Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.[5][6]
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]
Function
editAlpha-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.[8][9]
D3 agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.[10][11] Apomorphine has the ability to help PD patients with their cognition awareness.[12] 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.[13][14]
Animal studies
editD3 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.[15][16][17] In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.[18]
Ligands
editAgonists
edit- trans-N-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]cyclohexyl}-3-methoxybenzamide, full agonist, > 200-fold binding selectivity over D4, D2, 5-HT1A, and α1-receptors[19]
- (-)-7-{[2-(4-Phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol[20]
- 5-OH-DPAT
- 7-OH-DPAT
- Pergolide[21]
- 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[22]
- compound R,R-16: 250x binding selectivity over D2[23]
- Dopamine (endogenous agonist)
- ES609
- FAUC 54
- FAUC 73
- PD-128,907
- PF-219,061 (extremely selective) [24]
- PF-592,379[25]
- Piribedil[26] (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
edit- BP-897[27]
- Brexpiprazole (non-selective)
- Buspirone (non-selective)
- Cariprazine
- CJB 090
- CJ-1037 (extremely selective) [28]
- FAUC 460 (highly selective) [29]
- FAUC 346 (highly selective)[30]
- Pardoprunox (non-selective)
- Roxindole (possibly a partial agonist at the D3 autoreceptors, non-selective)
- OS-3-106
- UH-232
- WW-III-55
Antagonists
edit- Most Antipsychotics
- Amisulpride (non-selective)
- Buspirone
- Cyproheptadine (non-selective)
- PG 01037 [31][32]
- Domperidone (peripheral D2 and D3 antagonist)
- FAUC 365, silent antagonist, subtype selective[30]
- 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[33]
- Mesdopetam
- Nafadotride
- NGB-2904[34]
- 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
editInteractions
editDopamine receptor D3 has been shown to interact with CLIC6[35] and EPB41L1.[36]
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.[37][38][39][40]
See also
editReferences
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022705 – Ensembl, May 2017
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- ^ {{cite journal | vauthors = Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH | display-authors = 6 | title = Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 3 | pages = 839–848 | date = February 2005 | pmid = 15689168 | doi = 10.1021/jm049465g }}
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Further reading
edit- 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+. 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
edit- "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.