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Dopamine receptor D3

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DRD3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDRD3, D3DR, ETM1, FET1, dopamine receptor D3
External IDsOMIM: 126451; MGI: 94925; HomoloGene: 623; GeneCards: DRD3; OMA:DRD3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1814

13490

Ensembl

ENSG00000151577

ENSMUSG00000022705

UniProt

P35462

P30728

RefSeq (mRNA)

NM_007877

RefSeq (protein)

NP_000787
NP_001269492
NP_001277738
NP_387512

NP_031903

Location (UCSC)Chr 3: 114.13 – 114.2 MbChr 16: 43.57 – 43.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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.[8][9]

D3 agonists like 7-OH-DPAT, pramipexole, and rotigotine, among others, display antidepressant effects in rodent models of depression.[10][11]

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.[12][13][14] In contrast, D3-preferring antagonists have antipsychotic-like profiles in measures of PPI in rats.[15]

Ligands

Agonists

Partial agonists

Antagonists

Interactions

Dopamine receptor D3 has been shown to interact with CLIC6[32] and EPB41L1.[33]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000151577 – Ensembl, May 2017
  2. ^ a b c 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, Schwartz JC, Berger R (September 1991). "Chromosomal localization of the human D3 dopamine receptor gene". Human Genetics. 87 (5): 618–20. doi:10.1007/bf00209024. PMID 1916765. S2CID 28411786.
  6. ^ a b "Entrez Gene: DRD3 dopamine receptor D3".
  7. ^ Joyce JN, Millan MJ (February 2007). "Dopamine D3 receptor agonists for protection and repair in Parkinson's disease". Current Opinion in Pharmacology. 7 (1): 100–5. doi:10.1016/j.coph.2006.11.004. PMID 17174156.
  8. ^ 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. Berlin, Heidelberg: Springer Berlin Heidelberg. doi:10.1007/7854_2022_316.
  9. ^ Yang P, Perlmutter JS, Benzinger TL, Morris JC, Xu J (January 2020). "Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?". Ageing Research Reviews. 57: 100994. doi:10.1016/j.arr.2019.100994. PMC 6939386. PMID 31765822.
  10. ^ Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, Olivier B (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): 134–40. doi:10.1016/j.ejphar.2009.06.029. PMID 19549514.
  11. ^ Bertaina-Anglade V, La Rochelle CD, Scheller DK (October 2006). "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology. 548 (1–3): 106–14. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244.
  12. ^ Weber M, Chang WL, Breier M, Ko D, Swerdlow NR (December 2008). "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behavioural Pharmacology. 19 (8): 786–95. doi:10.1097/FBP.0b013e32831c3b2b. PMC 3255557. PMID 19020413.
  13. ^ Chang WL, Swerdlow NR, Breier MR, Thangaraj N, Weber M (June 2010). "Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats". Pharmacology Biochemistry and Behavior. 95 (4): 473–8. doi:10.1016/j.pbb.2010.04.001. PMC 2889248. PMID 20385162.
  14. ^ Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR (February 2012). "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Research. 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMC 3268831. PMID 22227455.
  15. ^ Weber M, Chang WL, Durbin JP, Park PE, Luedtke RR, Mach RH, Swerdlow NR (August 2009). "Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44". Pharmacology Biochemistry and Behavior. 93 (2): 141–7. doi:10.1016/j.pbb.2009.04.022. PMC 2720754. PMID 19426754.
  16. ^ Leopoldo M, Lacivita E, Colabufo NA, Berardi F, Perrone R (February 2006). "Synthesis and binding profile of constrained analogues of N-[4-(4-arylpiperazin-1-yl)butyl]-3-methoxybenzamides, a class of potent dopamine D3 receptor ligands". The Journal of Pharmacy and Pharmacology. 58 (2): 209–18. doi:10.1211/jpp.58.2.0008. PMID 16451749. S2CID 42910160.
