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]

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

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

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
• Aripiprazole (non-selective full agonist)
• 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]
• Brexpiprazole (non-selective)
• 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]}

See also

• Dopamine receptor

References

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Further reading

• 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.
• Sidhu A, Niznik HB (November 2000). "Coupling of dopamine receptor subtypes to multiple and diverse G proteins". International Journal of Developmental Neuroscience. 18 (7): 669–677. doi:10.1016/S0736-5748(00)00033-2. PMID 10978845. S2CID 21002590.
• 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. Bibcode:1990Natur.347..146S. doi:10.1038/347146a0. PMID 1975644. S2CID 4284114.
• Giros B, Martres MP, Sokoloff P, Schwartz JC (1991). "[Gene cloning of human dopaminergic D3 receptor and identification of its chromosome]". Comptes Rendus de l'Académie des Sciences, Série III. 311 (13): 501–508. PMID 2129115.
• Liu K, Bergson C, Levenson R, Schmauss C (November 1994). "On the origin of mRNA encoding the truncated dopamine D3-type receptor D3nf and detection of D3nf-like immunoreactivity in human brain". The Journal of Biological Chemistry. 269 (46): 29220–29226. doi:10.1016/S0021-9258(19)62033-8. PMID 7961889.
• Schmauss C, Haroutunian V, Davis KL, Davidson M (October 1993). "Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia". Proceedings of the National Academy of Sciences of the United States of America. 90 (19): 8942–8946. Bibcode:1993PNAS...90.8942S. doi:10.1073/pnas.90.19.8942. PMC 47477. PMID 8415635.
• Griffon N, Crocq MA, Pilon C, Martres MP, Mayerova A, Uyanik G, et al. (February 1996). "Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia". American Journal of Medical Genetics. 67 (1): 63–70. doi:10.1002/(SICI)1096-8628(19960216)67:1<63::AID-AJMG11>3.0.CO;2-N. PMID 8678117.
• Staley JK, Mash DC (October 1996). "Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities". The Journal of Neuroscience. 16 (19): 6100–6106. doi:10.1523/JNEUROSCI.16-19-06100.1996. PMC 6579196. PMID 8815892.
• Chen CH, Liu MY, Wei FC, Koong FJ, Hwu HG, Hsiao KJ (February 1997). "Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia". American Journal of Medical Genetics. 74 (1): 40–43. doi:10.1002/(SICI)1096-8628(19970221)74:1<40::AID-AJMG9>3.0.CO;2-Z. PMID 9034004.
• Gulcher JR, Jónsson P, Kong A, Kristjánsson K, Frigge ML, Kárason A, et al. (September 1997). "Mapping of a familial essential tremor gene, FET1, to chromosome 3q13". Nature Genetics. 17 (1): 84–87. doi:10.1038/ng0997-84. PMID 9288103. S2CID 1506516.
• Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, et al. (November 1998). "SH3 binding domains in the dopamine D4 receptor" (PDF). Biochemistry. 37 (45): 15726–15736. doi:10.1021/bi981634+. hdl:1807/13146. PMID 9843378.
• Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, et al. (July 1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics. 22 (3): 231–238. doi:10.1038/10290. PMID 10391209. S2CID 195213008.
• Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, et al. (July 1999). "Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist". Nature. 400 (6742): 371–375. Bibcode:1999Natur.400..371P. doi:10.1038/22560. PMID 10432116. S2CID 4351316.
• Ilani T, Ben-Shachar D, Strous RD, Mazor M, Sheinkman A, Kotler M, Fuchs S (January 2001). "A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 98 (2): 625–628. doi:10.1073/pnas.021535398. PMC 14638. PMID 11149951.
• Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R (April 2001). "Dopamine D2 and D3 receptors are linked to the actin cytoskeleton via interaction with filamin A". Proceedings of the National Academy of Sciences of the United States of America. 98 (9): 5258–5263. Bibcode:2001PNAS...98.5258L. doi:10.1073/pnas.011538198. PMC 33197. PMID 11320256.
• Oldenhof J, Ray A, Vickery R, Van Tol HH (June 2001). "SH3 ligands in the dopamine D3 receptor". Cellular Signalling. 13 (6): 411–416. doi:10.1016/S0898-6568(01)00157-7. PMID 11384839.
• Soma M, Nakayama K, Rahmutula D, Uwabo J, Sato M, Kunimoto M, et al. (January 2002). "Ser9Gly polymorphism in the dopamine D3 receptor gene is not associated with essential hypertension in the Japanese". Medical Science Monitor. 8 (1): CR1 – CR4. PMID 11796958.

External links

• "Dopamine Receptors: D₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Receptors,+Dopamine+D3 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.