Dopamine receptor D2

DRD2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5AER
Identifiers
Aliases	DRD2, D2DR, D2R, dopamine receptor D2
External IDs	OMIM: 126450 MGI: 94924 HomoloGene: 22561 GeneCards: DRD2
Targeted by Drug
benzquinamide, LP-12, LP-211, LP-44, ropinirole, rotigotine, vilazodone, 7-hydroxy-2-(di-N-propylamino)tetralin, bromocriptine, dopamine, pergolide, pramipexole, quinelorane, quinpirole, sumanirole, apomorphine, aripiprazole, brexpiprazole, cabergoline, lisuride, piribedil, roxindole, terguride, amisulpride, blonanserin, (+)-butaclamol, chlorpromazine, clozapine, domperidone, eticlopride, (Z)-flupentixol, fluphenazine, haloperidol, L-741,626, loxapine, mesoridazine, nafadotride, olanzapine, perospirone, perphenazine, pimozide, pipotiazine, prochlorperazine, promazine, quetiapine, raclopride, risperidone, sertindole, sulpiride, levosulpiride, trifluoperazine, ziprasidone, zotepine[1]
Gene ontology Molecular function • protein homodimerization activity • drug binding • protein heterodimerization activity • receptor binding • potassium channel regulator activity • dopamine neurotransmitter receptor activity, coupled via Gi/Go • identical protein binding • dopamine neurotransmitter receptor activity • ionotropic glutamate receptor binding • G-protein coupled receptor activity • protein binding • signal transducer activity • adrenergic receptor activity • dopamine binding Cellular component • cytoplasmic vesicle • nonmotile primary cilium • sperm flagellum • endocytic vesicle • acrosomal vesicle • dendritic spine • synaptic vesicle membrane • perikaryon • plasma membrane • dendrite • ciliary membrane • axon terminus • integral component of membrane • postsynaptic density • membrane • lateral plasma membrane • axon • integral component of plasma membrane • intracellular Biological process • negative regulation of cell proliferation • temperature homeostasis • adenylate cyclase-inhibiting dopamine receptor signaling pathway • adenohypophysis development • circadian regulation of gene expression • response to toxic substance • regulation of dopamine secretion • response to cocaine • response to amphetamine • sensory perception of smell • locomotory behavior • positive regulation of urine volume • response to ethanol • axonogenesis • positive regulation of glial cell-derived neurotrophic factor secretion • response to inactivity • phospholipase C-activating dopamine receptor signaling pathway • modulation of synaptic transmission • grooming behavior • negative regulation of protein kinase B signaling • associative learning • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • regulation of dopamine uptake involved in synaptic transmission • regulation of synaptic transmission, GABAergic • positive regulation of dopamine uptake involved in synaptic transmission • signal transduction • Wnt signaling pathway • adult walking behavior • branching morphogenesis of a nerve • negative regulation of cytosolic calcium ion concentration • negative regulation of innate immune response • regulation of phosphoprotein phosphatase activity • regulation of cAMP metabolic process • acid secretion • feeding behavior • positive regulation of G-protein coupled receptor protein signaling pathway • response to axon injury • striatum development • synaptic transmission, dopaminergic • neurological system process involved in regulation of systemic arterial blood pressure • peristalsis • regulation of long-term neuronal synaptic plasticity • activation of protein kinase activity • positive regulation of growth hormone secretion • regulation of sodium ion transport • forebrain development • response to light stimulus • orbitofrontal cortex development • prepulse inhibition • release of sequestered calcium ion into cytosol • response to morphine • response to iron ion • negative regulation of voltage-gated calcium channel activity • positive regulation of ERK1 and ERK2 cascade • long-term memory • positive regulation of renal sodium excretion • negative regulation of insulin secretion • neuron-neuron synaptic transmission • phosphatidylinositol metabolic process • intracellular signal transduction • negative regulation of adenylate cyclase activity • auditory behavior • behavioral response to ethanol • regulation of heart rate • adenylate cyclase-activating adrenergic receptor signaling pathway • positive regulation of cytokinesis • regulation of potassium ion transport • pigmentation • cellular calcium ion homeostasis • dopamine metabolic process • response to nicotine • regulation of MAPK cascade • response to histamine • negative regulation of synaptic transmission, glutamatergic • response to hypoxia • negative regulation of circadian sleep/wake cycle, sleep • negative regulation of protein secretion • synapse assembly • regulation of locomotion involved in locomotory behavior • dopamine receptor signaling pathway • negative regulation of dopamine receptor signaling pathway • startle response • positive regulation of receptor internalization • protein localization • G-protein coupled receptor signaling pathway • arachidonic acid secretion • positive regulation of transcription from RNA polymerase II promoter • G-protein coupled receptor internalization • positive regulation of multicellular organism growth • positive regulation of long-term synaptic potentiation • negative regulation of dopamine secretion • adult behavior • cerebral cortex GABAergic interneuron migration • regulation of synapse structural plasticity • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • response to drug • visual learning • negative regulation of cell migration • behavioral response to cocaine • positive regulation of neuroblast proliferation • chemical synaptic transmission, postsynaptic • negative regulation of blood pressure Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1813	13489
Ensembl	ENSG00000149295	ENSMUSG00000032259
UniProt	P14416	P61168
RefSeq (mRNA)	NM_016574 NM_000795	NM_010077
RefSeq (protein)	NP_000786.1 NP_057658.2 NP_000786.1	NP_034207.2
Location (UCSC)	Chr 11: 113.41 – 113.48 Mb	Chr 9: 49.34 – 49.41 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

