Dopamine receptor D3

Dopamine receptor D₃ is a protein that in humans is encoded by the DRD3 gene.^[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
View/Edit Human View/Edit Mouse

This gene encodes the D₃ subtype of the dopamine receptor. The D₃ subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that this receptor plays a role in cognitive and emotional functions.^{[citation needed]} It is a target for drugs which treat schizophrenia, drug addiction, and Parkinson's disease.^[7] Alternative splicing of this gene results in multiple transcript variants that would encode different isoforms, although some variants may be subject to nonsense-mediated decay (NMD).^[6] On a side note, it is also the Dopamine Receptor sub-type possessing the highest binding affinity for Dopamine itself and may explain why non-ergoline Dopamine Agonists are D₃-preffering^[8]

Function

Alpha-synuclein (α-Syn) aggregation via Lewy bodies inclusion, a pathogenic signature exclusively present in PD patients, is decreased by D3 agonists while DA content is elevated by inhibiting DA reuptake and breakdown. The regulation of α-Syn aggregation and clearance enhances brain-derived neurotrophic factor (BDNF) secretion, which ultimately ameliorates neuroinflammation and oxidative stress while promoting neurogenesis and interacting with other DA receptors.^[9][10]

D₃ agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.^[11][12] Apomorphine has the ability to help PD patients with their cognition awareness.^[13] In addition to having antidepressant properties such as regulating the depression-like behaviors and depression development, pramipexole has the capability to prevent and slow down cell apoptosis as well as to restore damaged neural networks and connections while rotigotine help PD patients to attenuates hyperpyrexia syndrome and schizophrenia.^[14][15]

Animal studies

D₃ agonists have been shown to disrupt prepulse inhibition of startle (PPI), a cross-species measure that recapitulates deficits in sensorimotor gating in neuropsychiatric disorders such as schizophrenia.^[16][17][18] In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.^[19]

Ligands

2D-Skeletal Formula of 3 common non-ergoline DA agonists and Dopamine

Agonists

• trans-N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D₄, D₂, 5-HT_1A, and α1-receptors^[20]
• (-)-7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol^[21]
• 5-OH-DPAT
• 7-OH-DPAT
• Pergolide^[22]
• 8-OH-PBZI (cis-8-Hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz[e]indole)
• Apomorphine (non-selective dopamine agonist)
• Bromocriptine (non-selective dopamine agonist)
• Captodiame
• CJ-1639^[23]
• compound R,R-16: 250x binding selectivity over D₂^[24]
• Dopamine (endogenous agonist)
• ES609
• FAUC 54
• FAUC 73
• PD-128,907
• PF-219,061 (extremely selective) ^[25]
• PF-592,379^[26]
• Piribedil^[27] (non-selective dopamine agonist)
• Pramipexole (non-selective dopamine agonist)
• Quinelorane (also D₂ agonist)
• Quinpirole (also D₂ agonist)
• Ropinirole (non-selective dopamine agonist)
• Rotigotine (non-selective dopamine agonist)

Partial agonists

• BP-897^[28]
• Aripiprazole (non-selective partial agonist)
• Brexpiprazole (non-selective partial agonist)
• Buspirone (non-selective)
• Cariprazine
• CJB 090
• CJ-1037 (extremely selective) ^[29]
• FAUC 460 (highly selective) ^[30]
• FAUC 346 (highly selective)^[31]
• Pardoprunox (non-selective)
• Roxindole (possibly a partial agonist at the D₃ autoreceptors, non-selective)
• OS-3-106
• UH-232
• WW-III-55

Antagonists

• Most Antipsychotics
• Amisulpride (non-selective)
• Buspirone
• Cyproheptadine (non-selective)
• PG 01037 ^[32][33]
• Domperidone (peripheral D₂ and D₃ antagonist)
• FAUC 365, silent antagonist, subtype selective^[31]
• GR-103,691
• GSK-598809 (highly selective)
• Haloperidol (non-selective, blocks all dopamine receptor subtypes, though D₃ with the strongest affinity)
• N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides^[34]
• Mesdopetam
• Nafadotride
• NGB-2904^[35]
• PNU-99,194 (moderately selective over D₂)
• Raclopride (also D₂ antagonist)
• S-14,297 (selective)
• S33084
• SB-277011-A, selective D₃ antagonist, 80x selectivity over D₂ with no partial agonist effects, used in drug addiction research as a potential therapy for addiction to several different drugs
• SR 21502 (highly selective)
• Sulpiride (also D₂ antagonist)
• U99194
• YQA14 (high affinity and selectivity)
• Risperidone

Allosteric modulators

• SB269652

Interactions

Dopamine receptor D₃ has been shown to interact with CLIC6^[36] and EPB41L1.^[37]

DRD3 Ser9Gly polymorphism(rs6280), which is a single nucleotide polymorphism (SNP) with variant base C/T is linked to variation in PD such as depression severity, impulse control disorders, behavioral addiction and aberrant decision-making.^{[38][39][40][41]}