Dopamine receptor D3

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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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]}

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

References

1. GRCh38: Ensembl release 89: ENSG00000151577 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022705 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, et al. (September 1991). "Chromosomal localization of the human D3 dopamine receptor gene". Human Genetics. 87 (5): 618–620. doi:10.1007/bf00209024. PMID   1916765. S2CID   28411786.
6. "Entrez Gene: DRD3 dopamine receptor D3".
7. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (January 1998). "Dopamine receptors: from structure to function". Physiological Reviews. 78 (1): 189–225. doi:10.1152/physrev.1998.78.1.189. PMID   9457173.
8. Robinson SW, Jarvie KR, Caron MG (August 1994). "High affinity agonist binding to the dopamine D3 receptor: chimeric receptors delineate a role for intracellular domains". Molecular Pharmacology. 46 (2): 352–356. doi:10.1016/S0026-895X(25)09690-7. PMID   7915820.
9. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (September 1990). "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics". Nature. 347 (6289): 146–151. doi:10.1038/347146a0. PMID   1975644.
10. Favier M, Carcenac C, Savasta M, Carnicella S (2022). "Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson's Disease". Current Topics in Behavioral Neurosciences. Vol. 60. Berlin, Heidelberg: Springer. pp. 109–132. doi:10.1007/7854_2022_316. ISBN   978-3-031-23057-8. PMID   35469394.
11. Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, et al. (August 2009). "Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats". European Journal of Pharmacology. 616 (1–3): 134–140. doi:10.1016/j.ejphar.2009.06.029. PMID   19549514.
12. Xi ZX, Gardner EL (2007). "Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction". CNS Drug Reviews. 13 (2): 240–259. doi:10.1111/j.1527-3458.2007.00013.x. PMC   3771110 . PMID   17627675.
13. Zhi Y, Yuan Y, Si Q, Wang M, Shen Y, Wang L, et al. (2019). "The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson's Disease". Parkinson's Disease. 2019: 1642087. doi: 10.1155/2019/1642087 . PMC   6501220 . PMID   31143436.
14. Krishnamoorthy S, Rajan R, Banerjee M, Kumar H, Sarma G, Krishnan S, et al. (September 2016). "Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients". Parkinsonism & Related Disorders. 30: 13–17. doi:10.1016/j.parkreldis.2016.06.005. PMID   27325396.
15. Griffon N, Jeanneteau F, Prieur F, Diaz J, Sokoloff P (September 2003). "CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors". Brain Research. Molecular Brain Research. 117 (1): 47–57. doi:10.1016/S0169-328X(03)00283-3. PMID   14499480.
16. Binda AV, Kabbani N, Lin R, Levenson R (September 2002). "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Molecular Pharmacology. 62 (3): 507–513. doi:10.1124/mol.62.3.507. PMID   12181426.

External links

• "Dopamine Receptors: D₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.