Dopamine receptor D2

Available structures
PDBOrtholog search: PDBe RCSB
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]
RNA expression pattern

More reference expression data
Species Human Mouse









RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 11: 113.41 – 113.48 Mb Chr 9: 49.34 – 49.41 Mb
PubMed search [2] [3]
View/Edit HumanView/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.


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.[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]


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]


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.[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]


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.


Partial agonists


D2sh selective (presynaptic autoreceptors)

Allosteric modulators

Functionally selective ligands

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]

The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[35] DRD5,[36] and 5-HT2A.[37]


  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–PKCNFAT pathway and G-protein independent PKBGSK3 pathway.[33][34]


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  3. "Mouse PubMed Reference:".
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  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.
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  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.
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  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.
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  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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  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)
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