Dopamine receptor D2

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Dopamine receptor D2
Protein DRD2 PDB 1I15.png
Rendering based on PDB 1I15.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols DRD2 ; D2DR; D2R
External IDs OMIM126450 MGI94924 HomoloGene22561 IUPHAR: 215 ChEMBL: 217 GeneCards: DRD2 Gene
RNA expression pattern
PBB GE DRD2 216924 s at tn.png
PBB GE DRD2 206590 x at tn.png
PBB GE DRD2 211624 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1813 13489
Ensembl ENSG00000149295 ENSMUSG00000032259
UniProt P14416 P61168
RefSeq (mRNA) NM_000795 NM_010077
RefSeq (protein) NP_000786 NP_034207
Location (UCSC) Chr 11:
113.41 – 113.48 Mb
Chr 9:
49.34 – 49.41 Mb
PubMed search [1] [2]

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.

Function[edit]

This gene encodes the D2 subtype of the dopamine receptor, which is coupled to Gi subtype of G protein-coupled receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity.[1]

In mice, regulation of D2R surface expression by the calcium sensor NCS-1 in the dentate gyrus is involved in exploration, synaptic plasticity and memory formation.[2]

In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking Parkinson's disease pathology.[3]

Isoforms[edit]

Alternative splicing of this gene results in three transcript variants encoding different isoforms.[4]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[5] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor and regulates the levels of dopamine in the synaptic cleft.[5] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[5] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[6]

Genetics[edit]

Allelic variants:

Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the DRD2 gene. However, the polymorphism resides in exon 8 of the ANKK1 gene.[10] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations in Parkinson's disease.[11]

Ligands[edit]

Most of the older antipsychotic drugs such as chlorpromazine and haloperidol are antagonists for the dopamine D2 receptor, but are, in general, very unselective, at best selective only for the "D2-like family" receptors and so binding to D2, D3 and D4, and often also to many other receptors such as those for serotonin and histamine, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for Parkinson's disease such as bromocriptine and cabergoline are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D2 agonists, they affect other subtypes as well. Several selective D2 ligands are, however, now available, and this number is likely to increase as further research progresses.

Agonists[edit]

Partial agonists[edit]

Antagonists[edit]

D2Sh selective (presynaptic autoreceptors)

Allosteric modulators[edit]

Functionally selective ligands[edit]

Protein-protein interactions[edit]

The dopamine receptor D2 has been shown to interact with EPB41L1,[23] PPP1R9B[24] and NCS-1.[25]

Receptor oligomers[edit]

The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[26]

The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[27] DRD5,[28] and 5-HT2A.[29]

See also[edit]

References[edit]

