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Dopamine receptor D2

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Dopamine receptor D2

Dopamine receptor D2

Rendering based on PDB .
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; D2DR; D2R
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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

Function

This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity.

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

Isoforms

Alternative splicing of this gene results in three transcript variants encoding different isoforms.[2]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[3] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor and regulates the levels of dopamine in the synaptic cleft.[3] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[3] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[4]

Genetics

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.[8]

Ligands

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

Partial agonists

Antagonists

D2Sh selective (presynaptic autoreceptors)

Allosteric modulators

Functionally selective ligands

Protein-protein interactions

The dopamine receptor D2 has been shown to interact with EPB41L1,[18] PPP1R9B[19] and NCS-1.[20]

Receptor oligomers

The D2 receptor forms heteromers with the following receptors: dopamine D1 (→ D1-D2),[21] D3,[22] 5-HT2A,[23] adenosine A2A,[24] CB1, mGlu5.

See also

References

  1. ^ 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.  
  2. ^ "Entrez Gene: DRD2 dopamine receptor D2". 
  3. ^ a b c Beaulieu JM, Gainetdinov RR (March 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacol. Rev. 63 (1): 182–217.  
  4. ^ UniProt
  5. ^ 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.  
  6. ^ 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.  
  7. ^ Glatt SJ,  
  8. ^ Lucht M, Rosskopf D (July 2008). "Comment on "Genetically determined differences in learning from errors"". Science 321 (5886): 200; author reply 200.  
  9. ^ "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. Retrieved 2010-01-21. 
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ Silvano E, Millan MJ, Mannoury la Cour C, et al. (2010). "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Mol. Pharmacol. 78 (5): 925–34.  
  17. ^ 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.  
  18. ^ 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.  
  19. ^ 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.  
  20. ^ Kabbani N, Negyessy L, Lin R, Goldman-Rakic, Levenson R. (2002). "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor.". J. Neurosci. 22 (19): 8476–86.  
  21. ^ Hasbi A, O'Dowd BF, George SR (2011): "Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance", Mol Brain, 26. PMID 21663703
  22. ^ Maggio R, Millan MJ (2010). "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology 10 (1): 100–7.  
  23. ^ 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.  
  24. ^ Kamiya T, Saitoh O, Yoshioka K, Nakata H (June 2003). "Oligomerization of adenosine A2A and dopamine D2 receptors in living cells". Biochem. Biophys. Res. Commun. 306 (2): 544–9.  

Further reading

External links

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