Dopamine receptor D₂, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups (including those of Solomon Snyder and Philip Seeman) used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D₂ receptor.^[4] The dopamine D₂ receptor is the main receptor for all antipsychotic drugs.

Function

This gene encodes the D₂ subtype of the dopamine receptor, which is coupled to G_i subtype of G protein-coupled receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity.^[5]

In mice, regulation of D2R surface expression by the neuronal calcium sensor-1 (NCS-1) in the dentate gyrus is involved in exploration, synaptic plasticity and memory formation.^[6]

In flies, activation of the D₂ autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking Parkinson's disease pathology.^[7]

Isoforms

Alternative splicing of this gene results in three transcript variants encoding different isoforms.^[8]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.^[9] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.^[9] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.^[9] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.^[10]

Genetics

Allelic variants:

• A-241G
• C132T, G423A, T765C, C939T, C957T, and G1101A^[11]
• Cys311Ser
• -141C insertion/deletion^[12] The polymorphisms have been investigated with respect to association with schizophrenia.^[13]

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.^[14] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.^[15][16]

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

• Bromocriptine – full agonist
• Cabergoline (Caberl)
• N,N-Propyldihydrexidine – analogue of the D₁/D₅ agonist dihydrexidine; Selective for postsynaptic D₂ receptor over the presynaptic D₂ autoreceptor.
• Piribedil – also D₃ receptor agonist and α₂–adrenergic antagonist
• Pramipexole – also D₃, D₄ receptor agonist
• Quinelorane – affinity for D₂ > D₃
• Quinpirole – also D₃ receptor agonist
• Ropinirole – full agonist
• Sumanirole – full agonist; highly selective
• Talipexole – selective for D₂ over other dopamine receptors, but also acts as α₂–adrenoceptor agonist and 5-HT₃ antagonist.

Partial agonists

• Aplindore
• Aripiprazole^[17]
• Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D₂ partial agonist.^[18]
• Brexpiprazole
• Cariprazine
• GSK-789,472 – Also D₃ antagonist, with good selectivity over other receptors ^[19]
• Ketamine (also NMDA antagonist)
• 2-Phenethylamine – (also a TAAR1 agonist and GABAb antagonist with effects at AMPA receptors)
• LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.^[20] LSD is also a 5-HT_2A agonist.
• OSU-6162 – also 5-HT_2A partial agonist, acts as "dopamine stabilizer"
• Roxindole (only at the D₂ autoreceptors)
• RP5063
• Salvinorin A – also κ-opioid agonist.

Antagonists

• Atypical antipsychotics (except aripiprazole, brexpiprazole, and any other D₂ receptor partial agonists)
• Desmethoxyfallypride
• Domperidone – D₂ and D₃ antagonist; does not cross the blood-brain barrier
• Eticlopride
• Fallypride
• Hydroxyzine (Vistaril, Atarax)
• Itopride
• L-741,626 – highly selective D₂ antagonist
• C¹¹ Raclopride radiolabled – commonly employed in positron emission tomography studies^[21]
• Typical antipsychotics
• SV 293^[22]
• Yohimbine

D₂sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• UH-232

Allosteric modulators

• Homocysteine – negative allosteric modulator^[23]
• PAOPA^[24]
• SB-269,652 ^[25][26][27]

Functionally selective ligands

• See reference^[28]

Protein–protein interactions

The dopamine receptor D₂ has been shown to interact with EPB41L1,^[29] PPP1R9B^[30] and NCS-1.^[31]

Receptor oligomers

The D₂ receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:^[32]

• D₁–D₂ dopamine receptor heteromer
• D₂–adenosine A_2A
• D₂–ghrelin receptor
• D_2sh–TAAR1^{[note 1]}

The D₂ receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD₃,^[35] DRD₅,^[36] and 5-HT_2A.^[37]