  17. ^ Biswas S, Zhang S, Fernandez F, Ghosh B, Zhen J, Kuzhikandathil E, Reith ME, Dutta AK (January 2008). "Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration of action". Journal of Medicinal Chemistry. 51 (1): 101–17. doi:10.1021/jm070860r. PMID 18072730.
  18. ^ Perachon, Sylvie; Schwartz, Jean-Charles; Sokoloff, Pierre (February 1999). "Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors". European Journal of Pharmacology. 366 (2–3): 293–300. doi:10.1016/S0014-2999(98)00896-6. PMID 10082211.
  19. ^ Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S (August 2011). "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Medicinal Chemistry Letters. 2 (8): 620–625. doi:10.1021/ml200100t. PMC 3224040. PMID 22125662.
  20. ^ Peglion JL, Poitevin C, Mannoury La Cour C, Dupuis D, Millan MJ (April 2009). "Modulations of the amide function of the preferential dopamine D3 agonist (R,R)-S32504: improvements of affinity and selectivity for D3 versus D2 receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2133–8. doi:10.1016/j.bmcl.2009.03.015. PMID 19324548.
  21. ^ Blagg J, Allerton CM, Batchelor DV, Baxter AD, Burring DJ, Carr CL, Cook AS, Nichols CL, Phipps J, Sanderson VG, Verrier H, Wong S (December 2007). "Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route". Bioorganic & Medicinal Chemistry Letters. 17 (24): 6691–6. doi:10.1016/j.bmcl.2007.10.059. PMID 17976986.
  22. ^ Collins GT, Butler P, Wayman C, Ratcliffe S, Gupta P, Oberhofer G, Caine SB (June 2012). "Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats". Behavioural Pharmacology. 23 (3): 280–91. doi:10.1097/FBP.0b013e3283536d21. PMC 3365486. PMID 22470105.
  23. ^ Cagnotto A, Parotti L, Mennini T (October 1996). "In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study". European Journal of Pharmacology. 313 (1–2): 63–7. doi:10.1016/0014-2999(96)00503-1. PMID 8905329.
  24. ^ Spiller K, Xi ZX, Peng XQ, Newman AH, Ashby CR, Heidbreder C, Gaál J, Gardner EL (March 2008). "The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats". Psychopharmacology. 196 (4): 533–42. doi:10.1007/s00213-007-0986-6. PMC 3713235. PMID 17985117.
  25. ^ Chen J, Collins GT, Zhang J, Yang CY, Levant B, Woods J, Wang S (October 2008). "Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile". Journal of Medicinal Chemistry. 51 (19): 5905–8. doi:10.1021/jm800471h. PMC 2662387. PMID 18785726.
  26. ^ Dörfler M, Tschammer N, Hamperl K, Hübner H, Gmeiner P (November 2008). "Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies". Journal of Medicinal Chemistry. 51 (21): 6829–38. doi:10.1021/jm800895v. PMID 18834111.
  27. ^ a b Bettinetti L, Schlotter K, Hübner H, Gmeiner P (October 2002). "Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists". Journal of Medicinal Chemistry. 45 (21): 4594–7. doi:10.1021/jm025558r. PMID 12361386.
  28. ^ Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH (February 2005). "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 of Medicinal Chemistry. 48 (3): 839–48. doi:10.1021/jm049465g. PMID 15689168.
  29. ^ Mason CW, Hassan HE, Kim KP, Cao J, Eddington ND, Newman AH, Voulalas PJ (June 2010). "Characterization of the transport, metabolism, and pharmacokinetics of the dopamine D3 receptor-selective fluorenyl- and 2-pyridylphenyl amides developed for treatment of psychostimulant abuse". The Journal of Pharmacology and Experimental Therapeutics. 333 (3): 854–64. doi:10.1124/jpet.109.165084. PMC 2879935. PMID 20228156.
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  31. ^ 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): 240–59. doi:10.1111/j.1527-3458.2007.00013.x. PMC 3771110. PMID 17627675.
  32. ^ 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.
  33. ^ 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): 507–13. doi:10.1124/mol.62.3.507. PMID 12181426. S2CID 19901660.

Further reading

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

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