Dopamine receptor D3 explained

Dopamine receptor D₃ is a protein that in humans is encoded by the DRD3 gene.^{[1] [2]}

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. It is a target for drugs which treat schizophrenia, drug addiction, and Parkinson's disease.^[3] 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).

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.^{[4] [5]}

D₃ agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.^{[6] [7]} Apomorphine has the ability to help PD patients with their cognition awareness.^[8] 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.^{[9] [10]}

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.^{[11] [12] [13]} In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.^[14]

Ligands

Agonists

• trans-N--3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D₄, D₂, 5-HT_1A, and α1-receptors^[15]
• (-)-7--5,6,7,8-tetrahydronaphthalen-2-ol^[16]
• 5-OH-DPAT
• 7-OH-DPAT
• Pergolide^[17]
• 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^[18]
• compound R,R-16: 250x binding selectivity over D₂^[19]
• Dopamine (endogenous agonist)
• ES609
• FAUC 54
• FAUC 73
• PD-128,907
• PF-219,061 (extremely selective) ^[20]
• PF-592,379^[21]
• Piribedil^[22] (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^[23]
• Brexpiprazole (non-selective)
• Buspirone (non-selective)
• Cariprazine
• CJB 090
• CJ-1037 (extremely selective) ^[24]
• FAUC 460 (highly selective) ^[25]
• FAUC 346 (highly selective)^[26]
• 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 ^{[27] [28]}
• Domperidone (peripheral D₂ and D₃ antagonist)
• FAUC 365, silent antagonist, subtype selective^[26]
• 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^[29]
• Mesdopetam
• Nafadotride
• NGB-2904^[30]
• 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^[31] and EPB41L1.^[32]

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.^{[33] [34] [35] [36]}

See also

• Dopamine receptor

Further reading

• Missale C, Nash SR, Robinson SW, Jaber M, Caron MG . Dopamine receptors: from structure to function . Physiological Reviews . 78 . 1 . 189–225 . January 1998 . 9457173 . 10.1152/physrev.1998.78.1.189 .
• Sidhu A, Niznik HB . Coupling of dopamine receptor subtypes to multiple and diverse G proteins . International Journal of Developmental Neuroscience . 18 . 7 . 669–677 . November 2000 . 10978845 . 10.1016/S0736-5748(00)00033-2 . 21002590 .
• Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC . Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics . Nature . 347 . 6289 . 146–151 . September 1990 . 1975644 . 10.1038/347146a0 . 1990Natur.347..146S . 4284114 .
• Giros B, Martres MP, Sokoloff P, Schwartz JC . [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 . 1991 . 2129115 .
• Liu K, Bergson C, Levenson R, Schmauss C . 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 . November 1994 . 7961889 . 10.1016/S0021-9258(19)62033-8 . free .
• Schmauss C, Haroutunian V, Davis KL, Davidson M . 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 . October 1993 . 8415635 . 47477 . 10.1073/pnas.90.19.8942 . free . 1993PNAS...90.8942S .
• Griffon N, Crocq MA, Pilon C, Martres MP, Mayerova A, Uyanik G, Burgert E, Duval F, Macher JP, Javoy-Agid F, Tamminga CA, Schwartz JC, Sokoloff P . 6 . Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia . American Journal of Medical Genetics . 67 . 1 . 63–70 . February 1996 . 8678117 . 10.1002/(SICI)1096-8628(19960216)67:1<63::AID-AJMG11>3.0.CO;2-N .
• Staley JK, Mash DC . Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities . The Journal of Neuroscience . 16 . 19 . 6100–6106 . October 1996 . 8815892 . 6579196 . 10.1523/JNEUROSCI.16-19-06100.1996 . free .
• Chen CH, Liu MY, Wei FC, Koong FJ, Hwu HG, Hsiao KJ . Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia . American Journal of Medical Genetics . 74 . 1 . 40–43 . February 1997 . 9034004 . 10.1002/(SICI)1096-8628(19970221)74:1<40::AID-AJMG9>3.0.CO;2-Z .
• Gulcher JR, Jónsson P, Kong A, Kristjánsson K, Frigge ML, Kárason A, Einarsdóttir IE, Stefánsson H, Einarsdóttir AS, Sigurthoardóttir S, Baldursson S, Björnsdóttir S, Hrafnkelsdóttir SM, Jakobsson F, Benedickz J, Stefánsson K . 6 . Mapping of a familial essential tremor gene, FET1, to chromosome 3q13 . Nature Genetics . 17 . 1 . 84–87 . September 1997 . 9288103 . 10.1038/ng0997-84 . 1506516 .
• Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH . 6 . SH3 binding domains in the dopamine D4 receptor . Biochemistry . 37 . 45 . 15726–15736 . November 1998 . 9843378 . 10.1021/bi981634+ .
• Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES . 6 . Characterization of single-nucleotide polymorphisms in coding regions of human genes . Nature Genetics . 22 . 3 . 231–238 . July 1999 . 10391209 . 10.1038/10290 . 195213008 .
• Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P . 6 . Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist . Nature . 400 . 6742 . 371–375 . July 1999 . 10432116 . 10.1038/22560 . 1999Natur.400..371P . 4351316 .
• Ilani T, Ben-Shachar D, Strous RD, Mazor M, Sheinkman A, Kotler M, Fuchs S . 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 . January 2001 . 11149951 . 14638 . 10.1073/pnas.021535398 . free .
• Lin R, Karpa K, Kabbani N, Goldman-Rakic P, Levenson R . 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 . April 2001 . 11320256 . 33197 . 10.1073/pnas.011538198 . free . 2001PNAS...98.5258L .
• Oldenhof J, Ray A, Vickery R, Van Tol HH . SH3 ligands in the dopamine D3 receptor . Cellular Signalling . 13 . 6 . 411–416 . June 2001 . 11384839 . 10.1016/S0898-6568(01)00157-7 .
• Soma M, Nakayama K, Rahmutula D, Uwabo J, Sato M, Kunimoto M, Aoi N, Kosuge K, Kanmatsuse K . 6 . Ser9Gly polymorphism in the dopamine D3 receptor gene is not associated with essential hypertension in the Japanese . Medical Science Monitor . 8 . 1 . CR1–CR4 . January 2002 . 11796958 .

External links

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

Notes and References

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2. Web site: Entrez Gene: DRD3 dopamine receptor D3.
3. Joyce JN, Millan MJ . Dopamine D3 receptor agonists for protection and repair in Parkinson's disease . Current Opinion in Pharmacology . 7 . 1 . 100–105 . February 2007 . 17174156 . 10.1016/j.coph.2006.11.004 .
4. Book: Favier M, Carcenac C, Savasta M, Carnicella S . Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson’s Disease . 2022 . 10.1007/7854_2022_316 . Current Topics in Behavioral Neurosciences . 60 . 109–132 . Berlin, Heidelberg . Springer Berlin Heidelberg . 35469394 . 978-3-031-23057-8 .
5. Yang P, Perlmutter JS, Benzinger TL, Morris JC, Xu J . Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment? . Ageing Research Reviews . 57 . 100994 . January 2020 . 31765822 . 6939386 . 10.1016/j.arr.2019.100994 .
6. Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, Olivier B . 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 . August 2009 . 19549514 . 10.1016/j.ejphar.2009.06.029 .
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33. Krishnamoorthy S, Rajan R, Banerjee M, Kumar H, Sarma G, Krishnan S, Sarma S, Kishore A . 6 . Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients . Parkinsonism & Related Disorders . 30 . 13–17 . September 2016 . 27325396 . 10.1016/j.parkreldis.2016.06.005 .
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