Details for: DRD4

Gene ID: 1815

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: DRD4

Ensembl ID: ENSG00000069696

Description: dopamine receptor D4

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • rod bipolar cell CL0000751
    CSI 7.47
    rCSI 13.43%
    PRS 80.74
  • retinal cone cell CL0000573
    CSI 7.05
    rCSI 11.35%
    PRS 77.73
  • ON-bipolar cell CL0000749
    CSI 3.01
    rCSI 4.48%
    PRS 85.87
  • retinal rod cell CL0000604
    CSI 2.87
    rCSI 5.06%
    PRS 81.98
  • melanocyte of skin CL1000458
    CSI 2.83
    rCSI 3.86%
    PRS 54.92
  • choroid plexus epithelial cell CL0000706
    CSI 2.23
    rCSI 3.65%
    PRS 77.76
  • retinal bipolar neuron CL0000748
    CSI 2.01
    rCSI 3.77%
    PRS 76.56
  • retinal pigment epithelial cell CL0002586
    CSI 1.59
    rCSI 3.17%
    PRS 82.53
  • basal cell of epidermis CL0002187
    CSI 1.22
    rCSI 2.16%
    PRS 56.15
  • amacrine cell CL0000561
    CSI 0.94
    rCSI 2.73%
    PRS 77.04

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [DRD4](/details-gene/1815) is a protein-coding gene located on chromosome 11 that encodes the D(4) dopamine receptor, a member of the G protein-coupled receptor (GPCR) superfamily. As a key component of the dopaminergic system, it binds dopamine, epinephrine, and norepinephrine to mediate inhibitory signal transduction, primarily through G alpha (i) signaling pathways that decrease intracellular cAMP levels. While extensively studied for its role in the central nervous system and its association with neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD) ([126452](https://omim.org/entry/126452)), expression data reveal its most pronounced significance is within the specialized cells of the retina. **Overall**, [DRD4](/details-gene/1815) is a defining marker for [rod bipolar cells](/details-cell/CL0000751) and [retinal cone cells](/details-cell/CL0000573), suggesting a critical function in visual signal processing and neuromodulation. ## Cellular Roles and Expression Landscape The expression profile of [DRD4](/details-gene/1815) highlights a highly specialized role in neural and pigmented cells, particularly within the eye. **Overall**, the gene shows its highest significance in the intricate cellular network of the retina. It is a top marker for [rod bipolar cells](/details-cell/CL0000751) (CSI: 7.47), [retinal cone cells](/details-cell/CL0000573) (CSI: 7.05), [ON-bipolar cells](/details-cell/CL0000749) (CSI: 3.01), and [retinal rod cells](/details-cell/CL0000604) (CSI: 2.87). This concentration in both photoreceptors and the second-order neurons they synapse with strongly suggests that [DRD4](/details-gene/1815) plays a pivotal role in modulating the initial stages of visual processing, potentially by regulating synaptic transmission and signal amplification. Beyond the retina, [DRD4](/details-gene/1815) is also significantly expressed in pigmented cells, including [melanocytes of the skin](/details-cell/CL1000458) and [retinal pigment epithelial cells](/details-cell/CL0002586). This pattern may indicate a function in catecholamine-mediated regulation of pigmentation or cellular homeostasis in these tissues. Additionally, its expression in the [choroid plexus epithelial cell](/details-cell/CL0000706) suggests a potential involvement in the regulation of cerebrospinal fluid production or composition. The highly specific expression landscape indicates that the function of [DRD4](/details-gene/1815) is tailored to sensory processing and specialized epithelial functions rather than being a ubiquitous neuromodulator throughout the body. ## Pathways and Molecular Function The [DRD4](/details-gene/1815) protein is an integral membrane protein that functions as a neurotransmitter receptor. It belongs to the [Class a/1 (rhodopsin-like receptors)](https://reactome.org/content/detail/R-HSA-373076) and is a key component of the [Dopamine receptors](https://reactome.org/content/detail/R-HSA-390651) pathway. Its primary molecular function is [Dopamine neurotransmitter receptor activity, coupled via gi/go](https://www.ebi.ac.uk/QuickGO/term/GO:0001591), which initiates [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594). This signaling cascade typically leads to the inhibition of adenylate cyclase ([Adenylate cyclase-inhibiting dopamine receptor signaling pathway](/details-cell/GO0007195)), reducing intracellular levels of the second messenger cAMP. While its canonical ligand is dopamine ([Dopamine binding](/details-cell/GO0035240)), research has shown it also binds epinephrine and norepinephrine with high potency, acting as a receptor for multiple catecholamines [Link](https://doi.org/10.1046/j.1471-4159.1997.68020804.x). Cellularly, the receptor is localized to the [plasma membrane](/details-cell/GO0005886), particularly in neuronal projections such as [dendrites](/details-cell/GO0030425) and at the [postsynapse](/details-cell/GO0098794). The biological processes associated with [DRD4](/details-gene/1815) signaling are diverse and primarily behavioral, including the regulation of [adult locomotory behavior](/details-cell/GO0008344), [social behavior](/details-cell/GO0035176), [fear response](/details-cell/GO0042596), and the [regulation of circadian rhythm](/details-cell/GO0042752). This functional profile is consistent with its established role in higher-order brain functions and its strong association with behavioral traits and neuropsychiatric disorders. ## Research Directions The prominent and highly specific expression of [DRD4](/details-gene/1815) in the retina, a context less explored than its role in the brain, opens up several avenues for future investigation. Based on the available data, two testable hypotheses can be proposed: 1. **[DRD4](/details-gene/1815) is a key modulator of light adaptation and signal processing in the outer retina.** The gene's high significance in both photoreceptors ([retinal cone cells](/details-cell/CL0000573), [retinal rod cells](/details-cell/CL0000604)) and bipolar cells ([rod bipolar cell](/details-cell/CL0000751)) suggests it fine-tunes the synaptic connection between these cells. We hypothesize that ambient dopamine levels in the retina, which are known to follow a circadian rhythm, act on DRD4 to adjust the gain and sensitivity of the retinal network, contributing to the shift between scotopic (night) and photopic (day) vision. 2. **In [melanocytes](/details-cell/CL1000458), [DRD4](/details-gene/1815) signaling mediates the skin's response to systemic or local catecholamine release during stress.** We hypothesize that activation of DRD4 on melanocytes by stress-induced catecholamines influences melanogenesis and cellular viability, providing a molecular link between psychological stress and skin pigmentation disorders or melanoma risk. To test the first hypothesis regarding the role of [DRD4](/details-gene/1815) in retinal function, a key experiment would involve using a retina-specific conditional knockout mouse model (e.g., using a Cre-Lox system with a driver specific for bipolar cells or photoreceptors). Electroretinography (ERG) could be performed on these animals to assess the b-wave (reflecting bipolar cell activity) and a-wave (photoreceptor activity) under different light- and dark-adapted conditions. Comparing the ERG responses between knockout and wild-type mice after administration of DRD4-specific agonists or antagonists would provide direct evidence of its role in modulating retinal signaling pathways. From a therapeutic perspective, [DRD4](/details-gene/1815) is a well-established but challenging drug target. Its high affinity for antipsychotics like clozapine underscores its relevance in psychiatry [Link](https://doi.org/10.1038/350610a0). However, the gene is known for its high degree of polymorphism, especially a variable number tandem repeat (VNTR) in exon 3, which can alter receptor function and complicates drug development [Link](https://doi.org/10.1093/hmg/2.6.767). Future therapeutic strategies would likely involve antagonism of the receptor for conditions like ADHD. The discovery of its significant role in the retina could open new possibilities for treating degenerative retinal diseases, but would require the development of highly targeted therapies (e.g., intraocular delivery) to avoid significant off-target effects in the central nervous system.