Notes

1. D2sh–TAAR1 is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.^[33][34]

References

1. "Drugs that physically interact with D(2) dopamine receptor view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Madras BK (2013). "History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia". Journal of the History of the Neurosciences. 22 (1): 62–78. doi:10.1080/0964704X.2012.678199. PMID 23323533.
5. Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (Nov 2000). "Distinct functions of the two isoforms of dopamine D2 receptors". Nature. 408 (6809): 199–203. doi:10.1038/35041572. PMID 11089973.
6. Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC (Sep 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.
7. Wiemerslage L, Schultz BJ, Ganguly A, Lee D (Aug 2013). "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry. 126 (4): 529–40. doi:10.1111/jnc.12228. PMID 23452092.
8. "Entrez Gene: DRD2 dopamine receptor D2".
9. Beaulieu JM, Gainetdinov RR (Mar 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews. 63 (1): 182–217. doi:10.1124/pr.110.002642. PMID 21303898.
10. Universal protein resource accession number P14416 for "D(2) dopamine receptor" at UniProt.
11. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (Feb 2003). "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics. 12 (3): 205–16. doi:10.1093/hmg/ddg055. PMID 12554675.
12. Arinami T, Gao M, Hamaguchi H, Toru M (Apr 1997). "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics. 6 (4): 577–82. doi:10.1093/hmg/6.4.577. PMID 9097961.
13. Glatt SJ, Faraone SV, Tsuang MT (Jul 2004). "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". American Journal of Medical Genetics Part B. 128B (1): 21–3. doi:10.1002/ajmg.b.30007. PMID 15211624.
14. Lucht M, Rosskopf D (Jul 2008). "Comment on "Genetically determined differences in learning from errors"". Science. 321 (5886): 200; author reply 200. doi:10.1126/science.1155372. PMID 18621654.
15. Wang J, Liu ZL, Chen B (Jun 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.
16. Wang J, Zhao C, Chen B, Liu ZL (Jan 2004). "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters. 355 (3): 193–6. doi:10.1016/j.neulet.2003.11.006. PMID 14732464.
17. "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. Retrieved 2010-01-21.
18. Seeman, P; Guan, HC; Hirbec, H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil.". Synapse (New York, N.Y.). 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150.
19. 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 (Mar 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.
20. 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 Sciences. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051.
21. Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004). "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". Journal of Addictive Diseases. 23 (3): 39–53. doi:10.1300/J069v23n03_04. PMID 15256343.
22. 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.
23. 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.
24. Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK (Mar 2013). "PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine–sensitized preclinical animal model of schizophrenia". European Neuropsychopharmacology. 23 (3): 253–62. doi:10.1016/j.euroneuro.2012.04.010. PMID 22658400.
25. 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 (Sep 2014). "A new mechanism of allostery in a G protein–coupled receptor dimer". Nature Chemical Biology. 10 (9): 745–52. doi:10.1038/nchembio.1593. PMID 25108820.
26. Maggio R, Scarselli M, Capannolo M, Millan MJ (Sep 2015). "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". European Neuropsychopharmacology. 25 (9): 1470–9. doi:10.1016/j.euroneuro.2014.09.016. PMID 25453482.
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28. Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P (Jun 2014). "Functionally selective dopamine D₂, D₃ receptor partial agonists". Journal of Medicinal Chemistry. 57 (11): 4861–75. doi:10.1021/jm5004039. PMID 24831693.
29. Binda AV, Kabbani N, Lin R, Levenson R (Sep 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.
30. Smith FD, Oxford GS, Milgram SL (Jul 1999). "Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein". The Journal of Biological Chemistry. 274 (28): 19894–900. doi:10.1074/jbc.274.28.19894. PMID 10391935.
31. Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R (Oct 2002). "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor". The Journal of Neuroscience. 22 (19): 8476–86. PMID 12351722.
32. Beaulieu JM, Espinoza S, Gainetdinov RR (Jan 2015). "Dopamine receptors - IUPHAR Review 13". British Journal of Pharmacology. 172 (1): 1–23. doi:10.1111/bph.12906. PMC 4280963. PMID 25671228.
33. Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139. This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions ... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
34. Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, Dernick G, Wettstein JG, Iglesias A, Rolink A, Bettler B, Hoener MC (2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". Eur Neuropsychopharmacol. 25 (11): 2049–61. doi:10.1016/j.euroneuro.2015.08.011. PMID 26372541. Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
35. Maggio R, Millan MJ (Feb 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.
36. Hasbi A, O'Dowd BF, George SR (Feb 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.
37. Albizu L, Holloway T, González-Maeso J, Sealfon SC (Sep 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

• Receptors, Dopamine D2 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Pappas, Stephanie. "Study: Genes Influence Who Your Friends Are". Imaginova Corp. LiveScience. Retrieved 20 January 2011.

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