Dopamine receptor D3

Dopamine receptor D₃ (DRD3) is a protein belonging to the dopamine receptor family of G protein-coupled receptors. In humans, it is encoded by the DRD3 gene located on chromosome 3q13.3.^[5][6]

DRD3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3PBL
Identifiers
Aliases	DRD3, D3DR, ETM1, FET1, dopamine receptor D3
External IDs	OMIM: 126451; MGI: 94925; HomoloGene: 623; GeneCards: DRD3; OMA:DRD3 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q13.31 Start 114,127,580 bp[1] End 114,199,407 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 B4|16 28.44 cM Start 43,574,389 bp[2] End 43,643,295 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle nucleus accumbens putamen caudate nucleus granulocyte prefrontal cortex lymph node hypothalamus left testis right testis Top expressed in morula zygote superior frontal gyrus right ventricle lumbar subsegment of spinal cord ventricular zone meninges dentate gyrus of hippocampal formation granule cell blastocyst tibiofemoral joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding signal transducer activity G protein-coupled receptor activity dopamine neurotransmitter receptor activity dopamine neurotransmitter receptor activity, coupled via Gi/Go dopamine binding protein domain specific binding D1 dopamine receptor binding adrenergic receptor activity Cellular component endocytic vesicle apical part of cell cell projection integral component of membrane membrane plasma membrane integral component of plasma membrane dopaminergic synapse glutamatergic synapse GABA-ergic synapse integral component of postsynaptic density membrane Biological process negative regulation of sodium:proton antiporter activity dopamine receptor signaling pathway dopamine metabolic process regulation of circadian sleep/wake cycle, sleep negative regulation of dopamine receptor signaling pathway positive regulation of cell population proliferation regulation of dopamine uptake involved in synaptic transmission response to histamine response to ethanol prepulse inhibition social behavior learning positive regulation of renal sodium excretion arachidonic acid secretion negative regulation of protein secretion negative regulation of transcription by RNA polymerase II gastric emptying regulation of blood volume by renin-angiotensin regulation of locomotion involved in locomotory behavior cellular calcium ion homeostasis regulation of locomotion learning or memory response to amphetamine positive regulation of transcription by RNA polymerase II positive regulation of cytokinesis signal transduction regulation of lipid metabolic process regulation of multicellular organism growth visual learning G protein-coupled receptor internalization regulation of dopamine secretion negative regulation of protein kinase B signaling adenylate cyclase-activating dopamine receptor signaling pathway locomotory behavior behavioral response to cocaine negative regulation of blood pressure acid secretion musculoskeletal movement, spinal reflex action positive regulation of dopamine receptor signaling pathway circadian regulation of gene expression response to morphine negative regulation of oligodendrocyte differentiation adenylate cyclase-inhibiting dopamine receptor signaling pathway positive regulation of mitotic nuclear division response to cocaine synaptic transmission, dopaminergic G protein-coupled receptor signaling pathway autophagy negative regulation of apoptotic process regulation of neurotransmitter uptake regulation of postsynaptic neurotransmitter receptor internalization adenylate cyclase-modulating G protein-coupled receptor signaling pathway adenylate cyclase-activating adrenergic receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1814 13490 Ensembl ENSG00000151577 ENSMUSG00000022705 UniProt P35462 P30728 RefSeq (mRNA) NM_000796 NM_001282563 NM_001290809 NM_033658 NM_033659 NM_033660 NM_033663 NM_007877 RefSeq (protein) NP_000787 NP_001269492 NP_001277738 NP_387512 NP_031903 Location (UCSC) Chr 3: 114.13 – 114.2 Mb Chr 16: 43.57 – 43.64 Mb PubMed search [3] [4]
Wikidata
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Signaling

The D₃ receptor belongs to the D2-like receptor subfamily, which also includes D2 and D4 receptors. It couples primarily to Gi/Go proteins, leading to inhibition of adenylyl cyclase and reduced intracellular cAMP levels.^[7]

The D₃ receptor displays the highest binding affinity for dopamine among dopamine receptor subtypes, making it a key regulator of tonic dopamine signaling.^[8]

Expression

D₃ receptors are primarily expressed in limbic brain regions such as the nucleus accumbens, islands of Calleja, and olfactory tubercle. Their distribution in phylogenetically older brain areas suggests an important role in emotion, motivation, and cognition.^[9]

Function

Activation of the D₃ receptor regulates dopamine release and modulates neuronal excitability. Preclinical and clinical studies implicate it in:

• Parkinson’s disease – D₃ agonists such as pramipexole and rotigotine show neuroprotective effects, reduce alpha-synuclein aggregation, and improve motor and non-motor symptoms.^[10]
• Neuropsychiatric disorders – Altered DRD3 signaling has been associated with schizophrenia, bipolar disorder, and major depression. Some D₃ ligands exert antidepressant-like effects in animal models.^[11]
• Addiction – D₃ receptors modulate reward pathways; antagonists such as SB-277011-A show promise in reducing drug-seeking behavior in preclinical models.^[12]

Genetic polymorphisms

The DRD3 Ser9Gly polymorphism (rs6280) alters receptor binding characteristics and has been studied in relation to:

• Severity of depression in Parkinson’s disease^[13]
• Impulse control disorders and behavioral addictions^[14]

Pharmacology

D₃ ligands include:

• Agonists: pramipexole, ropinirole, rotigotine, 7-OH-DPAT, apomorphine
• Partial agonists: aripiprazole, brexpiprazole, cariprazine
• Antagonists: amisulpride, haloperidol, NGB-2904, SB-277011-A
• Allosteric modulators: SB269652

Many of these ligands are used clinically in Parkinson’s disease or schizophrenia, while others remain experimental.

Protein interactions

The D₃ receptor has been shown to interact with:

• CLIC6, an intracellular chloride channel protein^[15]
• EPB41L1, a cytoskeletal protein involved in membrane localization of GPCRs^[16]

Clinical significance

• Therapeutic target – Due to its role in motor control, motivation, and reward, DRD3 is a therapeutic target for Parkinson’s disease, schizophrenia, and substance use disorders.
• Drug design – High selectivity ligands for D₃ are actively pursued to minimize side effects associated with D₂ receptor blockade.
• Biomarker potential – Polymorphisms in DRD3 are under investigation as genetic biomarkers for treatment response and psychiatric vulnerability.

See also

• Dopamine receptor D2
• Dopamine receptor D4
• Parkinson’s disease
• Schizophrenia