Genular Protein ID: 3005699293

Symbol: DRD4_HUMAN

Name: D(4) dopamine receptor

UniProtKB Accession Codes:

P21917 B0M0J7 Q7Z7Q5 Q8NGM5

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChEBI 4 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 37 DrugCentral 1 EMBL 6 Ensembl 2 GO 45 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PIR 2 PRINTS 3 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 1319557

Title: Multiple dopamine D4 receptor variants in the human population.

PubMed ID: 1319557

DOI: 10.1038/358149a0

PubMed ID: 1840645

Title: Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.

PubMed ID: 1840645

DOI: 10.1038/350610a0

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 8353495

Title: A hypervariable segment in the human dopamine receptor D4 (DRD4) gene.

PubMed ID: 8353495

DOI: 10.1093/hmg/2.6.767

PubMed ID: 7512953

Title: D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells.

PubMed ID: 7512953

DOI: 10.1016/s0021-9258(17)32645-5

PubMed ID: 8078498

Title: Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes.

PubMed ID: 8078498

PubMed ID: 7769992

Title: Full-length cDNA cloning and distribution of human dopamine D4 receptor.

PubMed ID: 7769992

DOI: 10.1016/0169-328x(94)00245-a

PubMed ID: 7643093

Title: Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants.

PubMed ID: 7643093

DOI: 10.1046/j.1471-4159.1995.65031157.x

PubMed ID: 9003072

Title: Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor.

PubMed ID: 9003072

DOI: 10.1046/j.1471-4159.1997.68020804.x

PubMed ID: 12142540

Title: Modulation of postendocytic sorting of G protein-coupled receptors.

PubMed ID: 12142540

DOI: 10.1126/science.1073308

PubMed ID: 16423344

Title: [35S]GTPgammaS binding at the human dopamine D4 receptor variants hD4.2, hD4.4 and hD4.7 following stimulation by dopamine, epinephrine and norepinephrine.

PubMed ID: 16423344

DOI: 10.1016/j.ejphar.2005.11.063

PubMed ID: 18303015

Title: BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase.

PubMed ID: 18303015

DOI: 10.1074/jbc.m708473200

PubMed ID: 20836733

Title: The dopamine D(4) receptor, the ultimate disordered protein.

PubMed ID: 20836733

DOI: 10.3109/10799893.2010.513842

PubMed ID: 20100572

Title: KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation.

PubMed ID: 20100572

DOI: 10.1016/j.cellsig.2010.01.014

PubMed ID: 21184734

Title: Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions.

PubMed ID: 21184734

DOI: 10.1016/j.bbrc.2010.12.083

PubMed ID: 27659709

Title: Palmitoylation of the carboxyl-terminal tail of dopamine D4 receptor is required for surface expression, endocytosis, and signaling.

PubMed ID: 27659709

DOI: 10.1016/j.bbrc.2016.09.094

PubMed ID: 1358063

Title: Molecular modelling of D2-like dopamine receptors.

PubMed ID: 1358063

DOI: 10.1042/bj2870277

PubMed ID: 29051383

Title: D4 dopamine receptor high-resolution structures enable the discovery of selective agonists.

PubMed ID: 29051383

DOI: 10.1126/science.aan5468

PubMed ID: 7726213

Title: Dopamine D4 receptor variant, D4-glycine-194, in Africans, but not in Caucasians: no association with schizophrenia.

PubMed ID: 7726213

DOI: 10.1002/ajmg.1320540419

Sequence Information:

  • Length: 419
  • Mass: 43901
  • Checksum: 34CBE8320302008E
  • Sequence:
    • 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