BHF-UCL behavioral fear response Non-traceable author statement. Source: BHF-UCL behavioral response to cocaine Inferred from sequence or structural similarity. Source: BHF-UCL behavioral response to ethanol Traceable author statement. Source: BHF-UCL cellular calcium ion homeostasis Inferred by curator. Source: BHF-UCL dopamine metabolic process Inferred by curator Ref.2. Source: BHF-UCL inhibition of adenylate cyclase activity by dopamine receptor signaling pathway Inferred from direct assay. Source: BHF-UCL negative regulation of cAMP biosynthetic process Inferred from direct assay. Source: BHF-UCL negative regulation of calcium ion transport via voltage-gated calcium channel activity Inferred from direct assay. Source: BHF-UCL negative regulation of protein secretion Inferred from direct assay. Source: BHF-UCL positive regulation of dopamine uptake Inferred by curator Ref.2. Source: BHF-UCL positive regulation of sodium:hydrogen antiporter activity Inferred from direct assay. Source: BHF-UCL regulation of dopamine metabolic process Inferred from sequence or structural similarity. Source: BHF-UCL regulation of inhibitory postsynaptic membrane potential Inferred from sequence or structural similarity. Source: BHF-UCL response to amphetamine Inferred from sequence or structural similarity. Source: BHF-UCL response to histamine Inferred from direct assay. Source: BHF-UCL social behavior Non-traceable author statement. Source: BHF-UCL
Cellular component	integral to plasma membrane Inferred from direct assay. Source: BHF-UCL
Molecular function	SH3 domain binding Inferred from direct assay. Source: BHF-UCL dopamine binding Inferred from direct assay Ref.1. Source: BHF-UCL dopamine receptor activity, coupled via Gi/Go Inferred from direct assay Ref.2. Source: BHF-UCL drug binding Inferred from direct assay Ref.1Ref.2. Source: BHF-UCL potassium channel regulator activity Non-traceable author statement. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 467	467	D(4) dopamine receptor		PRO_0000069401
Regions
	Topological domain	1 – 37	37	Extracellular Potential
	Transmembrane	38 – 60	23	Helical; Name=1; Potential
	Topological domain	61 – 70	10	Cytoplasmic Potential
	Transmembrane	71 – 93	23	Helical; Name=2; Potential
	Topological domain	94 – 109	16	Extracellular Potential
	Transmembrane	110 – 131	22	Helical; Name=3; Potential
	Topological domain	132 – 151	20	Cytoplasmic Potential
	Transmembrane	152 – 175	24	Helical; Name=4; Potential
	Topological domain	176 – 191	16	Extracellular Potential
	Transmembrane	192 – 213	22	Helical; Name=5; Potential
	Topological domain	214 – 394	181	Cytoplasmic Potential
	Transmembrane	395 – 417	23	Helical; Name=6; Potential
	Topological domain	418 – 426	9	Extracellular Potential
	Transmembrane	427 – 449	23	Helical; Name=7; Potential
	Topological domain	450 – 467	18	Cytoplasmic Potential
	Repeat	249 – 264	16	1; approximate
	Repeat	265 – 280	16	2
	Repeat	281 – 296	16	3
	Repeat	297 – 312	16	4
	Repeat	313 – 328	16	5
	Repeat	329 – 344	16	6
	Repeat	345 – 360	16	7; approximate
	Region	249 – 360	112	7 X 16 AA approximate tandem repeats of [PA]-A-P-G-L-P-[PQR]-[DG]-P-C-G-P-D-C-A-P
Amino acid modifications
	Glycosylation	3	1	N-linked (GlcNAc...) Potential
	Disulfide bond	108 ↔ 185		By similarity
Natural variations
	Natural variant	194	1	V → G in Afro-Caribbeans. Ref.13 Corresponds to variant rs1800443 [ dbSNP | Ensembl ].		VAR_003464
	Natural variant	265 – 344	80	Missing in allele D4.2.		VAR_003465
	Natural variant	281 – 328	48	Missing in allele D4.4.		VAR_003466
	Natural variant	281	1	A → P. Corresponds to variant rs3889692 [ dbSNP | Ensembl ].		VAR_055914
	Natural variant	329	1	P → A in allele D4.4.		VAR_003467
	Natural variant	332	1	G → S in allele D4.4. Ref.4 Ref.6		VAR_003468
Experimental info
	Sequence conflict	237	1	R → F in BAC05985. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P21917 [UniParc]. Last modified February 1, 1996. Version 2. Checksum: B6FF2E09269A02AF	FASTA	467	48,361