  1. ^ Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000). "Distinct functions of the two isoforms of dopamine D2 receptors.". Nature 9 (408): 199–203. PMID 11089973. 
  2. ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC (2009). "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory.". Neuron 63 (5): 643–56. doi:10.1016/j.neuron.2009.08.014. PMID 19755107. 
  3. ^ Wiemerslage L, Schultz BJ, Ganguly A, Lee D (2013). "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture.". J Neurochem 126 (4): 529–40. doi:10.1111/jnc.12228. PMID 23452092. 
  4. ^ "Entrez Gene: DRD2 dopamine receptor D2". 
  5. ^ a b c Beaulieu JM, Gainetdinov RR (March 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacol. Rev. 63 (1): 182–217. doi:10.1124/pr.110.002642. PMID 21303898. 
  6. ^ UniProt P14416
  7. ^ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (February 2003). "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Hum. Mol. Genet. 12 (3): 205–16. doi:10.1093/hmg/ddg055. PMID 12554675. 
  8. ^ Arinami T, Gao M, Hamaguchi H, Toru M (April 1997). "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Hum. Mol. Genet. 6 (4): 577–82. doi:10.1093/hmg/6.4.577. PMID 9097961. 
  9. ^ Glatt SJ, Faraone SV, Tsuang MT (July 2004). "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". Am. J. Med. Genet. B Neuropsychiatr. Genet. 128B (1): 21–3. doi:10.1002/ajmg.b.30007. PMID 15211624. 
  10. ^ Lucht M, Rosskopf D (July 2008). "Comment on "Genetically determined differences in learning from errors"". Science 321 (5886): 200; author reply 200. doi:10.1126/science.1155372. PMID 18621654. 
  11. ^ Wang J, Liu ZL, Chen B. (June 2001). "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD". Neurology. 56 (12): 1757–9. doi:10.1212/WNL.56.12.1757. PMID 11425949. 
  12. ^ "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. Retrieved 2010-01-21. 
  13. ^ Holmes IP, Blunt RJ, Lorthioir OE, Blowers SM, Gribble A, Payne AH, Stansfield IG, Wood M, Woollard PM, Reavill C, Howes CM, Micheli F, Di Fabio R, Donati D, Terreni S, Hamprecht D, Arista L, Worby A, Watson SP (March 2010). "The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure". Bioorganic & Medicinal Chemistry Letters 20 (6): 2013–6. doi:10.1016/j.bmcl.2010.01.090. PMID 20153647. 
  14. ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B (1998). "Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro". Life Sci. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051. 
  15. ^ Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004). "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". J Addict Dis 23 (3): 39–53. doi:10.1300/J069v23n03_04. PMID 15256343. 
  16. ^ Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR (2013). "The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition.". Pharmacology 92 (1-2): 84–9. doi:10.1159/000351971. PMID 23942137. 
  17. ^ Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K (Nov 2006). "Allosteric modulation of dopamine D2 receptors by homocysteine.". Journal of proteome research 5 (11): 3077–83. doi:10.1021/pr0601382. PMID 17081059. 
  18. ^ Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK (2012). "PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia". Eur Neuropsychopharmacol 23 (3): 253–62. doi:10.1016/j.euroneuro.2012.04.010. PMID 22658400. 
  19. ^ Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, Shi L, López L, Scammells PJ, Capuano B, Sexton PM, Javitch JA, Christopoulos A (2014). "A new mechanism of allostery in a G protein-coupled receptor dimer". Nat. Chem. Biol. 10 (9): 745–52. doi:10.1038/nchembio.1593. PMID 25108820. 
  20. ^ Maggio R, Scarselli M, Capannolo M, Millan MJ (2014). "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". Eur Neuropsychopharmacol. doi:10.1016/j.euroneuro.2014.09.016. PMID 25453482. 
  21. ^ Silvano E, Millan MJ, Mannoury la Cour C, Han Y, Duan L, Griffin SA, Luedtke RR, Aloisi G, Rossi M, Zazzeroni F, Javitch JA, Maggio R (2010). "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Mol. Pharmacol. 78 (5): 925–34. doi:10.1124/mol.110.065755. PMC 2981362. PMID 20702763. 
  22. ^ Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P (2014). "Functionally selective dopamine D₂, D₃ receptor partial agonists". J. Med. Chem. 57 (11): 4861–75. doi:10.1021/jm5004039. PMID 24831693. 
  23. ^ 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". Mol. Pharmacol. 62 (3): 507–13. doi:10.1124/mol.62.3.507. PMID 12181426. 
  24. ^ Smith FD, Oxford GS, Milgram SL (July 1999). "Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein". J. Biol. Chem. 274 (28): 19894–900. doi:10.1074/jbc.274.28.19894. PMID 10391935. 
  25. ^ Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R (2002). "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor.". J. Neurosci. 22 (19): 8476–86. PMID 12351722. 
  26. ^ Beaulieu JM, Espinoza S, Gainetdinov RR (2015). "Dopamine receptors - IUPHAR Review 13". Br. J. Pharmacol. 172 (1): 1–23. doi:10.1111/bph.12906. PMID 25671228. 
  27. ^ Maggio R, Millan MJ (2010). "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology 10 (1): 100–7. doi:10.1016/j.coph.2009.10.001. PMID 19896900. 
  28. ^ Hasbi A, O'Dowd BF, George SR (2010). "Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms". Current Opinion in Pharmacology 10 (1): 93–9. doi:10.1016/j.coph.2009.09.011. PMC 2818238. PMID 19897420. 
  29. ^ Albizu L, Holloway T, González-Maeso J, Sealfon SC (2011). "Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors". Neuropharmacology 61 (4): 770–7. doi:10.1016/j.neuropharm.2011.05.023. PMC 3556730. PMID 21645528. 

External links[edit]

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