	10 20 30 40 50 60 MGNRSTADAD GLLAGRGPAA GASAGASAGL AGQGAAALVG GVLLIGAVLA GNSLVCVSVA 70 80 90 100 110 120 TERALQTPTN SFIVSLAAAD LLLALLVLPL FVYSEVQGGA WLLSPRLCDA LMAMDVMLCT 130 140 150 160 170 180 ASIFNLCAIS VDRFVAVAVP LRYNRQGGSR RQLLLIGATW LLSAAVAAPV LCGLNDVRGR 190 200 210 220 230 240 DPAVCRLEDR DYVVYSSVCS FFLPCPLMLL LYWATFRGLQ RWEVARRAKL HGRAPRRPSG 250 260 270 280 290 300 PGPPSPTPPA PRLPQDPCGP DCAPPAPGLP RGPCGPDCAP AAPGLPPDPC GPDCAPPAPG 310 320 330 340 350 360 LPQDPCGPDC APPAPGLPRG PCGPDCAPPA PGLPQDPCGP DCAPPAPGLP PDPCGSNCAP 370 380 390 400 410 420 PDAVRAAALP PQTPPQTRRR RRAKITGRER KAMRVLPVVV GAFLLCWTPF FVVHITQALC 430 440 450 460 PACSVPPRLV SAVTWLGYVN SALNPVIYTV FNAEFRNVFR KALRACC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Multiple dopamine D4 receptor variants in the human population." van Tol H.H., Wu C.M., Guan H.C., Ohara K., Bunzow J.R., Civelli O., Kennedy J., Seeman P., Niznik H.B., Jovanovic V. Nature 358:149-152(1992) [PubMed: 1319557] [Abstract] 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: 1840645] [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]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed: 16554811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] (ALLELE D4.4).
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases 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: 8353495] [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: 8078498] [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: 12142540] [Abstract] Cited for: INTERACTION WITH GPRASP1.
[10]	"The dopamine D(4) receptor, the ultimate disordered protein." Woods A.S. J. Recept. Signal Transduct. 30:331-336(2010) [PubMed: 20836733] [Abstract] Cited for: POSSIBLE INTERACTION WITH ADORA2A.
[11]	"Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions." Borroto-Escuela D.O., Van Craenenbroeck K., Romero-Fernandez W., Guidolin D., Woods A.S., Rivera A., Haegeman G., Agnati L.F., Tarakanov A.O., Fuxe K. Biochem. Biophys. Res. Commun. 404:928-934(2011) [PubMed: 21184734] [Abstract] Cited for: HOMOOLIGOMERIZATION, INTERACTION WITH DRD2.
[12]	"Molecular modelling of D2-like dopamine receptors." Livingstone C.D., Strange P.G., Naylor L.H. Biochem. J. 287:277-282(1992) [PubMed: 1358063] [Abstract] Cited for: 3D-STRUCTURE MODELING.
[13]	"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: 7726213] [Abstract] Cited for: VARIANT GLY-194.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00011225.
PIR	DYHUD4. S15079. S24195.
RefSeq	NP_000788.2. NM_000797.3.
UniGene	Hs.99922.
3D structure databases
ProteinModelPortal	P21917.
SMR	P21917. Positions 39-465.
ModBase	Search...
Protein family/group databases
GPCRDB	Search...
PTM databases
PhosphoSite	P21917.
Polymorphism databases
DMDM	1345939.
Proteomic databases
PRIDE	P21917.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000176183; ENSP00000176183; ENSG00000069696.
GeneID	1815.
KEGG	hsa:1815.
Organism-specific databases
CTD	1815.
GeneCards	GC11P000627.
HGNC	HGNC:3025. DRD4.
MIM	126452. gene.
neXtProt	NX_P21917.
PharmGKB	PA27480.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	HBG106962.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
Bgee	P21917.
CleanEx	HS_DRD4.
Genevestigator	P21917.
Family and domain databases
InterPro	IPR000276. 7TM_GPCR_Rhodpsn. IPR002185. Dopa_D4_rcpt. IPR000929. Dopamine_rcpt. IPR017452. GPCR_Rhodpsn_supfam. [Graphical view]
KO	K04147.
Pfam	PF00001. 7tm_1. 1 hit. [Graphical view]
PRINTS	PR00569. DOPAMINED4R. PR00242. DOPAMINER. PR00237. GPCRRHODOPSN.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. 1 hit. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
DrugBank	DB00714. Apomorphine. DB00363. Clozapine. DB00334. Olanzapine. DB00413. Pramipexole. DB00420. Promazine. DB00777. Propiomazine. DB00268. Ropinirole. DB00372. Thiethylperazine. DB00246. Ziprasidone.
NextBio	7401.
SOURCE	Search...

Entry information

Entry name

DRD4_HUMAN

Accession

Primary (citable) accession number: P21917
Secondary accession number(s): B0M0J7, Q7Z7Q5, Q8NGM5

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1991
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 116 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.